Diet for the prevention of demyelination. Neurochemistry - Ashmarin I.P. Autoimmune diseases of the nervous system

Component
	In myelin	In white matter	In gray matter
Squirrels
Total phospholipids
Fofatidylserine
Phosphatidylinositol
Cholesterol
Sphingomyelin
Cerebozides
Plasmogens
gangliosides

The structure of the nerve fiber. Myelin sheath

From the axons of neurons are formed nerve fibers... Each fiber consists of an axial cylinder (axon), inside which is an axoplasm with neurofibrils, mitochondria and synaptic vesicles.

Depending on the structure of the membranes that envelop the axons, nerve fibers are divided into: myelin-free (non-fleshy) and myelinated (pulp).

1. Myelin-free fiber

Myelin-free fiber consists of 7-12 thin axons that run inside a cord formed by a chain of neuroglial cells.

Myelin-free fibers have postganglionic nerve fibers that are part of the autonomic nervous system.

2. Myelin fiber

Myelin fiber consists of one axon, which is enveloped myelin sheath and is surrounded by glial cells.

Myelin sheath formed by the plasma membrane of the Schwann or oligodendroglial cell, which is folded in half and repeatedly wrapped around the axon. Along the length of the axon, the myelin sheath forms short sheaths - internodes, between which there are unmyelized areas - interceptions of Ranvier.

Myelin fiber is more perfect than myelin-free fiber, because it has a higher speed of transmission of nerve impulses.

Myelin fibers have the conduction system of the somatic nervous system, preganglionic fibers of the autonomic nervous system.

Molecular organization of the myelin sheath (according to H. Hiden)

1-axon; 2-myelin; 3-axis fiber; 4-protein (outer layers); 5-lipids; 6-protein (inner layer); 7-cholesterol; 8-cerebroside; 9- sphingomyelin; 10-phosphatidylserine.

The chemical composition of myelin

Myelin contains many lipids, little cytoplasm and proteins. The membrane of the myelin sheath, calculated on dry weight, contains 70% lipids (which in total is about 65% of all brain lipids) and 30% proteins. 90% of all myelin lipids are cholesterol, phospholipids and cerebrosides. Myelin contains some gangliosides.

The protein composition of myelin in the peripheral and central nervous systems is different. CNS myelin contains three proteins:

Proteolipid, makes 35 - 50% of the total protein content in myelin, has a molecular weight of 25 kDa, soluble in organic solvents;

Basic protein A 1 , makes up 30% of the total protein content in myelin, has a molecular weight of 18 kDa, is soluble in weak acids;

Wolfgram proteins - several acidic proteins of a large mass, soluble in organic solvents, the function of which is unknown. Make up 20% of the total protein content in myelin.

In the myelin of the PNS, the proteolipid is absent, the main protein is presented proteins A 1 (Little), R 0 and R 2 .

Enzymatic activity was found in myelin:

cholesterol esterase;

phosphodiesterase, hydrolyzing cAMP;

protein kinase A, which phosphorylates basic protein;

sphingomyelinase;

carbonic anhydrase.

Myelin, due to its structure, has a higher stability (resistance to degradation) than other plasma membranes.

EXCHANGE OF SUBSTANCES AND ENERGY IN THE NERVOUS TISSUE

Energy metabolism of nervous tissue

The brain is characterized by a high intensity of energy metabolism with a predominance of aerobic processes. With a mass of 1400g (2% of body weight), it receives about 20% of the blood expelled by the heart and about 30% of all oxygen in the arterial blood.

The maximum energy metabolism in the brain is observed by the period of the end of myelination and the completion of differentiation processes in children aged 4 years. At the same time, the rapidly growing nervous tissue consumes about 50% of all oxygen entering the body.

The maximum respiration rate was found in the cerebral cortex, the minimum - in the spinal cord and peripheral nerves. Neurons are characterized by aerobic metabolism, while the metabolism of neuroglia is also adapted to anaerobic conditions. The respiration rate of gray matter is 4 times higher than that of white matter.

Unlike other organs, the brain has practically no oxygen reserves. The brain's reserve oxygen is consumed within 10-12 seconds, which explains the high sensitivity of the nervous system to hypoxia.

The main energy substrate of the nervous tissue is glucose, oxidation of which is provided by its energy by 85-90%. The nervous tissue consumes up to 70% of the free glucose released from the liver into the arterial blood. Under physiological conditions, 85-90% of glucose is metabolized aerobic, and 10-15% - anaerobic.

As additional energy substrates, neurons and glial cells can use amino acids , primarily glutamate and aspartate.

In extreme conditions, the nervous tissue switches to ketone bodies(up to 50% of all energy).

In the early postnatal period, the brain is also oxidized free fatty acids and ketone bodies .

The received energy is spent in the first place:

for membrane capacity building , which is used to conduct nerve impulses and active transport;

for the work of the cytoskeleton providing axonal transport, release of neurotransmitters, spatial orientation of the structural units of the neuron;

for the synthesis of new substances , primarily neurotransmitters, neuropeptides, as well as nucleic acids, proteins, lipids;

for neutralization of ammonia .

Metabolism of carbohydrates in the nervous tissue

The nervous tissue is characterized by high carbohydrate metabolism, in which glucose catabolism predominates. Since the nervous tissue insulin independent , with high activity hexokinase (has a low Michaelis Menton constant) and a low glucose concentration, glucose is constantly supplied from the blood to the nervous tissue, even if there is little glucose in the blood and no insulin.

The PPS activity of the nervous tissue is low. NADPH 2 is used in the synthesis of neurotransmitters, amino acids, lipids, glycolipids, nucleic acid components and for the antioxidant system.

High PFS activity is observed in children during the period of myelination and with brain injuries.

Exchange of proteins and amino acids of the nervous tissue

The nervous tissue is characterized by a high exchange of amino acids and proteins.

The rate of synthesis and breakdown of proteins in different parts of the brain is not the same. The proteins of the gray matter of the large hemispheres and the proteins of the cerebellum are distinguished by a high rate of renewal, which is associated with the synthesis of mediators, biologically active substances, and specific proteins. White matter, rich in conductive structures, renews itself especially slowly.

Amino acids in nerve tissue are used as:

source of "raw materials" for the synthesis of proteins, peptides, some lipids, a number of hormones, vitamins, biogenic amines, etc. Synthesis of biologically active substances prevails in the gray matter, in the white matter - the proteins of the myelin sheath.

neurotransmitters and neuromodulators. Amino acids and their derivatives are involved in synaptic transmission (glu), in the implementation of interneuronal connections .

Energy source ... Nervous tissue oxidizes amino acids of the glutamine group and branched chain amino acids (leucine, isoleucine, valine) in the TCA.

To remove nitrogen . When the nervous system is excited, the formation of ammonia increases (primarily due to the deamination of AMP), which binds with glutamic acid to form glutamine. The reaction with the expense of ATP is catalyzed by glutamine synthetase.

Glutamine group amino acids have the most active metabolism in the nervous tissue.

N -acetylaspartic acid (AcA) is part of the intracellular pool of anions and a reservoir of acetyl groups. The acetyl groups of exogenous ACA serve as a carbon source for the synthesis of fatty acids in the developing brain.

Aromatic amino acids are of particular importance as precursors of catecholamines and serotonin.

Methionine is a source of methyl groups and 80% is used for protein synthesis.

Cystathionine important for the synthesis of sulfitides and sulfated mucopolysaccharides.

Nitrogen exchange in nervous tissue

The direct source of ammonia in the brain is the indirect deamination of amino acids with the participation of glutamate dehydrogenase, as well as deamination with the participation of the AMP – IMP cycle.

Neutralization of toxic ammonia in the nervous tissue occurs with the participation of α-ketoglutarate and glutamate.

Lipid metabolism of nervous tissue

A feature of lipid metabolism in the brain is that they are not used as an energy material, but are mainly used for construction needs. Lipid metabolism is generally low and differs in white and gray matter.

In gray matter neurons, phosphotidylcholines and especially phosphotidylinositol, which is a precursor of the intracellular messenger ITP, are most intensively renewed from phosphoglycerides.

The exchange of lipids in the myelin sheaths proceeds slowly, cholesterol, cerebrosides and sphingomyelins are very slowly renewed. In newborns, cholesterol is synthesized in the nervous tissue itself; in adults, this synthesis decreases sharply, up to a complete cessation.

All lipids found in the rat brain are also present in myelin, i.e., there are no lipids localized exclusively in nonmyelinated structures (with the exception of the specific mitochondrial lipid diphosphatidylglycerol). The converse is also true - there are no myelin lipids that would not be found in other subcellular fractions of the brain.

Cerebroside is the most common component of myelin. With the exception of the earliest period of development of the organism, the concentration of cerebroside in the brain is directly proportional to the amount of myelin in it. Only 1/5 of the total content of galactolipids in myelin occurs in the sulfated form. Cerebrosides and sulfatides play an important role in maintaining myelin stability.

Myelin is also characterized by high levels of its main lipids - cholesterol, total galactolipids and ethanolamine-containing plasmalogen. It has been found that up to 70% of brain cholesterol is in myelin. Since almost half of the white matter of the brain may be myelin, it is clear that the brain contains the highest amount of cholesterol compared to other organs. A high concentration of cholesterol in the brain, especially in myelin, is determined by the main function of neuronal tissue - to generate and conduct nerve impulses. The high content of cholesterol in myelin and the peculiarity of its structure lead to a decrease in ionic leakage through the neuron membrane (due to its high resistance).

Phosphatidylcholine is also an essential constituent of myelin, although sphingomyelin is relatively small.

The lipid composition of both the gray matter and the white matter of the brain is distinctly different from that of myelin. The composition of myelin in the brain of all studied mammalian species is almost the same; there are only minor differences (eg rat myelin has less sphingomyelin than bovine or human myelin). There are some variations and depending on the location of the myelin, for example, myelin isolated from the spinal cord has a higher lipid-to-protein ratio than myelin from the brain.

The composition of myelin also includes polyphosphatidylinositides, of which triphosphoinositide makes up from 4 to 6% of the total phosphorus of myelin, and diphosphoinositide - from 1 to 1.5%. Minor components of myelin include at least three cerebroside esters and two glycerol-based lipids; some long-chain alkanes are also present in myelin. Mammalian myelin contains from 0.1 to 0.3% gangliosides. Myelin contains more monosialoganglioside bM1 compared to what is found in the brain membranes. The myelin of many organisms, including humans, contains a unique ganglioside sialosylgalactosylceramide OM4.

Myelin lipids PNS

Myelin lipids of the peripheral and central nervous systems are qualitatively similar, but there are quantitative differences between them. PNS myelin contains less cerebrosides and sulfatides and significantly more sphingomyelin than CNS myelin. It is interesting to note the presence of ganglioside OMR characteristic of PNS myelin in some organisms. Differences in the composition of myelin lipids in the central and peripheral nervous systems are not as significant as their differences in protein composition.

