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NOTE ON THE BIOCHEMISTRY OF THE NERVOUS SYSTEM (based on the book “Functional biochemistry of nervous tissue” by Zhukov V.I. et al., Kharkov, 2012 (in Ukrainian language) The nervous system is a complex, heterogeneous and thus a unique biological system due to its structural, morphological and functional organization. In the course of evolution, the nervous system got involved in the mechanisms of regulation, coordination and integration of a living organism. The nature of the nervous system determines the characteristics of its chemical composition, metabolism and function. The functions of the nervous system include generation of electrical signals of nerve impulses, maintenance of vital processes, memory and intellectual activity, emotions, behavior etc. One of the important functions of the nervous system is its regulatory and integrative role with respect to the biochemical processes occurring in the whole human body, which are significantly determined by the specific features of metabolism in the nervous tissue, complex communication and compensatory mechanisms. Neurochemistry is a biological science that deals with the molecular basis of the functioning of nervous system. Biochemical background of excitation and inhibition mechanisms, the molecular basis of synaptic signaling and chemical composition of nervous tissue related to the functions performed are important issues of neurochemistry as well as violations of biochemical proceses in the nervous system in certain diseases. However, a number of fundamental problems of neurochemistry and the mechanisms of thinking, memory, emotions, learning, consciousness still remains significantly unsolved.

Peculiarities of biochemical composition and metabolism of nervous tissue. Chemical composition of brain. The basic structural and functional unit of the nervous system is the neuron. There are several types of neurons that differ in size (10,000 - 100,000 nm3). Neurons do not work alone, but form complex neuronal systems. Neurons are located mainly in the gray matter of the brain. Along with neurons in the nervous tissue, an important role belongs to different neuroglial cells - astrocytes, oligodendrocytes and microglia. The close morphological, functional and metabolic interrelationship of neurons and glial cells provides functional activity of the nervous tissue. The system of interneuronal communication involves synapses that provide transmission and modulation of chemical and electrical processes from presynaptic to postsynaptic membrane. One neuron can form from a few dozen to several thousand synapses.

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Fig. 1. The structure of a neuron. Source: http://users.tamuk.edu/ Human brain consists of proteins (8% of total weight), abundant amount of lipids (10-12%), carbohydrates (1%) and other low-weight biomolecules, inorganic salts and water (77-78%). The gray and white brain matter significantly differ in chemical composition. In the gray matter of the brain, which is a cluster of neurons, the water content is 84%, and the dry residue makes 16%. One half of the dry residue is composed of proteins and one third belongs to lipids. Chemical composition of the brain is very different compared to the other tissues of human body due to the presence of the blood-brain barrier, which has a selective permeability for different metabolites. Table 1. Chemical composition of white and gray matter. Content, % Water Dry residue Proteins Lipids Mineral compounds

Gray matter 84 16 8 5 1

White matter 70 30 9 17 3

Neurospecific proteins and lipids. The plasma of neurons, and axons contains protein-lipid complexes, but the main part of them is involved in the construction of complex membranes (myelin) that cover dendrites, axons and nerve fibers (trunks). Many of the brain proteins contain phosphorus. A characteristic feature of the brain neurons is the presence of significant amount of ribonucleic acids. Lipids are the most typical and very di verse components of the brain tissue. Lipids are part of the structural formations inside brain cells. Brain lipids are divided into four groups: 1) Phospholipids 2) Sterols

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3) Glycolipids 4) Sulphatides Phospholipids (choline phosphatides, ethanolamine phosphatides, serine phosphatides, inosyl phosphatides etc) make about a half of brain lipids. Another (due to the quantitative content) group of brain lipids includes sterols, which mainly are composed of free cholesterol. A peculiar group of brain lipids includes glycolipids, cerebrosides (cerebron, cerasine etc.). It should be noted that triglycerides and polyunsaturated fatty acids do not prevail among brain lipids. In different areas of gray matter lipids vary in composition and structure. Many of brain lipids are linked to a complex of proteins. The grey matter contains 24.6% phospholipids, 18.6% phosphoglycerides, 1.8% sphingolipids, 4.2 % glycolipids (cerebrosides), 5.1% cholestherol. The white matter contains 42.5% phospholipids, 22.8% of phosphoglycerides, 3.7% sphingolipids, 16.0 % glycolipids (cerebrosides), 13.8%. cholestherol. Human brain contains a high level of conjugated polar lipids – glycerophospholipids, sphingolipids, glycolipids) and cholesterol, whereas triacylglycerols level is low. The content of proteins in white matter is higher than in the gray matter, this is explained by the high number of myelin membranes of nerves in it. About 30 thousand genes encoding various proteins are expressed in brain that occur only in the central nervous system. Neuroproteins mainly include neuroalbumins, neuroglobulins, neuroscleroproteins. Nervous tissue proteins perform mediator functions. The white matter of the brain includes specific proteins - neuroceratine. Brain proteins contain about 26% glutamic acid. Table 2. Composition of the myelin, white and grey matter of human brain Proteins (% of dry 30,0 39,0 55,3 residue) Lipids (% of dry residue) 70,0 54,9 32,7 Percentage from total lipids fraction Cholesterol Cerebrosides

