CNS FOR physiology of nervous system PH.pptx

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1. Biochemistry of NS System Neuro -transmitters and Energy sources for the nervous system . By; B ereket Mihretu Msc,Bsc 2/20/2025 1

2. Biochemistry of Neurotransmitters . The nervous system is the part of an animal that coordinates its actions by transmitting signals to and from different parts of its body. The nervous system detects environmental changes that impact the body, then works in tandem with the endocrine system to respond to such events. In vertebrates it consists of two main parts, the central nervous system (CNS) and the peripheral nervous system (PNS). 2/20/2025 2

3. Con’d ... The CNS consists of the brain and spinal cord . The PNS consists mainly of nerves , which are enclosed bundles of the long fibers or axons , that connect the CNS to every other part of the body . Nerves that transmit signals from the brain are called motor or efferent nerves, while those nerves that transmit information from the body to the CNS are called sensory or afferent . 2/20/2025 3

4. Cont’d The PNS is divided into three separate subsystems, the somatic autonomic , and enteric nervous systems . Somatic nerves mediate voluntary movement . II)The autonomic nervous system is further subdivided into the sympathetic and the parasympathetic nervous systems. The sympathetic nervous system is activated in cases of emergencies to mobilize energy, while the parasympathetic nervous system is activated when organisms are in a relaxed state . 2/20/2025 4

5. III) The enteric nervous system functions to control the gastrointestinal system. Both autonomic and enteric nervous systems function involuntarily . Nerves that exit from the cranium are called cranial nerves while those exiting from the spinal cord are called spinal nerves . 2/20/2025 5

6. Nervous System CNS PNS Spinal Cord White mater (myelin Sheath) Gray mater (Interneurons + cell bodies) Brain Myelencephalon: Medulla Oblongata Metencephalon Pons Cerebellum Mesencephalon: Mid-brain Diencephalon Thalamus Hypothalamus Telencephalon Basal ganglia Cerebral Cortex Frontal Parietal Temporal Occipital Autonomic ganglia Dorsal root ganglia Peripheral nerves Cranial nerves = 12 pairs Spinal nerves Cervical = 8x2 Thoracic = 12x2 Lumbar = 5x2 Sacral = 5x2 Coccygeal = 1x1 2/20/2025 6

7. At the cellular level, the nervous system is defined by the presence of a special type of cell, called the neuron , also known as a " nerve cell". Neurons have special structures that allow them to send signals rapidly and precisely to other cells. They send these signals in the form of electrochemical waves traveling along thin fibers called axons , which cause chemicals called neurotransmitters to be released at junctions called synapses . 2/20/2025 7

8. A cell that receives a synaptic signal from a neuron may be excited, inhibited, or otherwise modulated . The connections between neurons can form neural pathways , neural circuits , and larger networks that generate an organism's perception of the world and determine its behavior. 2/20/2025 8

9. As a nerve impulse, or action potential , reaches the end of a presynaptic axon, molecules of neurotransmitter are released into the synaptic space. The neurotransmitters are a diverse group of chemical compounds ranging from simple amines such as dopamine amino acids such as g- aminobutyrate (GABA) polypeptides such as the enkephalins . The mechanisms by which they elicit responses in both presynaptic and postsynaptic neurons are as diverse as the mechanisms employed by growth factor and cytokine receptors. 2/20/2025 9

10. Neurotransmitter Receptors Once the molecules of neurotransmitter are released from a cell as the result of the firing of an action potential, they bind to specific receptors on the surface of the postsynaptic cell. In all cases in which these receptors have been cloned and characterized in detail it has been shown that there are numerous subtypes of receptor for any given neurotransmitter. As well as being present on the surfaces of postsynaptic neurons , neurotransmitter receptors are found on presynaptic neurons . In general, presynaptic neuron receptors act to inhibit further release of neurotransmitter. 2/20/2025 10

11. The vast majority of neurotransmitter receptors belong to a class of proteins known as the serpentine receptors . This class exhibits a characteristic transmembrane structure: that is, it spans the cell membrane, not once but seven times 2/20/2025 11