Myelin proteins of the central nervous system

The protein composition of myelin in the central nervous system is simpler than that of other brain membranes, and is represented mainly by proteolipids and basic proteins, which make up 60-80% of the total. Glycoproteins are present in much smaller amounts. The myelin of the central nervous system contains unique proteins.

The myelin of the human CNS is characterized by the quantitative prevalence of two proteins: the positively charged cationic protein myelin (myelin basic protein, MBP) and the proteolipid myelin (myelin proteolipid protein, PLP). These proteins are the main constituents of the myelin of the central nervous system of all mammals.

The myelin proteolipid PLP (proteolipid protein), also known as the Folch protein, has the ability to dissolve in organic solvents. The molecular weight of PLP is approximately 30 kDa (Da = Dalton). Its amino acid sequence is extremely conserved; the molecule forms several domains. The PLP molecule includes three fatty acids, typically palmitic, oleic, and stearic, linked to amino acid radicals by an ester bond.

CNS myelin contains slightly smaller amounts of another proteolipid, DM-20, named for its molecular weight (20 kDa). Both DNA analysis and elucidation of the primary structure showed that DM-20 is formed as a result of the cleavage of 35 amino acid residues from the PLP protein. During development, DM-20 appears earlier than PLP (in some cases even before the appearance of myelin); suggest that in addition to its structural role in myelin formation, it may be involved in oligodendrocyte differentiation.

Contrary to the notion that PLP is required for the formation of compact multilamellar myelin, the process of myelin formation in PLP / DM-20 knockout mice occurs with only minor deviations. However, these mice have a reduced lifespan and impaired general mobility. In contrast, naturally occurring mutations in PLP, including normal PLP over-expression, have serious functional implications. It should be noted that significant amounts of PLP and DM-20 proteins are present in the CNS, messenger RNA for PLP is also present in the PNS, and a small amount of protein is synthesized there, but not included in myelin.

Cationic myelin protein (MBP) attracts the attention of researchers due to its antigenic nature - when administered to animals, it causes an autoimmune reaction, the so-called experimental allergic encephalomyelitis, which is a model of a severe neurodegenerative disease - multiple sclerosis.

The amino acid sequence of MBP is highly conserved in many organisms. MBP is located on the cytoplasmic side of myelin membranes. It has a molecular weight of 18.5 kDa and lacks signs of a tertiary structure. This basic protein exhibits microheterogeneity upon electrophoresis under alkaline conditions. Most of the mammals studied contained varying amounts of MBR isoforms with a significant common amino acid sequence. The molecular weight of mice and rats MBR is 14 kDa. Low molecular weight MBR has the same amino acid sequences on the N- and C-terminal parts of the molecule as the rest of MBR, but differs by a reduction of about 40 amino acid residues. The ratio of these major proteins changes during development: mature rats and mice have more MBRs with a molecular weight of 14 kDa than MBRs with a molecular weight of 18 kDa. Two other MBR isoforms, also found in many organisms, have molecular weights of 21.5 and 17 kDa, respectively. They are formed by attaching a polypeptide sequence of about 3 kDa to the base structure.

The electrophoretic separation of myelin proteins reveals proteins with a higher molecular weight. Their number depends on the type of organism. For example, mice and rats can contain up to 30% of the total amount of such proteins. The content of these proteins also changes depending on the age of the animal: the younger it is, the less myelin in its brain, but the more proteins with a higher molecular weight it contains.

Enzyme 2 "3" -cyclic nucleotide 3 "-phosphodiesterase (CNP) makes up a few percent of the total content of myelin protein in CNS cells. This is much higher than in other types of cells. CNP protein is not the main component of compact myelin, it is concentrated only in certain areas of the myelin sheath associated with the cytoplasm of oligodendrocytes.The protein is localized in the cytoplasm, but part of it is associated with the membrane cytoskeleton - F-actin and tubulin.The biological function of CNP may be to regulate the structure of the cytoskeleton to accelerate the growth and differentiation processes in oligodendrocytes.

Myelin-associated glycoprotein (MAG) is a quantitatively minor component of purified myelin, has a molecular weight of 100 kDa, and is contained in the central nervous system in a small amount (less than 1% of the total protein). MAG has a single transmembrane domain that separates the highly glycosylated extracellular moiety, composed of five immunoglobulin-like domains, from the intracellular domain. Its overall structure is similar to the neuronal cell adhesion protein (NCAM).

MAG is not present in compact, multilamellar myelin, but is found in the periaxonal membranes of oligodendrocytes that form myelin layers. Recall that the periaxonal membrane of the oligodendrocyte is located most closely to the plasma membrane of the axon, but nevertheless these two membranes do not merge, but are separated by an extracellular gap. This feature of the localization of MAG, as well as the fact that this protein belongs to the immunoglobulin superfamily, confirms its participation in the processes of adhesion and information transfer (signaling) between the axolemma and myelin-forming oligodendrocytes during myelination. In addition, MAG is one of the components of the white matter of the central nervous system, which inhibits the growth of neurites in tissue culture.

Other white matter and myelin glycoproteins include the minor myelin-oligodendrocytic glycoprotein (MOG). MOG is a transmembrane protein containing a single immunoglobulin-like domain. Unlike MAG, which is located in the inner layers of myelin, MOG is localized in its superficial layers, due to which it can participate in the transfer of extracellular information to the oligodendrocyte.

Small amounts of characteristic membrane proteins can be identified by polyacrylamide gel electrophoresis (PAGE) (eg tubulin). High resolution electrophoresis demonstrates the presence of other minor protein bands; they can be associated with the presence of a number of myelin sheath enzymes.

Myelin proteins PNS

Myelin of the PNS contains both some unique proteins and several proteins common to the myelin proteins of the CNS.

P0 is the main protein of PNS myelin, has a molecular weight of 30 kDa, makes up more than half of the PNS myelin proteins. It is interesting to note that although it differs from PLP in amino acid sequence, post-translational modification pathways, and structure, both of these proteins are equally important for the formation of the structure of CNS and PNS myelin.

The content of MBP in the myelin of the PNS is 5-18% of the total amount of protein, in contrast to the central nervous system, where its share reaches one third of the total protein. The same four forms of MBP protein with molecular weights of 21, 18.5, 17 and 14 kDa, respectively, found in the myelin of the CNS, are also present in the PNS. In adult rodents, MBP with a molecular weight of 14 kDa (according to the classification of peripheral myelin proteins, it was named "Pr") is the most significant component of all cationic proteins. In the myelin of the PNS, there is also an MBP with a molecular weight of 18 kDa (in this case, it is called "protein P1"). It should be noted that the importance of the MBP protein family is not as great for the myelin structure of the PNS as for the central nervous system.

Myelin glycoproteins PNS

Compact myelin PNS contains a glycoprotein with a molecular weight of 22 kDa, called peripheral myelin protein 22 (PMP-22), the share of which is less than 5% of the total protein content. PMP-22 has four transmembrane domains and one glycosylated domain. This protein does not play a significant structural role. However, abnormalities in the pmp-22 gene are responsible for some hereditary neuropathologies in humans.

Several decades ago, it was believed that myelin creates an inert membrane that does not perform any biochemical functions. However, later, a large number of enzymes were found in myelin that are involved in the synthesis and metabolism of myelin components. A number of enzymes present in myelin are involved in the metabolism of phosphoinositides: phosphatidylinositol kinase, diphosphatidylinositol kinase, corresponding phosphatases and diglyceride kinases. These enzymes are of interest due to the high concentration of polyphosphoinositides in myelin and their rapid metabolism. There is evidence of the presence in myelin of muscarinic cholinergic receptors, G-proteins, phospholipases C and E, protein kinase C.

In the myelin of the PNS, Na / K-ATPase, which carries out the transport of monovalent cations, as well as 6'-nucleotidase, were found.The presence of these enzymes suggests that myelin may take an active part in axonal transport.

6. MYELIN PROTEINS

The protein composition of myelin is unique, but much simpler than in neurons and glial cells.

Myelin contains a high proportion of the cationic protein, MBM. It is a relatively small polypeptide with M g = 16-18 kDa. CBM contains a significant proportion of diamino acids and, at the same time, about half of its constituent amino acids are non-polar. This provides, on the one hand, close contact with the hydrophobic components of myelin lipids, and on the other hand, determines its ability to form ionic bonds with acidic lipid groups.

The so-called Folch proteolipid proteins, which make up most of the remaining myelin proteins, are characterized by an unusually high hydrophobicity. In turn, the main of these proteins is lipophilin, in which 2/3 of the constituent amino acids are non-polar. Of interest is the specific selectivity of the contacts of lipophilin with lipids, for example, the displacement of cholesterol from its environment. It is believed that this is due to the peculiarities of the secondary structure of lipophilin.

The share of the so-called Wolfgram protein is also quite large - an acidic proteolipid, quite rich in dicarboxylic amino acid residues, and, at the same time, containing about half of the residues of non-polar amino acids.

Finally, among several dozen other myelin proteins, we note the myelin-associated glycoprotein located on the extradellular surface of membranes; it also occurs in oligodendrocytes before myelination and in the myelin of the peripheral nervous system. In the human CNS, it is represented by three polypeptide chains with M g = 92, 107, 113 kDa, and in the peripheral nervous system - by one protein with M g = 107 kDa. MAG refers to glycoproteins with a relatively low content of carbohydrate residues - about 30% of the molecular weight, but contains a set of carbohydrates characteristic of glycoproteins: N-acetylglucosamine, N-acetylneuraminic acid, fucose, mannose and galactose. The protein part of the molecule is characterized by a high content of glutamic and aslaragic acids.

The functions of the Wolfgram protein and MAG are unknown, except for general considerations about their participation in the organization of the structure of the myelin sheaths.

7. NEUROSPECIFIC GLIA PROTEINS

Protein S-100 is found both in neurons and in glial cells, and its share in the latter is large - about 85%.

In 1967, neurospecific a 2 -glycoprotein with a molecular weight of 45 kD was isolated from a 2 -globulins of the brain. In the human brain, it appears at the 16th week of embryonic development. Its carbohydrate components include glucosamine, mannose, glucose, galactose, galactosamine and N-acetylneuraminic acid. a 2 -glycoprotein is localized only in astrocytes, but is absent in neurons, oligodendrocytes and endothelial cells. Therefore, it can be considered as one of the specific markers of astrocytes.

Another protein, again, is characteristic only of glial cells. It was isolated from areas of the human brain rich in fibrous astrocytes, and subsequently, in much larger quantities, from the brains of patients with multiple sclerosis. This substance was named glial fibrillar acidic protein. It is specific only to the central nervous system, and it is not found in the PNS. Its content in the white matter of the brain exceeds that in the gray matter. In the ontogeny of mice, the maximum GFA content is observed between the 10th and 14th days of postnatal development, i.e. coincides in time with the period of myelination and the peak of differentiation of astrocytes. The molecular weight of the protein is 40–54 kDa. Glial localization of this protein also allows it to be used as a "marker" protein for these cells.

The functions of a 2 -glycoprotein and GFA protein are unknown.