27,7 22,7

27,5 19,8

22,0 5,4

Sulphatides

3,8

5,4

1.7

Total galactolipids

27,5

26,4

7,3

Phospholipids Phosphatidylcholine

43,1 11,2

45,9 12,8

69,5 26,7

Phosphatidylethanolamine 15,6

14,7

22,7

Phosphatidylserine Plasmalogens

4,8 12,3

7,9 11.2

8,7 8,8

Sphingomyelin

7.9

7,7

6,9

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Various enzymes were found in brain, including amylase, maltase, sucrase, lipase, lecithinase, cholinesterase, proteases, ribonuclease, etc, redox enzymes (peroxidase, catalase, cytochromes), enzymes of glycolysis and others. The content of glycogen (free and bound) in brain tissue is small - 70-150 mg%, glucose makes about 100 mg%. Macroelements were also detected in brain: phosphorus (mostly in the form of phosphate part of organic matter) - 360 mg%, sodium – 312 mg%, potassium – 530 mg%, chlorine – 171 mg%, calcium - 15 mg%. The high content of potassium is characteristic for nervous tissue. The trace elements, which occur in brain include copper, zinc, manganese, iodine. The presence of molybdenum is typical for the gray matter. Peculiarities of aminoacid composition of brain tissue The concentration of amino acids in the brain is nearly 8-fold higher than in plasma and liver. The particularly high levels of glutamate and aspartate are detected in the nervous tissue. These amino acids are formed in the reaction of transamination of intermediate metabolites of citric acid cycle - α-ketoglutarate and oxoloacetate. In the brain, metabolic conversion of amino acids - oxidative deamination, transamination, radical conversion go very quickly. Particularly important for the normal functioning of the brain is glutamate decarboxylation reaction, which produces γaminobutyric acid (GABA). GABA shunt is characteristic for cells of the central nervous system, but does not play a significant role in other tissues. Some amino acids such as glycine, aspartate, glutamate, GABA, taurine act as neurotransmitters. They are stored in the synapses and out when nerve impulses are received. Table 3. Content of free amino acids in human brain, plasma and liqor, µmol/g of tissue (ml) Amino acids Brain Blood plasma Liqor Glutamate 10,6 0,05 0,225 N-Acetylasparaginate 5,7 75% 23% Glutamine 4,3 0,70 0,030 60% GABA 2,3 Asparaginic acid 2,2 0,01 0,007 Cysthathion 1,9 Taurine 1,9 0,10 Glycine 1,3 0,40 0,013 Alanine 0,9 0,40 0,017 Glutathion 0,7 0,10 0,010 Serine 0,7 0,10 0,010 Treonine 0,2 0,15 0,025 Tryptophan 0,05 0,5 0,010 Valine 0,2 0,25 0,013 25% 77% Lysine 0,1 0,12 0,014 40% Leucine 0,1 0,15 0,004 Proline 0,1 0,10 -

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Asparagine Methionine Isoleucine Arginine Cystein Phenylalanine Tyrosine Histidine