12. The link between neurotransmitters and intracellular signaling is carried out by association either with G-proteins (small GTP-binding and hydrolyzing proteins) or with protein kinases , by the receptor itself in the form of a ligand -gated ion channel (for example, the acetylcholine receptor). One additional characteristic of neurotransmitter receptors is that they are subject to ligand-induced desensitization : That is, they can become unresponsive upon prolonged exposure to their neurotransmitter. 2/20/2025 12

13. Table of Neurotransmitters 2/20/2025 13

14. Functionally not all neurotransmitters are uniform in nature; Among neurotransmitters, dopamine, serotonin, nor-adrenalin, and acetylcholine contribute profoundly to the psycho- behavioural events in humans. However, the significant role of several other proteins and peptides such as neurotrophic factors growth factors and endogenous chemical compounds are also recognized in this regard. Each of these entities plays selective roles in the maintenance of proper brain function, such as, the feedback mechanisms of the synthesis of particular neurotransmitters 2/20/2025 14

15. C atecholamines The principal catecholamines are norepinephrine , epinephrine and dopamine. These compounds are formed from phenylalanine and tyrosine. Tyrosine is produced in the liver from phenylalanine through the action of phenylalanine hydroxylase . 2/20/2025 15

16. C atecholamines The tyrosine is then transported to catecholamine-secreting neurons where a series of reactions convert it to dopamine, to norepinephrine and finally to epinephrine . Catecholamines exhibit peripheral nervous system excitatory and inhibitory effects as well as actions in the CNS such as respiratory stimulation and an increase in psychomotor activity 2/20/2025 16

17. Synthesis of the C atecholamines from T yrosine T yrosine hydroxylase requires tetrahydrobiopterin as cofactor . The hydroxylation reaction generates DOPA . (3,4-dihydrophenylalanine) DOPA decarboxylase converts DOPA to dopamine . D opamine b- hydroxylase converts dopamine to norepinephrine . P henylethanolamine N- methyltransferase converts norepinephrine to epinephrine . Take over : http://themedicalbiochemistrypage.org/amino-acid-metabolism.html 2/20/2025 17

18. Dopamine Among the major neurotransmitters, dopamine is known to control most of the psychological events in human Is the molecule of happiness’, responsible for movement,memory , cognition, attention, pleasure, reward,motivation , sleep regulation, creativity, and personality determination. 2/20/2025 18

19. Chronic decrease in dopamine levels is an indicator of the neurodegenerative pathology of Parkinson’s disease (PD) . Besides neurodegeneration, scarcity of dopamine is also associated with depression and mood swings 2/20/2025 19

20. Norepinephrine Norepinephrine ( noradrenaline ) has a dual role of a hormone and a neurotransmitter. This particular molecule is effective for ‘ fight-or-flight situation’ and controls stressful events through regulating the central nervous system . Norepinephrine is associated with the occurrence of Attention deficit hyperactivity disorder (ADHD ) Depression and low blood pressure. The role of norepinephrine and serotonin was found to be crucial in depression. Medication related to serotonin- norepinephrine reuptake inhibitors is a well-known treatment for chronic depression. 2/20/2025 20

21. Functions of norepinephrine and epinephrine Outside the nervous system, norepinephrine, and its methylated derivative, epinephrine act as regulators of carbohydrate and lipid metabolism. Norepinephrine and epinephrine are released from storage vesicles in the adrenal medulla in response to fright, exercise, cold and low levels of blood glucose. They increase the degradation of glycogen and triacylglycerol as well as increase blood pressure and the output of the heart. These effects are part of coordinated response to prepare the individual for emergencies, and are often called the “ flight or fight reactions ”.