As for the proteins of microglia, it should be borne in mind the participation of these cells in the construction of myelin. Many of the myelin proteins are found in microglia.

Glia also contains many receptor and enzymatic proteins involved in the synthesis of secondary messengers, precursors of neurotransmitters and other regulatory compounds that can be classified as neurospecific.

8. INTENSITY OF PROTEIN METABOLISM IN DIFFERENT DEPARTMENTS OF THE NERVOUS SYSTEM

The modern concept of the dynamic state of proteins in the nervous tissue was established thanks to the use of isotopes by A.V. Palladin, D. Richter, A. Lighta and other researchers. Starting from the late 50s and during the 60s, in the study of protein metabolism, various precursors of their biosynthesis labeled with C, H, S were used. It was shown that proteins and amino acids in the brain of an adult animal metabolize, in general, more more intensely than in other organs and tissues.

For example, in experiments in vivo when uniformly labeled C-1-6-glucose was used as a precursor, it turned out that, according to the intensity of amino acid formation from glucose, a number of organs can be arranged in the following order:

brain> blood> liver> spleen and lungs> muscle.

A similar picture was observed when using other labeled precursors. It has been shown that the carbon skeleton of amino acids, especially monoaminodicarboxylic acids and, above all, glutamate, is intensively synthesized from C-acetate in the brain; glycine, alanine, serine, etc. are formed quite intensively from monoaminomonocarbic acids. It should be noted that glutamate occupies a special place in the metabolism of amino acids. In vitro experiments using labeled glutamate have shown that if only one glutamic acid is added to the reaction medium of the brain homogenate, it can be the source of 90–95% of amino acids.

Numerous studies have been carried out to study the differences in the metabolic rate of total and individual proteins using labeled precursors. In in vivo experiments with the use of C-glutamate, it was shown that it is included 4–7 times more intensively in the proteins of the gray matter than in the white matter. In all cases, the intensity of the exchange of total proteins of the gray matter of the cerebral hemispheres of the brain and cerebellum was significantly higher than that of the white matter of the same parts of the brain, no matter what precursor was used in the study. At the same time, the difference in the exchange rate of total gray matter proteins in comparison with white matter proteins occurs not only in the norm, but, as a rule, also under various functional states of the organism.

Studies have also been carried out to study the differences in the intensity of the incorporation of labeled precursors into the total proteins of the central and peripheral nervous systems. It turned out that despite significant differences in the composition, metabolism and functional activity of various parts of the CNS and PNS, as well as the complexity and heterogeneity of the proteins that make up their composition, the total proteins of the central nervous system of adult animals are renewed much more intensively than the total proteins of the PNS.

A lot of research is devoted to the metabolism of proteins in various parts of the brain. For example, when studying the distribution of radioactivity in the brain after the introduction of C-glutamate, it turned out that the share of the gray matter of the cerebral hemispheres accounts for 67.5 radioactivity, the cerebellum - 16.4, the medulla oblongata - 4.4, the share of other parts of the brain - about 11.7. In in vivo experiments with the introduction of various precursors to adult animals, namely C-glutamate, C-1-6-glucose, C-2-acetate, it turned out that according to the intensity of the inclusion of the label in the total proteins, various parts of the nervous system are located in the following sequence: gray matter of the cerebral hemispheres and cerebellum> thalamus> optic tubercle> middle and diencephalon> pons pons> medulla> white matter of the cerebral hemispheres and cerebellum> spinal cord> sciatic nerve> myelin.

Studies have also been conducted to study the intensity of protein metabolism in various parts of the central nervous system using the autoradiographic method. A similar picture was obtained: the most intense inclusion of the label took place in the proteins of the gray matter of the cerebral hemispheres and the cerebellum, slower - in the spinal cord and even slower - in the proteins of the sciatic nerve. As for the subcortical formations, the intensity of their protein metabolism was average between the rate of renewal of the proteins of the gray and white matter of the cerebral hemispheres and the cerebellum. Less significant differences are observed between individual subcortical formations than between the metabolic activity of white and gray matter.

The total proteins of various regions of the cerebral cortex - frontal, temporal, parietal, and occipital - were also studied. According to Welsh and WAPalladin, proteins of the sensory cortex have a higher renewal capacity, and proteins of the temporal lobe of the cerebral hemispheres have a lower renewal capacity. The same authors showed that higher protein renewability is characteristic of phylogenetically younger and functionally more active structural formations of the brain.

Against a background of generally highly renewable brain proteins, a few relatively inert proteins deserve special mention. These include the histones of neurons, the neocortex-cationic proteins of the chromatin of these cells. In an adult organism, neocortex neurons do not multiply. Accordingly, the rate of histone renewal is very insignificant. The average statistical timing of the renewal of half of the molecules of some histone fractions is measured in tens of days.

Absolutely inert proteins are absent in the brain, and individual proteins and protein complexes of neurons undergo continuous restructuring associated with their participation in the functional activity of neurons and neuroglia. In addition to the synthesis and decay of whole protein molecules, changes occur in their structure, which occur, in particular, during the amination and deamination of brain proteins. They should be considered as a partial renewal of individual fragments of a protein molecule.

1. In the nervous tissue, neurospecific proteins characteristic only of it were found. By chemical nature, they can be acidic or basic, simple or complex, often they are glycoproteins or phosphoproteins. Many neurospecific proteins have a subunit structure. The number of discovered neurospecific proteins has already exceeded 200 and is growing rapidly.

2. Neurospecific proteins are directly or indirectly involved in the implementation of all functions of the nervous system - the generation and conduction of a nerve impulse, the processes of processing and storing information, synaptic transmission, cellular recognition, reception, etc.

3. By localization in the tissue of the nervous system, exclusively or predominantly neuronal and glial neurospecific proteins are distinguished. According to their subcellular localization, they can be cytopyasmic, nuclear or membrane-associated. Of particular importance are neurospecific proteins localized in the membranes of synaptic formations.

4. Many acidic calcium-binding neurospecific proteins are involved in the processes of ion transport. In particular, they are thought to play a significant role in the formation of memory.

5. A special group of neurospecific proteins are contractile proteins of the nervous tissue, which provide orientation and mobility of cytostructural formations, active transport of a number of neuron components and are involved in neurotransmitter processes in synapses.

6. The group of neurospecific proteins associated with humoral regulation by the brain includes some hypothalamic glycoproteins, as well as neurophysins and similar proteins that are carriers of peptide regulators.

7. Various neurospecific glycoproteins are involved in the formation of myelin, in the processes of cell adhesion, neuroreception and mutual recognition of neurons in ontogenesis and regeneration.

8. A number of neurospecific proteins are brain isoenzymes of known enzymes, for example, enolase, aldolase, creatine kinase, etc.

9. Many neurospecific proteins are very actively metabolized in the brain of animals, and the metabolic rate is different in different parts of the brain and depends on the functional state of the nervous system. In general, in terms of the intensity of renewal, the proteins of the brain are significantly superior to the proteins of other tissues and organs.

Diseases, one of the main manifestations of which is the destruction of myelin, is one of the most pressing problems of clinical medicine, mainly neurology. In recent years, there has been a clear increase in the number of cases of diseases accompanied by damage to myelin.

Myelin- a special type of cell membrane that surrounds the processes of nerve cells, mainly axons, in the central (CNS) and peripheral nervous system (PNS).

The main functions of myelin:
axon nutrition
isolation and acceleration of nerve impulse conduction
supporting
barrier function.

By chemical composition myelin is a lipoprotein membrane consisting of a biomolecular lipid layer located between monomolecular layers of proteins, spirally twisted around the internodal segment of the nerve fiber.

Myelin lipids are represented by phospholipids, glycolipids and steroids. All these lipids are built according to a single plan and necessarily have a hydrophobic component ("tail") and a hydrophilic group ("head").

Proteins make up up to 20% of the dry weight of myelin. They are of two types: proteins located on the surface, and proteins immersed in lipid layers or penetrating the membrane through and through. In total, more than 29 myelin proteins have been described. Myelin basic protein (MBP), proteolipid protein (PLP), myelin-associated glycoprotin (MAG) make up 80% of the protein mass. They perform structural, stabilizing, transport functions, have pronounced immunogenic and encephalitogenic properties. Among small myelin proteins, myelin-oligodendrocyte glycoprotein (MOG) and myelin enzymes, which are of great importance in maintaining structural and functional relationships in myelin, deserve special attention.

Myelins of the CNS and PNS differ in their chemical composition
in the PNS, myelin is synthesized by Schwann cells, with several cells synthesizing myelin for one axon. One Schwann cell produces myelin for only one segment between areas without myelin (Ranvier interceptions). The myelin of the PNS is noticeably thicker than that of the central nervous system. All peripheral and cranial nerves have such myelin; only short proximal segments of the cranial nerves and spinal roots contain CNS myelin. The optic and olfactory nerves contain predominantly central myelin
in the central nervous system, myelin is synthesized by oligodendrocytes, and one cell takes part in the myelination of several fibers.

Destruction of myelin is a universal mechanism for the response of nerve tissue to damage.

Myelin diseases are classified into two main groups
myelinopathies - associated with a biochemical defect in the structure of myelin, usually genetically determined

Myelinoclastic - myelinoclastic (or demyelinating) diseases are based on the destruction of normally synthesized myelin under the influence of various influences, both external and internal.

The division into these two groups is rather arbitrary, since the first clinical manifestations of myelinopathies can be associated with the influence of various external factors, and myelinoclasts are most likely to develop in predisposed individuals.

The most common disease of the entire group of myelin diseases is multiple sclerosis. It is with this disease that differential diagnostics have to be carried out most often.

Hereditary myelinopathies

The clinical manifestations of most of these diseases are more often noted already in childhood. At the same time, there are a number of diseases that can begin at a later age.

Adrenoleukodystrophy (ALD) are associated with insufficient function of the adrenal cortex and are characterized by active diffuse demyelination of various parts of both the central nervous system and the PNS. The main genetic defect in ALD is associated with a locus on the X chromosome - Xq28, the genetic product of which (ALD-P protein) is a peroxisomal membrane protein. The type of inheritance in typical cases is recessive, sex-dependent. Currently, more than 20 mutations have been described at different loci associated with different clinical variants of ALD.

The main metabolic defect in this disease is an increase in the content of long-chain saturated fatty acids (especially C-26) in tissues, which leads to gross violations of the structure and functions of myelin. Along with the degenerative process in the pathogenesis of the disease, chronic inflammation in the brain tissue associated with increased production of tumor necrosis factor alpha (TNF-a) is essential. The ALD phenotype is determined by the activity of this inflammatory process and is most likely due to both a different set of mutations on the X chromosome and an autosomal modification of the influence of a defective genetic product, i.e. a combination of the main genetic defect in the sex X chromosome with a peculiar set of genes on other chromosomes.

According to the type of inheritance and characteristics of the onset of ALD, they are classified into

X-linked ALD in children
X-linked ALD in adults
autosomal recessive neonatal ALD.