0,1 0,1 0,1 0,1 0,1 0,1 0,1 0,1

0,07 0,02 0,10 0,10 0,10 0,10 0,10 0,10

0,003 0,080 0,060 0,002 0,010 0,006 0,003

Violations of , enzymatic system of the metabolism and transport of amino acids cause severe neurological consequences. Role of glutamic acid system in brain. Glutamate and glutamine together comprise from 8 to 10% of the total amino acid residues in the protein hydrolyzate of the brain. Glutamate is also a part of a number of small and medium-regulatory brain peptides. Some neuropeptides contain cyclic derivative of glutamate – pyroglutamate, luliberin, thyroliberin, neurotensin, bombesin and others. The main source of neurotransmitter glutamate fund is glutamine, which is synthesized mainly in astrocytes, where glutamine synthetase is localized. Hence, functions of glutamate in nervous tissue may be summarized as follows: 1.Energetic (glutamic acid supports the normal level of metabolites of the citric acid cycle); 2.Participation in the reactions of deamination of the other amino acids and temporary neutralization of ammonia; 3.Production of neurotransmitter GABA (from glutamate); 4.Synthesis of glutathione - one of the components of the antioxidant system of the body. Energetic metabolism in human brain tissue. The brain making about 2% of body weight, consumes about 20% of all absorbed oxygen and 60% of glucose, which is completely oxidised to CO 2 and H2O in the citric acid cycle and glycolysis. No other tissue absorbs blood glucose at a such high rate and in such amount as the brain, and no other tissue has so urgent need for th e substrate oxidation to maintain normal functional state. Stocks of glucose in the brain are very small compared with the high speed of oxidation, it requires constant inflow of blood.

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Fig.2. Glycogen stores in the brain cells are insignificant. Fatty acids which are transported in the blood plasma in a complex with albumin, do not reach the brain cells because of the blood-brain barrier. Amino acids can not serve as a source of energy for ATP synthesis in brain, since neurons do not perform gluconeogenesis. Dependence of brain on glucose means that an accute decrease of the blood glucose level, for example, in the case of an overdose of insulin in diabetic patients is life-threatening. Although brain can oxidize ketone bodies, which are considered as an alternative source of energy for the central nervous system.

Fig.3 Source: http://www.nature.com/

In the cells of the central nervous system the most energy-intensive process, consuming up to 40% of produced ATP is the functioning of the transporting Na + / K + -

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ATP-ase (Na + / K + - «pump") in the cell membranes. In addition, ATP is used in many biosynthetic reactions.

Fig. 4. Relationship of astrocytes to oxygen and energy metabolism in the brain. Glucose taken up by astrocytes undergoes glycolysis for generation of ATP to meet astrocytic energy requirements (for glutamate reuptake, predominantly). The lactate that this process generates is shuttled to neurons, which utilize it aerobically in the citric acid cycle. Source: http://what-when-how.com/

Fig.5 Changes of brain metabolism under conditions of physiological sleep and narcosis. Brain metabolism in a state of wakefulness and sleep differ. It was shown that during sleep an increase of the concentration of lactic acid occurs, indicating the activation of anaerobic processes and reducing the intensity of the Krebs cycle. In addition to glucose, brain more actively consumes blood ketone bodies during sleep. Interestingly, oxygen consumption of brain tissue depends on the stage of sleep. In the phase of slow wave sleep

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oxygen consumption is reduced for 30% compared to the daily value, whereas in a phase of rapid wave sleep oxygen consumption by brain tissue increases for 12%. Intensity of lipid peroxidation decreases during sleep as well as ammonia level diminishes, whereas synthetic processes and metabolism of nucleic acids, proteins and polypeptides are activated. Release of serotonin is known to inhibit the active structures of brain, responsible for waking, ie induce sleep. Sleep is characterized by the intensive biosynthesis of acetylcholine. In a state of anesthesia inhibition of oxygen consumption is observed, ATP and creatine phosphate content get increased and levels of inorganic phosphate decreases. Neurotransmitters (acetylcholine, norepinephrine, dopamine, serotonin, excitatory and inhibitory amino acids). Development of concepts of chemical mediation of nerve impulses began in the early XX century as a result of research O. Levy, J. Elliott, G. Dale, who showed that the signal transmission is mediated by a release of acetylcholine or norepinephrine from the nerve endings. Today, mediator compounds are divided into two groups: neurotransmitters, which transmit signals in the synapses and neuromodulators, that regulate the signals. More than one neuropeptide can be synthesized in a neuron, each capable of releasing several mediators in the presynaptic ending, the combination of which may not be the same for different synapses of the same neuron.

Acetylcholine is widely represented in different parts of the nervous system. Synthesis and cleavage of acetylcholine occurs in cholinergic structures of the central and peripheral nervous system. It is mainly focused in peripheral neuromuscular synapses. The receptors, responding to acetylcholine in pregangliar synapses of sympatic and parasympatic nervous system are classified as nicotinic (n-cholinergic) receptors, being stimulated by nicotine. In postgangliar neural endings and in some parts of the central nervous system, the effect of acetylcholine is realized through another type cholinergic receptors - muscarinic (m-cholinergic receptors), being stimulated by muscarine - fungal toxin. Damage of cholinergic innervation in brain structures results in violation of complex mobile functions. For example, in parkinsonism, along with violations of dopaminergic transmission hyperactivity of some cholinergic systems in the brain is observed. Violation of cholinergic transmission in the peripheral nervous system is associated with symptoms of "fatigue" and "weak" muscles. It is believed that the basis of serious illness - myasthenia gravis (miastenia gravis) is an autoimmune process in which antibodies block the function of cholinergic receptors. Monoamines. This group includes neurotransmitters catecholamines, serotonin and histamine. The group of catecholamines includes norepinephrine, epinephrine, dopamine.