Clinical variants of adrenoleukodystrophies can be divided into two main groups

Predominantly cerebral forms
predominantly polyneuropathic, developing more often in adults.

Depending on the predominant symptom complex in the ALD, in addition to polyneuritic, several clinical variants are distinguished:
1) progressive encephalopathy with cortical blindness in young people;
2) progressive myelopathy in mature men;
3) encephalopathy in combination with myelopathy;
4) malignant encephalopathy in newborn boys;
5) predominantly endocrinological disorders (Addison's disease) linked to the X chromosome and accompanied by moderate neurological disorders;
6) myelopathy in women - carriers of a pathological gene, etc.

In typical cases, cerebral forms of ALD affect boys 3 - 15 years old, there are progressive movement disorders, decreased vision, hearing loss, typical convulsive syndromes and dementia. Separate symptoms of encephalopathy and myelopathy can also be detected in heterozygous women - carriers of the pathological gene.

Among the more rare polyneuritic forms, there are adrenomyeloneuropathy, which can begin between the ages of 25 and 35 and is characterized by progressive myelopathy and polyneuropathy. Clinical manifestations: increasing weakness in the legs, sensitivity disorders of the polyneuritic type ("socks" and "gloves"), impaired coordination. For differential diagnosis, family history, a steadily progressive type of disease course, a decrease in blood adrenaline levels and an increase in long-chain fatty acids are of great importance.

Recently, an increasing role in monitoring the activity of the pathological process in various variants of ALD has been acquired by magnetic resonance imaging.

There is no effective specific treatment for ALD yet, symptomatic therapy is carried out. Currently, approaches are being developed to conduct genetic counseling as a method for preventing ALD based on screening for mutations in the ALD protein gene and other loci to identify carriers of pathogenic mutations.

Described a late form of Sudanophilic leukodystrophy Pelizaeus-Merzbacher with the onset of the disease in the second decade of life... Severe demyelinating brain damage in these patients is accompanied by a decrease in the content of cholesterol esters. In these patients, coordination disorders, spastic paresis, and intellectual impairments progressively increase.

Late forms of this leukodystrophy often have a favorable course and are usually very difficult to differentiate from multiple sclerosis.

Alexander's disease - a rare disease, predominantly inherited in an autosomal recessive manner, belongs to the group of leukodystrophies, which are characterized by demyelination with diffuse fibrous degeneration of the white matter of the brain and the formation of globoid cells in the brain tissue.

This dysmyelinopathy is characterized by the accumulation of glucolipids in myelin instead of galactolipids and cerebrosides.

She is characterized by
gradually increasing spastic paralysis
decreased visual acuity
dementia
epileptic syndrome
hydrocephalus.

In the brain tissue in Alexander's disease, in addition to diffuse demyelination, cavities and hyalinous seals of fibers around the vessels of the brain are revealed.

The disease can begin at any age; in the early stages, a remitting course is possible.

The prognosis is extremely unfavorable, although slowly progressive variants are described, close downstream to multiple sclerosis.

The group of globoid cell leukodystrophies also includes such rare diseases as Krabbe's disease and Canavan's disease ... These diseases rarely develop in adulthood.
Clinically, they are characterized by progressive damage to myelin in different parts of the central nervous system with the development of paresis, impaired coordination, dementia, blindness, and epileptic syndrome. Studies of blood leukocytes or skin fibroblasts often reveal a deficiency of the enzyme b-galactocerebrosidase.

At different ages, the so-called mitochondrial diseases can begin with damage to the central nervous system and the development mitochondrial leukoencephalopathy ... Various mutations, including in mitochondrial DNA, can cause enzymatic defects and disrupt the processes of transport and utilization of substances, storage and transfer of energy, and disrupt the respiratory chain.

Mitochondrial encephalopathy is characterized by o an increase in the content of lactate and pyruvate in blood plasma and cerebrospinal fluid, in mitochondria. These disorders can lead to the development of polymorphic neurological symptoms, sometimes similar to those of multiple sclerosis. Often, mitochondrial encephalopathy is manifested by weakness and rapid muscle fatigue, ophthalmoplegia, and other symptoms.

Myelinoclastic diseases

Among myelinoclastic diseases, special attention should be paid to viral infections, in the pathogenesis of which the destruction of myelin is of great importance. This is first and foremost
neuroAIDS caused by the human immunodeficiency virus (HIV) and associated nervous system damage
tropical spinal paraparesis (TSP) caused by the retrovirus HTLV-I.

The pathogenesis of primary damage to the central nervous system in neuro AIDS is associated with the direct neurotoxic effect of the virus, as well as with the pathological action of cytotoxic T cells, anti-brain antibodies and neurotoxic substances produced by infected immunocytes. Direct brain damage in HIV infection leads to the development of subacute encephalitis with areas of demyelination. At the same time, monocytes and macrophages with a large amount of the virus can be detected in the brain tissue. These cells merge into giant multinucleated formations with a huge amount of viral material (syncytia), which was the reason for the designation of this encephalitis as giant cell. At the same time, a mismatch between the severity of clinical manifestations and the severity of pathomorphological changes is characteristic of this infection. In many patients with distinct clinical manifestations of HIV-associated dementia, pathomorphological only the "paleness" of myelin and mild central astrogliosis can be detected.

Clinically, the so-called HIV-associated cognitive-motor complex is most often observed in HIV infection.
This complex, previously referred to as AIDS-dementia, includes three diseases:
HIV-associated dementia
HIV-associated myelopathy
HIV-associated minimal cognitive-movement disorders.

In the most common syndrome, HIV dementia, there is a slowdown in psychomotor processes, inattention, and memory loss. Subsequently, dementia progresses rapidly, possibly focal neurological symptoms. In HIV-associated vacuolar myelopathy, movement disorders predominate, mainly in the lower extremities, associated with spinal cord injury.

Patients with immunodeficiencies of various origins may develop progressive multifocal leukoencephalopathy (PML) , which is caused by polyomavirus (JC virus from the papovavirus group). In addition to AIDS patients, this infection can occur in patients with sarcoidosis, tuberculosis, SLE, lymphoma, leukemia, and immunodeficiency after kidney transplantation. The virus is detected in oligodendrocytes and astrocytes, and the latter can fuse to form giant cells. In the pathogenesis of demyelination, both direct damage to oligodendrocytes and autoimmune reactions against the background of immunodeficiency are important. PML is characterized by a steadily progressive course with early development of dementia, extrapyramidal disorders, disorientation in place and time. The detection of the JC virus in the cells of the cerebrospinal fluid is of decisive importance in the diagnosis of PML.

Chronic inflammation in the white matter of the brain with the development of demyelination is characteristic of TSP (tropical spinal paraparesis) or HTLV-1 myelopathy ... This disease, endemic to the countries of Southeast Asia, is characterized by a steadily progressive lower paraparesis. During MRI in patients with TSP, subclinical foci of demyelination in the brain can also be detected. Detection of retrovirus HTLV-I or antibodies to it is of diagnostic value.

Treatment of all viral infections is based on the use of antiviral drugs that stop the virus from replicating in infected cells.

In persons with cachexia, suffering from chronic alcoholism, severe chronic diseases of the liver and kidneys, with diabetic ketoacidosis, during resuscitation measures, a severe demyelinating disease may develop - acute or subacute central pontic and / or extrapontal myelinolysis.

In this disease, symmetrical bilateral foci of demyelination are formed in the subcortical nodes and the brain stem. It is assumed that the basis of this process is a disturbance in the balance of electrolytes, primarily Na ions.

The risk of developing myelinolysis is especially high with rapid correction of hyponatremia.

Clinically this syndrome can manifest itself as minimal neurological symptoms, and severe alternating syndromes and the development of coma. The disease usually ends in death after a few weeks, but in some cases, massive doses of corticosteroids prevent death.

After irradiation, chemotherapy and radiation therapy, it may develop toxic leukoencephalopathy with focal demyelination in combination with multifocal necrosis. Development is possible
acute
early delayed
late demyelinating processes.

The latter begin several months or years after irradiation and are characterized by a severe course with polymorphic focal neurological symptoms. In the pathogenesis of these leukoencephalopathies, autoimmune responses to myelin antigens, damage to oligodendrocytes and, consequently, impaired remyelination are essential.

Toxic damage to myelin can also occur when
porphyrias
hypothyroidism
mercury intoxication
lead
CO
cyanide
for all types of cachexia
overdose of anticonvulsants
isoniazid
actinomycin
when using heroin and morphine

A number of myelinoclastic diseases deserve special attention, which can be classified as special variants of multiple sclerosis.

Clinically, the onset of multiple sclerosis is extremely difficult to distinguish from acute disseminated encephalomyelitis (WEM) - an autoimmune inflammatory disease of the central nervous system, which usually develops after infections or vaccinations. Differentiation from multiple sclerosis in many cases is possible only on the basis of follow-up data
in the case of a wholesale electricity market, the process is always single-phase, i.e. spicy
in MS, chronic.

In most cases WECM develops after an infectious disease or vaccination.

Among post-vaccination encephalitis, encephalitis is especially often described after the administration of vaccines against pertussis and smallpox, as well as after anti-rabies vaccinations.

WECM can develop after or during
viral diseases (measles, rubella, smallpox, chickenpox, mumps, infectious mononucleosis, herpes infection, influenza)
less often - with mycoplasma
another bacterial infection.

The pathogenesis of the disease is based on the development of an autoimmune reaction and acute inflammation due to cross reactions between antigens of viruses (less often bacteria) and antigens of the brain.

Typically, there is a latency period of 4 to 6 days. The disease begins acutely or subacutely, with general infectious, cerebral and focal symptoms, in severe cases - with convulsive syndrome and impaired consciousness.

WECM is often combined with acute polyneuritis of the Guillain-Barre motor polyneuritis type.

On MRI with WECM, multiple foci of increased intensity appear on T2-weighted images, actively accumulating contrast in the T1-mode. These foci are very close to those observed in multiple sclerosis, but in WECM they are often larger in size, sometimes symmetrical, with involvement of the thalamus and basal nuclei. With WREM, repeated tomograms do not show the appearance of new foci, as in multiple sclerosis, but on the contrary, a number of foci may decrease in size.

WECM treatment is based on the use of pulse doses of corticosteroids and adequate symptomatic therapy. In some cases, a good clinical effect has been registered from the use of plasmapheresis, large doses of immunoglobulin G class (IgG) intravenously.

(!!!) Malignant forms of WECM with the development of multiple hemorrhages in the brain tissue are sometimes classified asacute hemorrhagic leukoencephalitis or Hirst's disease.

A special variant of multiple sclerosis was described by Davis in 1894 and was named opticomyelitis Devik ... This disease is characterized by symptoms of damage to the spinal cord (transverse myelitis) and optic nerves on one or both sides, as well as a malignant, steadily progressive course and a poor prognosis. The most common cases of Davis disease occur in indigenous women in Southeast Asia. Pathomorphologically, the foci of demyelination in this disease are close to multiple sclerosis, but sometimes diffuse inflammatory changes atypical for the latter are observed with pronounced edema of the brain tissue and, in rare cases, with hemorrhages. MRI and autopsy data indicate the possibility of plaque formation not only in the spinal cord and optic nerves, but also in the periventricular white matter, rarely in the brainstem and cerebellum. In the pathogenesis of Davis opticomyelitis, humoral autoimmune reactions with the formation of antibodies to various antigens of the nervous tissue are of great importance.

Concentric sclerosis, or Ballo's disease , is a steadily progressive demyelinating disease in young people. With this disease, large foci of demyelination are formed mainly in the white matter of the frontal lobes, sometimes with the involvement of gray matter. The lesions consist of alternating areas of complete and partial demyelination with pronounced early lesions of oligodendrocytes. The zones of demyelination and remyelination are located concentrically or chaotically; this gives the lesions on the tomograms a characteristic appearance. Before the introduction of MRI, the diagnosis of Ballot's disease was confirmed only by autopsy. The prognosis is extremely unfavorable. In recent years, data have been obtained on the improvement in the condition of patients against the background of active immunosuppression, which makes the prognosis not as fatal as before.

Schilder's leukoencephalitis children are more often ill, although often this disease begins in adulthood. It is characterized by widespread, steadily progressive demyelination with the formation of confluent zones of inflammation and destruction of myelin. Typically, such a zone of demyelination spreads from one hemisphere to another through the corpus callosum. The clinical picture of Schilder's disease depends on the volume and location of the lesion.

Development is characteristic
epileptic syndrome,
psychosis,
central paresis,
hyperkinesis, ataxia,
decreased vision
dementia,
pseudobulbar syndrome.

Another malignant variant of multiple sclerosis is Marburg disease , described as a progressive disease with an acute onset, a predominant lesion of the brain stem, extremely malignant, with a rapidly progressive course and rapid death. In addition to the brainstem, multiple foci of demyelination in this disease are often localized in the optic nerves and cervical spinal cord. Pathomorphological foci of demyelination in Marburg disease are characterized by the rapid development of axonal degeneration, sometimes necrosis. Active immunosuppression in some cases contributed to the onset of remission, which confirms the commonality of Marburg disease and multiple sclerosis.

(!!!) It should be noted that foci of demyelination in the central nervous system are quite often detected in patients with
- systemic lupus erythematosus
-primary Sjogren's syndrome
- vasculitis of various origins and other systemic autoimmune diseases.

The destruction of myelin and the development of autoimmune reactions to its components is observed in many vascular and paraneoplastic processes in the central nervous system. what should be considered when making a differential diagnosis.

Table of contents

1. Neurospecific proteins

Myelin basic protein

Neuron Specific Enolase

Neurotropin-3 and neurotropin-4/5

Brain neurotrophic factor

Ciliary neurotrophic factor

Phosphorylated neurofilament H

Pigment factor of epithelial origin

Glial Fibrillar Sour Protein

2. Alzheimer's disease

Glycosylation End Product Receptor

Nikastrin

... β-amyloid

Chlamydia pneumoniae

Melatonin and melatonin sulfate

Serotonin

Diagnostic significance of the determination of autoantibodies to glycolipids in peripheral NP

Antibodies to myelin-associated glycoprotein

Antibodies to sulfated glucuronate paraglobozide

Antibodies to gangliosides

Antibodies to ganglioside M1

Antibodies to ganglioside GD1b

Antibodies to ganglioside GQ1b

Antibodies to interferon β

Antibodies to sphingomyelin

Antibodies to laminin β

Anticochlear antibodies

Anti-neuronal autoantibodies

Antibodies to ribosomal proteins P and RNA

Section abbreviations

AD - Alzheimer's disease

DNP - demyelinating neuropathy

NP - neuropathy

NSB - neurospecific proteins

PNS - peripheral nervous system

CSF - cerebrospinal fluid

CNS - central nervous system

NGF - nerve growth factor

Methods of neuroimaging and electrophysiological examination are traditional for the diagnosis of conditions associated with damage to brain tissue. Recently, more and more attention has been attracted by laboratory diagnostics, including the determination of neurospecific proteins (NSPs) - biologically active molecules specific to nerve tissues and performing functions characteristic of the nervous system. Over the past 30 years, more than 60 different NSPs of the brain have been characterized. They can be classified according to the localization-structural principle (neuronal, glial; membrane-associated and cytoplasmic, etc.), according to their functional role, and also a subgroup of NSBs present in health and disease can be distinguished. Determination of the level of NBP contributes to early diagnosis, because significant changes in their concentration often occur earlier than those damages that can be detected by instrumental examination methods. In addition, they allow assessing the prognosis of the course and outcome of the disease, monitoring the patient's treatment.

Neurospecific proteins

Myelin basic protein (MBP)

MVR is released into the cerebrospinal fluid (CSF) in any damage to the nerve tissue. The level of MBR increases with CNS injuries, tumors, multiple sclerosis, subacute sclerosing panencephalitis, viral encephalitis, and other neurological disorders. Also, the level of MBP rises for several days after stroke and reflects the destruction of the myelin sheaths. It is assumed that the MBR secreted in the CSF is not identical to that in the tissue.

Neuron Specific Enolase (NSE)

NSE is a neurospecific marker. Refers to intracellular enzymes of the central nervous system, which allows the use of NSE for the determination of postischemic brain damage. However, NSE can also increase in some other neurological processes (epilepsy, subarachnoid hemorrhage). It is also a marker of small cell lung cancer, neuroblastoma.

S-100 is a specific astrocytic glial protein capable of binding calcium. The protein got its name due to the property of remaining dissolved in a saturated solution of ammonium sulfate. The S-100 family of proteins consists of 18 tissue-specific monomers. Two of the monomers, α and β, form homoi heterodimers, which are present in high concentrations in the cells of the nervous system. S-100 (ββ) is present in high concentrations in glial and Schwann cells, the S100 (αβ) heterodimer is found in glial cells, and the S-100 (αα) homodimer is found in striated muscles, liver and kidneys. S-100 is metabolized by the kidneys and has a half-life of 2 hours. Astroglial cells are the most abundant cells in brain tissue. They form a three-dimensional network, which is a supporting frame for neurons. An increase in the concentration of S-100 (αβ) and S-100 (ββ) in CSF and plasma is a marker of brain damage. In patients with brain damage, when detected early, the S-100B content reflects the degree of brain damage. S-100 studies are useful for both monitoring and predicting disease progression.

Subarachnoid hemorrhage leads to a significant increase in CSF S-100 levels. It should be noted that the plasma protein concentration remains low. The concentration of S-100 is significantly increased in plasma in patients operated on under cardiopulmonary bypass. The concentration peak occurs at the end of extracorporeal circulation and then decreases in uncomplicated cases. A slowdown in the decrease in the S-100 concentration in a patient in the postoperative period indicates the presence of complications and damage to brain cells. Early detection and control of S-100 levels, as well as simultaneous S-100 and NSE studies, can detect and confirm the presence of brain damage at an early stage, when successful treatment is possible. The S-100 test can also be used to predict neurological complications in patients with cardiac arrest.

An increase in S-100 in serum and CSF in cerebrovascular accidents is due to the activation of microglia. It was shown that in the early phase of cerebral infarction, microglial cells in the peri-infarction zone express S-100 and actively proliferate, and proteins are expressed no more than three days after the infarction. This suggests that activation of a constant population of microglia is an early response of brain tissue to ischemia and can be used as an early marker of damage.

The results of the S-100 study can be used to predict the possible development of various symptoms in traumatic brain injuries, conditions after bruises and concussions. It should be borne in mind that the concentration of protein S-100 increases significantly with age, and in men to a greater extent than in women.

S-100 is one of the earliest NBPs in the developing brain. It is found already at 3 months of the prenatal period in the pons, midbrain, cerebellum and occipital lobe, and by 6 months protein synthesis is observed in the frontal cortex. The functions of the central nervous system, in which S-100 is involved, begin to appear at 12-15 weeks of embryogenesis, and by the time of birth they are already well formed. A number of studies show the participation of this protein in the regulation of learning and memorization.

Protein S-100 increases during and after a reversible deterioration of the intrauterine state with the development of hypoxia. Its concentration in various biological fluids rises 48-72 hours before any standard procedure reflects cerebral disorders or fetal death. The high significance of the determination of S-100B in the amniotic fluid for the prediction of intrauterine fetal death was shown (Fig.): At the cut-o level ff 1.19 μg / L test sensitivity is 90.9%, specificity is ~ 100%.

Cord blood S-100B levels can be used to assess intrauterine growth retardation (IUGR) (Figure).

In newborns, a strong correlation was shown between the S-100 level and the severity of intraventricular hemorrhage (IVH) (Fig.)

The S-100B level in the first 72 hours of life in term infants with birth asphyxia is a reliable marker of the prognosis of the development and severity of cerebral disorders.

S-100 (αβ + ββ) can be defined as an additional diagnostic and prognostic marker in malignant melanoma.

Neurotropin-3 (NT3) and neurotropin-4/5 (NT4 / 5)

The family of neurotrophins includes nerve growth factor (NGF), brain neurotrophic factor (BDNF), NT3 and NT4 / 5. They support different populations of neurons in the CNS and PNS. NT are secreted proteins found in the bloodstream that are able to signal individual cells to survive, differentiate, or grow. NTs act by preventing the initiation of apoptosis in a neuron. They also induce the differentiation of progenitor cells, the formation of neurons. NT play an important role in the functioning of the nervous system, in the regeneration of damaged neuronal structures.

Although the vast majority of neurons in the mammalian brain are formed during embryonic development, the adult brain partially retains the ability to neurogenesis - the formation of new neurons from neuronal stem cells. NT controls and stimulates this process. The trophic (survival) and tropic (direction of axon growth) properties of NT are the basis for their possible use in the treatment of various types of neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's diseases, as well as peripheral neuropathies of various origins.

NT3 is a growth factor with mm. 13.6 kDa (m.m. of the active form-dimer - 27.2 kDa). NT3 plays a role in the development of the sympathetic nervous system. In mice, increased levels of NT3 were found in sympathetic ganglia and organs with hyperinnervation and spontaneous hypertension. In patients with asthma, corticosteroids increase serum NT3 levels. The concentration of NT3 in the frontal and parietal areas of the cortex is significantly reduced in patients with schizophrenia. NT3 is able to stimulate the largest number of neuronal populations because it activates two of the three NT tyrosine kinase receptors (TrkC and TrkB).

NT4 / 5 prevents the death of motor neurons in the perinatal and postnatal periods. NT4 / 5 acts mainly through the TrkB tyrosine kinase receptor.

Brain neurotrophic factor (BDNF)

The mature mammalian BDNF molecule has m.w. 13 kDa and consists of 119 amino acid residues. BDNF is 52% identical in amino acid composition to NGF. In solution, it exists as a homodimer. BDNF is expressed in fibroblasts, astrocytes, neurons of various phenotypes and localization, megakaryocytes / platelets, Schwann cells (in areas of injury), and possibly smooth muscle cells. BDNF is found in plasma in amounts of the order of pg / ml, while in serum it is present in amounts of the order of ng / ml. The difference is due to the release of BDNF during platelet degranulation and blood clotting. The identity of the BDNF structure in different mammals potentially allows the use of this test system for different animal species.