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The precursor of catecholamines is L-tyrosine, which the body gets from food. L-tyrosine may also be synthesized in the liver from the amino acid phenylalanine. Catecholamines are deposited in large synaptic vesicles (40-140nm). Cleavage of catecholamines involves monoamine oxidase and catechol-O-methyltransferase. Norepinephrine

Norpenephric neurons in the central nervous system, are located in the trunk of the brain, especially in the bridge of the brain (lateral reticular formation of the pons), the medulla oblongata and the nucleus of the solitary tract. Epinephrine and norepinephrine are synthesized by the medullar part of adrenal glands. In some parts of the central nervous system norepinephrine is predominantly inhibitory neuromediator, for example, in the cerebral cortex. In the hypothalamus norepinephrine serves as a excitatory neurotransmitter. It is believed that monoamine neurotransmitters are related to the manifestation of emotions, mood regulation. Violation of the turnover of monoamines is associated with the emergence of psycho-emotional disorders (schizophrenia, manic-depression).

Epinephrine: Compared to norepinephrine, the number of adrenergic ways is more limited. The neurons containing phenilethanolamin-N-methyltransferase (an enzyme that performs synthesis of epinephrine) are located in the lower bridge and the medulla oblongata. Neurotransmitter role of epinephrine is questionable. Norepinephrine is obviously a neurotransmitter of adrenergic neurons.

Dopamine: Dopaminergic neurons are located in the midbrain (substantia nigra, ventral lid), olfactory bulb, paraventricular hypothalamus and medulla oblongata region. Dopamine has properties of a mediator, it is involved in the regulation of behavior, the cardiovascular system, intestines and kidneys. The important role of dopamine in neurotransmitter system belongs to the regulation of complex mobile functions. Violation of dopaminergic tract leads to woodiness, particularly stereotyped movements, symptoms of Parkinson's disease. Hyperfunction of dopaminergic system is closely related to the mechanisms of schizophrenia. Serotonine (5-hydroxytryptamin, 5- HT):

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The predecessor of biogenic amine 5-hydroxytryptamin is an essential amino acid Ltryptophan. Serotonin plays an important role in the regulation of emotional behavior, moving activity, thermoregulation and participates in the control of the neuroendocrine system. Serotonin functions not only as neurotransmitter and neuromodulator but also as neurohormone). All the drugs used to treat clinical depression increase the content of these neurotransmitters (dopamine, norepinephrine and serotonin ) in the brain and potentiate their effects. Some amino acids are supposed to be very prevalent neurotransmitters in the brain tissue. They are divided into two groups: the excitatory amino acids (glutamate, aspartate) and inhibitory (GABA, glycine, taurine). Excitatory amino acids are one of a group of amino acids that affects the central nervous system by acting as neurotransmitters and in some cases as neurotoxins. Examples include L-glutamate and L-aspartate, which cause depolarization but may also trigger the death of neurons. Some excitatory amino acids are produced by plants and fungi and may be responsible for hypoxic or hypoglycemic brain damage. L-glutamic acid is the main excitatory neurotransmitter. Glutamate is found in all parts of the central nervous system, it is clear that it is not only a neurotransmitter, but also a precursor for the synthesis of other amino acids. Glutamatergic synapses exist in myndal, striatum, the cells of the cerebellum. In the spinal cord glutamate is concentrated in primary afferent fibers of dorsal roots. Glutamatergic synapses are distributed in the cerebral cortex, hippocampus, striatum and hypothalamus. Violation of glutamatergic mediation occurs in a number of pathological conditions of the nervous system: epilepsy, disorders of the vestibular system, hypoxia and others. Aspartic acid:

The highest content of aspartate is found in the midbrain. In the spinal cord, aspartate is contained in the dorsal and ventral gray matter. It is involved in excitation of interneurons that regulate various spinal reflexes. Inhibitory amino acids include GABA, glycine, thaurine, beta-alanine. γ-aminobutyric acid (GABA) is an inhibitory neurotransmitter:

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In the cerebral cortex GABA appears in about 5% of nerve endings. It is located in the neurons of the striatum that give a projection on a black ...