At least 2 types of BDNF receptors are known, the first being low affinity NGF receptors with m.m. 75 kDa (LNGFR), the second - high affinity receptors for tropomyosine kinase-B with a molecular weight of 145 kDa (TrkB). It is known that LNGFR can enhance signaling along certain paths. The biological significance of the activation of these pathways is poorly understood. LNGFRs can participate in the migration of Schwann cells to the damaged area and / or modulate TrkB activity on cells expressing both receptors simultaneously. TrkB has the ability to bind NT3 and 4. TrkB receptors are believed to require homodimerization, while there is evidence of the formation of functional heterodimers of TrkB and TrkC receptor molecules on cells expressing both of these receptors simultaneously. These cells include granular neurons of the cerebellum and cells of the dental nucleus of the hippocampus. There is evidence of TrkB expression on spinal cord motor neurons, pyramidal cells of the hippocampus, almost all cells of the developing brain, and thymocytes, which indicates the role of BDNF in lymphopoiesis.

The functional activity of BDNF is quite high. During development, it is involved in neuronal differentiation, maturation, survival, and synapse formation. In an adult organism, the main function of BDNF is neuroprotection, protection of brain neurons from ischemic attacks and motor neurons from death induced by the removal of axons.

Ciliary neurotrophic factor (CNTF)

Human CNTF is a single-chain polypeptide of 200 amino acid residues, mw. 22.7 kDa. The molecule is highly conserved in various species. Comparison of amino acid sequences of human, rat, and rabbit CNTFs revealed 83 and 87% homology, respectively. CNTF is localized in Schwann cells and type 1 astrocytes.

CNTF belongs to a limited family of neuropoietic cytokines, including leukemia inhibitory factor (LIF) and oncostatin M (OSM). CNTF is regarded as a key differentiation factor for developing neurons and glial cells. CNTF mediates trophism and is involved in the protection of damaged or axonotomized neurons. In particular, the death of motor neurons after axotomy of the rat facial nerve was prevented by applying CNTF to the proximal axonal segment. CNTF has demonstrated in vitro induction of cholinergic properties in adrenergic sympathetic motor neurons. These influences included the expression of acetylcholine as a neurotransmitter and the synthesis of substance P (SP) and vasoactive intestinal peptide (VIP) as acetylcholine-associated neuropeptides. The effect of CNTF on non-autonomous sensory neurons is less well understood. It was found that the cells of the dorsal root ganglion in vivo increase the expression of SP, while the expression of SP and VIP does not increase in response to CNTF in vitro. In addition, CNTF is presumably involved in glial differentiation. Other effects of CNTF include: promoting pluripotency of embryonic stem cells, induction of survival and differentiation of adrenal chromaffin cells, and, like IL-6, induction of fever after intravenous injections. Interest in the study of CNTF is due to its ability to promote the survival of neurons.

Phosphorylated neurofilament H (pNF-H)

pNF-H is a sensitive marker of axonal damage. Neurofilaments make up the bulk of the cytoskeleton of neurons. The three main proteins of neurofiloment are NF-L, -M and -H. Their concentration is especially high in axons. The NF-H protein has some unique properties. In axonal neurofilaments, the serine residues of this protein contained in the lysine-serine-proline repeats are highly phosphorylated. Phosphorylated forms of NF-H (pNF-H) are resistant to proteases after exiting damaged axons. Therefore, the determination of this protein in CSF or blood can provide information about the extent of axonal damage.

pNF-H is determined in serum samples only in the presence of damage to the spinal cord or brain. PNF-H concentrations can reach high levels (> 250 ng / ml) and return to zero levels weeks after injury. Since pNF-H is expressed only in axons, the determination of its content is a convenient and sensitive biomarker for assessing axonal damage. It has been shown that pNF-H can be detected in plasma in people with optic neuritis or in CSF in patients with malignant brain tumors or stroke.

Pigment factor of epithelial origin (PEDF)

PEDF is a glycoprotein with m.m. ~ 50 kDa, which has many biological functions. It is a neuroprotective and neurotrophic factor that affects various types of neurons. It has been shown that PEDF is a potent activator of neuronal differentiation of human retinoblastoma cells. It has been shown in birds and mice to ensure the survival and differentiation of developing motor neurons of the spinal cord, support the normal development of the photoreceptor neuron in amphibians and the expression of opsin in the absence of retinal pigment epithelium (RPE) cells.

In rats, PEDF is a survival factor for cerebellar granular neurons, protecting them from apoptosis and glutamate neurotoxicity. It also protects motor neurons and developing neurons in the hippocampus from glutamate-induced degeneration. It has been shown in cell cultures that it protects retinal neurons from peroxide-induced death.

Glial fibrillar acidic protein (GFAP)

GFAP is a member of the cytoskeleton family of proteins and is the major 8-9 nm intermediate filament in mature CNS astrocytes. GFAP is a monomeric molecule with m.m. 40-53 kDa and an isoelectric point of 5.75.8. It is a highly specific brain protein that is not found outside the CNS. It has been shown that GFAP is very rapidly released into the blood after traumatic brain injury (may serve as a marker of injury severity and predictive of outcome), but no GFAP is released in multiple trauma without brain injury. In the central nervous system, after injury (whether it is the result of trauma, disease, genetic disorder or chemical stroke) astrocytes, as a result of typical behavior, respond with astrogliosis. Astrogliosis is characterized by rapid GFAP synthesis. It is known that GFAP levels generally rise with age. Due to its high specificity and early release from the central nervous system after traumatic brain injury, GFAP may prove to be a very useful marker for early diagnosis.

Alzheimer's disease

Alzheimer's disease (AD) is a progressive senile dementia that affects about half of the population over 85 years of age. The hallmarks of this disease are memory loss and other behavioral abnormalities that correlate with the loss of neurons initially in the cerebral cortex and hippocampus. AD is characterized by the presence of extracellular plaques and intracellular neurofibrillary tangles in the brain tissue.

Receptor for glycosylation end products (RAGE)

RAGE is a type I multiligand transmembrane glycoprotein belonging to the immunoglobulin (Ig) superfamily. RAGE has been suggested to be involved in a variety of pathological processes, including diabetes mellitus, Alzheimer's disease (AD), systemic amyloidosis, and tumor growth. RAGE may be involved in physiological functions such as growth, neuronal survival and regeneration, and pro-inflammatory responses. High expression of RAGE is observed during development, especially in the central nervous system. RAGE ligands include advanced glycosylation end products (AGEs), amyloid-β (Aβ), HMG-1 (also known as amphotericin), and some proteins of the S-100 family. Aβ is a major component of senile or amyloid plaques, one of the key neuromorphological signs of AD. RAGE is a receptor for β-sheet structures characteristic of amyloid; a localized increase in its level near Aβ in AD brain has been found. The interaction of Aβ with RAGE expressed on endothelial cells, neurons, and microglia leads to the formation of reactive oxygen species and the production of proinflammatory factors, which is a putative mechanism underlying the neurodegenerative process in AD. Recent studies have shown the possibility of RAGE being involved in Aβ transport across the blood-brain barrier and its accumulation in the CNS.

The interaction of RAGE with its ligand HMG-1 has been shown to regulate cell motility. For example, HMG-1 / RAGE is able to stimulate axonal growth in neuroblastoma cells. Blocking HMG-1 / RAGE binding suppresses tumor growth and metastasis in animal experiments. In addition, RAGE and S-100 concentrations have been shown to increase in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE).

Nikastrin

Nicastrin is a 709 amino acid type I transmembrane glycoprotein that has recently been described as a key component of an AD-related multiprotein complex formed with proteases (presenilin-1 and -2). The formation of this complex is the final step in the formation of the neurotoxic β-amyloid peptide (also known as amyloid), which can be found in brain plaques in patients with familial AD. The amyloid protein is formed from the membrane bound precursor protein β-amyloid (βAPP) in two steps. First, β-APP is cleaved by the protease β-secretase (BACE-2) and then the amyloid protein is released during subsequent γ-secretase processing. It was shown that presenilins-1 and -2 possess protease catalytic activity, which is necessary for the formation of neurotoxic β-amyloid peptide. It is known that nicastrin binds to β-APP and is able to modulate the formation of β-amyloid peptide. This indicates the direct role of nicastrin in the pathogenesis of AD and allows us to consider it as a potential target for therapeutic intervention.

β-amyloid (Ab40, Ab42)

The main protein component of plaques in AD is β-amyloid, a peptide consisting of 40-43 amino acid residues, cleaved from the precursor protein (APP) by β-secretase enzymes and, possibly, γ-secretase.

Increase in the secretion of peptides with a higher molecular weight. (Aβ42 or Aβ43) occurs with certain genetic mutations, with the expression of some ApoE alleles, or with the participation of other, as yet unknown, factors. Not only proteolytic cleavage of APP and the subsequent appearance of Aβ may be important factors in the progression of AD, but aggregation of Aβ may also be critical in the development of this disease, leading to the development of dense plaques that are found in the brains of AD patients. It has been shown that Aβ42 or Aβ43 tend to aggregate to a much greater extent than peptides with a lower molecular weight. It has been shown that an increase in Aβ42 / Aβ43 concentration leads to abnormal accumulation of Aβ and is associated with neurotoxicity in AD brain tissues. For patients with AD, a decrease in the level of Aβ42 in the CSF is a prognostic factor. Determination of Aβ peptide can also be used to identify human Aβ in mice in AD modeling. Identification of various fragments of peptides to study the cellular response to the action of Aβ peptides can help to understand the early events that lead to the death of nerve cells. Aβ peptides can activate various signal transduction pathways. For example, fibrillar Aβ has recently been shown to activate tyrosine kinases Lyn and Syk, thus initiating a signaling cascade that activates proline-rich / calcium-dependent tyrosine kinase Pyk2.

Given that Aβ peptides tend to aggregate, the quality of diagnostic kits can vary from manufacturer to manufacturer, from lot to lot. BioS ource International has developed highly sensitive and highly specific ELISA kits for the quantitative determination of Aβ 1-40 or 42.

Chlamydia pneumoniae

Using the PCR method, independent studies have shown that 89-92% of patients with asthma had a positive reaction to the Ch antigen. pneumoniae (brain). Ch antigen. pneumoniae has been identified in extracellular plaques in the brains of AD patients, in contrast to the brains of patients with other brain lesions leading to dementia.

Ch. pneumoniae infects monocytes, which leads to an increase in their migration across the blood brain barrier. Ch. pneumoniae leads to dysregulation of β-cathepsin, N-cadherin, VE-cadherin and other molecules of intercellular adhesion. When determining antibodies in sera of patients with AD and Parkinson's disease using ELISA, the following results were obtained:

Alzheimer's disease: IgA - 45%, IgG - 36% of positive results;

Parkinson's disease: IgA - 35%, IgG - 83% of positive results.

Alzheimer's disease: the role of oxidative stress

It has been shown that oxidative stress (OS) plays an important role in the pathogenesis of AD. BA develops in presenile or senile age in parallel with an increase in OS. The main signs of AD in patients with advanced stages are neurofibrillary tangles (NFTs) and β-amyloid (senile) plaques in the cerebral cortex. Many studies have shown that in the early stages of AD patients, various signs of OS can be observed - oxidative damage to nucleic acids, proteins, and lipids; the presence of various OS biomarkers has also been shown (Fig). At the moment, numerous studies are underway on new therapeutic approaches to prevent or slow down the development of this disease, based on protection against oxidative stress.

Markers of the functional state of the pineal gland

The pineal gland is part of the central system of neurohumoral regulation of the body. The pineal gland plays a leading role in the transmission of information to all life-supporting systems of the body about the change of day and night, as well as in the organization of seasonal and circadian rhythms and the regulation of reproductive functions. To assess the functional state of the pineal gland, it is currently necessary to determine melatonin and serotonin in the blood and the metabolic products of melatonin (melatonin sulfate) in urine.

Melatonin and melatonin sulfate

Melatonin, or N-acetyl-5-methoxy-tryptamine, is the main hormone of the pineal gland. It is synthesized in the pineal gland from the intermediate metabolite of serotonin - N-acetylserotonin. The level of melatonin in the blood has significant individual fluctuations, the maximum values ​​of melatonin in the blood are observed between midnight and 4 am. The regulation of melatonin secretion is under the control of the sympathetic nervous system, which exerts its regulatory influence through norepinephrine. The half-life of melatonin is 45 minutes. This means that for research purposes, blood samples must be collected at short intervals in order to determine the period in melatonin production. In addition, disrupting a patient's sleep during the night for the purpose of collecting samples can affect blood melatonin levels. These problems can be avoided by measuring the levels of melatonin metabolites: melatonin sulfate (6-sulfate kimelatonin) and 6-hydroxyglucuronide in urine. 80-90% of melatonin is secreted in the urine as sulfate. The concentration of melatonin sulfate in urine correlates well with the total level of melatonin in the blood during the collection period.

Currently, the physiological and pathophysiological role of melatonin is being actively studied. Disturbances in blood melatonin levels correspond to sleep disorders, depression, schizophrenia, hypothalamic amenorrhea, and some types of malignant neoplasms. Premature puberty may be due to the presence of a tumor in the pineal gland. If the tumor develops from enzyme active elements of the parenchyma, then the phenomena of hyperpinealism or dyspinealism prevail. Insufficient secretion of melatonin by the pineal gland leads to increased production of FSH and, consequently, to follicle persistence, polycystic ovary disease, and general hyperestrogenism. Against this background, uterine fibromatosis, dysfunctional uterine bleeding can develop. Pineal gland hyperfunction, on the contrary, induces hypoestrogenism, sexual frigidity. An increase in the level of melatonin in the blood and its excretion in the urine is observed in patients with manic conditions.

Disruption of melatonin production, both quantitatively and its rhythm, is the starting point, leading at the initial stages to desynchronosis, followed by the appearance of organic pathology. Consequently, the very fact of a violation of melatonin production can be the cause of various diseases. The data obtained allow to consider melatonin as one of the most powerful endogenous antioxidants. Moreover, unlike most other intracellular antioxidants, localized mainly in certain cellular structures, the presence of melatonin and, consequently, its antioxidant activity is determined in all cellular structures, including the nucleus.

Serotonin

Serotonin is an intermediate product of tryptophan metabolism, which is formed mainly in enterochromaffin cells of the small intestine, in serotoninergic neurons in the brain, and in blood platelets. Almost all of the serotonin in the circulating blood is concentrated in platelets. Changes in the concentration of circulating serotonin are observed in chronic headache, schizophrenia, hypertension, Huntington's disease, Duchenne muscular dystrophy and early stage of acute appendicitis. Determination of serum serotonin levels is of great clinical importance for the diagnostic evaluation of carcinoid syndrome.

Autoimmune diseases of the nervous system

Polyneuropathies (neuropathies, NP) can be classified by etiology (vascular, allergic, toxic, metabolic, etc.) or by clinical manifestations (sensory, motor, sensorimotor, mononeuropathies, etc.). Weakness and loss of sensation or pain in the extremities are common signs of peripheral neuropathies. Accurate diagnosis of peripheral neuropathies requires a combined analysis of clinical signs, medical history and laboratory tests that can identify, confirm, classify and monitor the disease.

In recent years, many glycoconjugates have been considered as putative targets for various NS. Increasingly, NP is characterized not only by clinical and electrophysiological criteria, but also immunochemically, depending on the type of antigen recognized by antiglycolipid antibodies. Glycoconjugates include both glycoproteins (eg, MAG) and glycolipids (eg, gangliosides, SGPGs, sulfatides, or sulfolipids). They are found in all tissues and are components of the myelin sheath of nerve fibers. Among the wide variety of glycolipids, so far, three have shown important clinical significance in the diagnosis of NP and the choice of treatment (Fig.). A significant correlation was revealed between individual clinical features and types of antibodies to various serum glycoconjugates.

The main targets for autoantibodies in autoimmune peripheral NS are sulfated paraglobozide glucuronate (SGPG) and GM1 ganglioside. The first is a target mainly in demyelinating NPs associated with monoclonal IgM gammopathies. The second is a predominant target in motor NP, mainly in multifocal motor neuropathy. Anti-GQlb IgG antibodies are characteristic of a subgroup of patients with Miller-Fisher syndrome (a variant of Guillain-Barré syndrome). Elucidating the structure of the epitope may also be important in determining the pathological role of antibodies.

In many cases, separate definitions of IgG and IgM classes of autoantibodies are of great importance, since IgG antibodies are more common in acute neuropathies, and IgM antibodies are more common in chronic conditions.

Structure and localization of the three major glycoconjugate antigens on peripheral nerves A. Myelin-associated glycoprotein containing five extracellular Ig-like domains accessible to autoantibodies, a transmembrane domain, and a cytoplasmic tail. B. Sulfated glycolipids and GM1 ganglioside, whose oligosaccharide chains are located close to the lipid bilayer of the myelin membrane.

The diagnostic significance of the determination of autoantibodies to glycolipids in peripheral NP:

They are an important addition to electrodiagnostic methods for identifying various subgroups of autoimmune NS: various neurological symptoms are determined by the profile of antiglycolipid antibodies.

Possibility of accurate differential diagnosis of NP, which are based on immunological disorders (for example, NP in monoclonal gammopathies, multifocal motor NP, or Guillain-Barré syndrome).

Control of NP therapy associated with monoclonal gammopathies.

Conducting scientific research in the field of neuroimmunology.

Antibodies to myelin-associated glycoprotein (anti-MAG)

MAG belongs to cell adhesion molecules and is expressed on oligodendrogliocytes and Schwann cells. It is a mediator of interactions of oligodendrogliocytes with each other and with neurons. When axons are myelinated, it is also found on their outer surfaces and the adjacent surfaces of myelin-forming cells. More than 50% of patients with peripheral NP and IgM monoclonal gammopathy have monoclonal IgM antibodies that bind to MAG.

Determination of anti-MAG antibodies is essential for differentiating IgM-associated NP from other commonly encountered acquired polyneuropathies such as CIDP (Chronic Inflammatory Demyelinating NP). Both disorders can progress slowly and appear on morphological and electrophysiological studies mainly as demyelinating NP (DNP). In addition, in these diseases, the protein concentration in the CSF is increased, and this indicator can be used to judge the effectiveness of the immunosuppressive therapy performed.

Table. Peripheral neuropathies associated with specific autoantibodies

Clinical syndromes / specific antibodies	MAG SGPG	GM1	asialo- GM1	GM2	GD1a	GD1b	GQ1b
Guillain-Barré Syndrome (GBS)		+++ IgG IgG> IgM 20-30%	(+)	+ IgM 6%	+ IgG 5%	+ IgG 2%
GBS options: AMSAN and AMSAN		+++	+		+++	+
GBS with ophthalmoplegia							++ IgG
GBS with ataxic syndrome						++
GBS as a complication of CMV infection				+ IgM			+++ IgG> 90%
Miller-Fisher syndrome
Multifocal motor neuropathy (MMN)		++ IgM 20-80%	(+)			+
Defeat syndrome lower motor neuron		(+) IgM 5%	+
Neuropathy associated with anti-MAG / SGPG IgM monocl nal gammopathy	+++ m-IgM 50%
Motor neuropathy IgM-associated monoclonal gammopathy		+++ m-IgM 10%				+++
Sensory ataxic neuropathy and CANOMAD syndrome						+++ m-IgM	+++ m-IgM
Chronic inflammatory demyelinating polyneuropathy (CIDP)	++ m-IgM	+

Symbols:

Determination of the level of titer of antibodies to glycolipids: (+) - weakly positive, + - moderately positive, ++ - positive, +++ - highly positive;

. [%] - the percentage of patients in whom autoantibodies to glycolipids are detected.

. The blue color of the cell indicates the IgG class or the predominance of IgG antiglycolipid antibodies; orange color belongs to the IgM class.

Use case 1: antibodies to GM1 in GBS are often detected, in high titers, while the IgG isotype predominates. GM1 IgG is detected in 20-30% of patients.

Use case 2: Monoclonal antibodies IgM to GD1b are usually present in high titers in sensory ataxic neuropathy and CANOMAD syndrome.

Antibodies to sulfated paraglobozide glucuronate (SGPG)

The oligosaccharide sequence SGPG with glucuronyl sulfate (i.e. the HNK-1 epitope) is common to sulfated glucuronate paraglobozide and its derivatives and proteins, mainly myelin-associated proteins, myelin oligodendrocyte glycoprotein (MOG) in the CNS and peripheral myelin PMR protein22 PNS, isoforms of acetylcholinesterase, and subgroups of several adhesion molecules such as the nerve cell adhesion molecule (NCAM). There is an opinion that, regardless of the specificity of the protein, IgM anti-SGPG is almost always detected in biological samples in DNP and in some diseases of motor neurons. It has been shown that with typical sensory DNP, both anti-MAG and anti-SGPG antibodies are detected, while with axonal NP, only monoclonal IgM-anti-SGPG antibodies are present. In patients, there is a relationship between the titer of antibodies to the HNK-1 epitope and the degree of demyelination.

Antibodies to gangliosides (GanglioCombi)

The GanglioCombi kit is intended for the screening of autoantibodies in human serum against the gangliosides asialo-GM1, -GM2, -GD1a, -GD1b and -GQ1b. Gangliosides form a family of sialylated acidic glycolipids, consisting of carbohydrate and lipid components. They are mainly found on the outer surface of the plasma membrane. The external arrangement of carbohydrate residues suggests that they serve as antigenic targets in autoimmune neurological disorders. Antibodies that bind to carbohydrate antigens have been found in various peripheral NS. Significant heterogeneity of ganglioside expression in PNS tissues is observed. GM1 and GD1 are mainly present on motor nerves, GQ1b are found in increased amounts in the motor cranial nerves of the muscles of the eyeball. High expression of GD1b is observed in sensory nerves. A clear correlation has been shown between the content of specific anti-ganglioside antibodies and various variants of Guillain-Barré syndrome (GBS). Patients with elevated levels of antiganglioside antibodies have a good therapeutic prognosis.

Antibodies to ganglioside M1 (anti-GM1 autoantibodies)

Multifocal motor neuropathy (MMN) is characterized by blockade of impulse conduction along the axons of lower motor neurons. Clinically, it is difficult to differentiate between MMN and amyotrophic lateral sclerosis (ALS). Since MMN, unlike ALS, is a curable disease, it is extremely important to differentiate these diseases at an early stage. While high titers of anti-GM1 antibodies are virtually undetectable in ALS patients, over 80% of MMN patients have these antibodies. For MMN, simultaneous determination of IgG and IgM isotypes of anti-GM1 antibodies is recommended. Anti-GM1 antibodies are found in approximately 5% of healthy people, especially the elderly, and their production may be a manifestation of normal immune system activity. Determination of anti-GM1 antibodies is used to monitor the dynamics of seroconversion and the effectiveness of MMN therapy to prevent possible recurrence of the disease, as well as to confirm the diagnosis in all cases of polyneuropathies of unknown origin. It is recommended to perform this test in all patients with motor impairments, and especially with motor NP, Guillain-Barré syndrome (GBS), and diseases of the proximal lower motor neurons.

Antibodies to ganglioside GD1b (anti-GD1b autoantibodies)

The analysis of anti-GD1b autoantibodies can be useful for the clinical assessment of patients with Guillain-Barré syndrome (GBS) without ophthalmoplegia (see also anti-Q1b), with sensory NP, in particular, with chronic sensory NP of large fibers (large nerve trunks) with ataxia. Anti-GM1 antibodies are found in approximately 5% of healthy people, especially the elderly. Determination of anti-GD1b autoantibodies may be useful: to screen patients with signs of inflammatory DNP but negative for anti-GM1 autoantibodies; to monitor the effectiveness of therapy for acute and chronic inflammatory DNP; as an addition to the diagnosis of NP of unknown origin. It is recommended that this test be performed in all patients with motor impairment, and especially with motor NP.

Antibodies to ganglioside GQ1b (anti-GQ1b autoantibodies)

Miller-Fischer syndrome (MFS) is highly associated with the presence of polyclonal serum IgG antibodies to the GQ1b antigen, which can be found in the serum of more than 90% of patients with acute MFS. During the acute stage of the disease, antibody titers reach very high levels and completely disappear upon recovery. In healthy blood donors, patients with Guillain-Barré syndrome (GBS) without ophthalmoplegia, and in patients with other immunological or neurological diseases, anti-GQIb autoantibodies are not detected. MFS is a variant of GBS with which they have overlapping clinical and neurophysiological features. The similarity between MFS and GBS has recently been confirmed by the presence of anti-GQ1b in ophthalmoplegic GBS patients. In some cases, MFS can also detect IgA and IgM autoantibodies, but to a lesser extent and only for a short period of time. Most patients with MFS or GBS with ophthalmoplegia and anti-GQ1b autoantibodies have a history of Campylobacter jejuni infection. This fact supports the hypothesis of molecular similarity between the surface epitopes of C. jejuni and GQ1B, and that MFS is initiated by antecedent C. jejuni infection.

Antibodies to interferon β (anti-IFNβ antibodies)

In recent years, recombinant interferon beta (rIFNβ) therapy has been used to treat relapsing-remitting multiple sclerosis (RRMS). Continuous long-term (from a month to several years) administration of any exogenous substance can provoke an immune response. Many RRMS patients treated with IFNβ develop anti-IFNβ antibodies that decrease the drug's therapeutic effect. It has been shown that in patients with multiple sclerosis, only a small part of anti-IFNβ antibodies are able to neutralize the immunomodulatory effect of IFNβ. Determination of these antibodies is also shown in sensory NP, in Guillain-Barré syndrome (GBS).

Antibodies to sphingomyelin (SM)

CM (sphingomyelin) is a phospholipid containing sphingosine, fatty acid, phosphoric acid and choline. CM is a natural component of membranes and lipoprotein particles. Large amounts of SM are present in the brain and nervous tissue. Suppression of CM biosynthesis in laboratory mice reduces plasma concentrations of cholesterol (CS) by 46%, and triglycerides by 44%, compared with the control group. In addition, the content of cholesterol in the particles of LDL and very low density lipoproteins (VLDL) decreases and the concentration of cholesterol in high density lipoproteins (HDL) increases. Studies on laboratory animals have shown that suppression of CM synthesis also leads to a significant decrease in the severity of atherosclerotic lesions and macrophage infiltration. It is likely that the suppression of sphingolipid synthesis is a promising direction in the treatment of dyslipidemia and atherosclerosis. Antibodies to sphingolipids are involved in the pathogenesis of autoimmune demyelination and are found in multiple sclerosis and autoimmune encephalomyelitis.

Antibodies to laminin β

Laminin is the main glycoprotein of the basement membranes, the extracellular matrix that surrounds epithelial tissues, nerves, fat cells, smooth, striated and cardiac muscles. This multifunctional, high molecular weight, multi-domain glycoprotein consists of 3 polypeptides - A, B1 and B2, linked together by interchain disulfide bridges. Laminin promotes cell adhesion, growth, migration and proliferation, neurite growth, tumor metastasis, and possibly cell differentiation. Recombinant human antibodies to laminin are known to block the development of vascular endothelium.

Anticochlear antibodies (anti-68 kD, hsp-70)

Hearing loss can be caused by many reasons. Some types of hearing loss can be reversible if diagnosed and treated promptly. Sensorineural hearing loss (SNHL), commonly referred to as nerve-related deafness, may be due to genetic or acquired factors such as infection, or may be due to immunological causes. In most cases, the cause of SNHL cannot be determined. Such cases are referred to as idiopathic SNHL. There is a subgroup of idiopathic SNHL patients with very good immunosuppressive therapy results. Laboratory tests to identify these patients should include the determination of serum antibodies to the 68 kDa (hsp-70) inner ear antigen. 22% of patients with bilateral rapidly progressive SNHL and 30% of patients with Meniere's disease have antibodies to this antigen. Anti-68 kDa (hsp-70) antibodies are also found in approximately 60% of patients with bilateral and 35% of patients with unilateral Meniere's syndrome. In the group of patients who develop unexplained progressive deafness, there is an approximately 30 percent chance that hearing loss is of an immune etiology. Recent studies in a large group of 279 patients with idiopathic bilateral SNHL identified 90 (32%) positive cases of anti-68 kDa (hsp-70) antibodies (among them 63% were women).

Antibodies to the 68 kDa antigen have been identified in patients whose hearing improved with immunosuppressive therapy. It has been shown that 89% of patients with progressive bilateral SNHL in the active phase have antibodies to the 68 kDa antigen, while in patients with inactive disease the results were always negative. Among patients who tested positive, 75% responded to steroid therapy, compared with 18% of patients who tested negative for 68 kDa antigen.

Frequency of Anti-68 kDa (hsp-70) Antibodies in Idiopathic Bilateral SNHL (IPBSNHL)

Disease	the patients	% positive
IPBSNHL	72	58
Otosclerosis	11	0
Kogan syndrome	8	0
Healthy people	53	2

Moscicki RA et al. JAMA 272: 611-616, 1994

Correlation of anti-68kD (hsp-70) antibodies with disease activity

In retrospective studies, testing for antibodies to the hsp-70 antigen has been shown to be the best predictor of response to corticosteroid therapy.

Anti-neuronal autoantibodies

Autoimmune diseases of the central nervous system are considered as paraneoplastic neurological diseases resulting from the antitumor response of the immune system. These diseases include paraneoplastic encephalomyelitis (PE), sensory neuropathy (PSN), progressive cerebellar degeneration (PCD), paraneoplastic myoclonus and ataxia (POMA), and Stiffmann's syndrome.

Clinical manifestations include loss of memory, sensation, brain stem dysfunction, cerebellar, motor, or autonomic dysfunction (PE or PSN); involuntary jerky movements of the eye, myoclonus and ataxia (POMA). Diagnosing these conditions reliably is a difficult task. In most cases, unfortunately, the tumor that is the cause of the development of the paraneoplastic syndrome is not detected by the time the patient has neurological symptoms. Paraneoplastic disorders are characterized by the presence of neuronal autoantibodies in the serum of patients. The detection of such antibodies is useful for the clinician because confirms the presence of an underlying tumor. Paraneoplastic neurological diseases can develop in small cell lung cancer, neuroblastoma, breast cancer, ovarian cancer, and testicular cancer. With paraneoplastic syndrome, the following autoantibodies are detected:

1. anti-Hu - anti-neuronal nuclear antibodies (ANNA-1), associated with small cell lung cancer, lead to the development of PE.

2. anti-Yo - antibodies to Purkinje cells (PCA-1), associated with ovarian cancer or breast cancer, lead to the development of PCD.

3. anti-Ri - antibodies to the neuron nucleus of type II (ANNA-2), associated with neuroblastoma (children) and cancer of the fallopian tube or breast (adults), leads to the development of POMA.

The presence of such antibodies confirms the clinical diagnosis of paraneoplastic syndrome and leads to a targeted search for the underlying tumor.

These markers help to differentiate between true paraneoplastic syndrome and other inflammatory diseases of the nervous system similar to paraneoplastic syndrome.

Western immunoblotting is a sensitive technique that allows simultaneous screening and confirmatory testing to detect autoantibodies against various neuronal antigens present in the nucleus or in the cytoplasm of cells. Anti-Hu and anti-Ri reactions can be easily observed in the 35-40 kDa and 55 kDa regions, respectively.

Antibodies to ribosomal proteins P and RNA

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of various circulating autoantibodies. Psychiatric disorders are common in patients with SLE, and the range is very wide. CNS-related manifestations occur in a large number of SLE patients and cause behavioral abnormalities reminiscent of schizophrenia. Circulating autoantibodies to ribosomal P proteins are found in approximately 90% of SLE patients with mental disorders. This is a group of autoantibodies directed to ribosomal phosphoproteins P0 (38 kDa), P1 (19 kDa), and P2 (17 kDa). An increase in autoantibodies to ribosomal P proteins may precede the onset of a psychotic episode. In addition, in such patients, with a frequency of 17 to 80% (according to various literature data), autoantibodies to RNA directed against 28S rRNA are also detected. Anti-ribosomal P autoantibodies usually coexist with anti-RNA autoantibodies. A correlation has been shown between anti-RNA antibodies and disease activity. Thus, both anti-ribosomal P and anti-RNA autoantibodies contribute to the pathogenesis of CNS disorders in SLE.