22. g -aminobutyric acid (GABA) Inhibitory neurotransmitter (CNS). Directly regulates muscle tone. Its lack leads to convulsions, epilepsia. Involved in mechanism of memory. 2/20/2025 22

23. Serotonin Tryptopan serves as the precursor for the synthesis of serotonin and melatonin H ydroxylation reaction ( tryptophan-5-monooxygenase ) D ecarboxylation ( aromatic L-amino acid decarboxylase ) Acetylation ( serotonin N- acetylase 2/20/2025 23

24. Serotonin 5-hydroxytryptamine (5-HT) is another important neurotransmitter which has a diverse set of functions. Serotonin functions sometimes overlap with that of dopamine. Serotonin is regulates Social behaviour , mood, sleep, Digestion,appetite , memory, and sexual desire. Serotonin deficiency has been linked with depression and anxiety Large quantity of serotonin is available in the gastrointestinal tract, where it regulates the appetite and bowel movement . As brain and systemic serotonin are not inter-exchangeable due to the blood brain- barrier , the brain’s own serotonin regulates the functions in the central nervous system 2/20/2025 24

25. Serotonin is also associated with breast milk production, liver regeneration and bone metabolism. It assists in blood clotting following release from platelets. It also plays a role in vasoconstriction . 2/20/2025 25

26. Acetylcholine Acetylcholine ( ACh ) is a simple molecule synthesized from choline and acetyl-CoA through the action of cholin acetyltransferase . Acetylcholine plays a crucial role in memory and cognitive aptitude related tasks. Acetylcholine deficiency has been reported in the disease profiles of AD, PD, and Myasthenia Gravis Neurons that synthesize and release ACh are termed cholinergic neurons . 2/20/2025 26

27. 2/20/2025 27

28. How to release ACh When an action potential reaches the terminal button of a presynaptic neuron a voltage-gated calcium channel is opened. The influx of calcium ions, Ca 2+ , stimulates the exocytosis of presynaptic vesicles containing ACh, which is thereby released into the synaptic cleft. Once released, ACh must be removed rapidly in order to allow repolarization to take place; this step, hydrolysis, is carried out by the enzyme, acetylcholinesterase . The acetylcholinesterase found at nerve endings is anchored to the plasma membrane through a glycolipid . 2/20/2025 28

29. ACh receptors are ligand-gated cation channels composed of four different polypeptide subunits arranged in the form [( α 2)( β )( γ )( δ )]. Two main classes of ACh receptors have been identified on the basis of their responsiveness to the toadstool alkaloid, muscarine , and nicotine , respectively: Both receptor classes are abundant in the human brain. The activation of ACh receptors by the binding of ACh leads to an influx of Na + into the cell and an efflux of K + , resulting in a depolarization of the postsynaptic neuron and the initiation of a new action potential 2/20/2025 29

30. Neuronal metabolism Neurons share with other cells the need and ability to synthesize nucleic acids, proteins, carbohydrates and lipids. Likewise they share the metabolic processes required to generate chemical energy for these processes: glycolysis, pentose-phosphate shunt, citric acid cycle, oxidative phosphorylation . Neurons must be able to synthesize and metabolize neurotransmitters. Neurons must also synthesize second messenger molecules needed to mediate signal transduction. 2/20/2025 30

31. Glycolysis and TCA cycle Within the cell, glucose enters the glycolysis pathway in the cytoplasm , and via pyruvate and acetyl-CoA, in the mitochondrial tri-carboxylic acid cycle (TCA) or Krebs cycle. In these systems, reducing equivalents are generated and via oxidative phosphorylation they generate ATP, the chemical fuel for the brain.   Glycolysis and the TCA cycle are also the source of non-essential amino acid precursors(Fig 1 ) used to synthesize the neurotransmitters glutamate, aspartate , GABA, and glycine . 2/20/2025 31

32. The brain makes use of general metabolism to find precursors and in some cases the finished products for synaptic physiology. glycine Fig 1 2/20/2025 32

33. Astrocytes display a very high glycolytic activity (Figure 2). Although in comparison with neurons they have lower rates of oxygen metabolism , they very quickly metabolize glucose via the glycolytic pathway. The glycolytic nature of astrocytes and their preferences for the production and release of lactate are also conducive to the production of pyruvate, which is then included in the kreb’s cycle 2/20/2025 33

34. Figure 2. Metabolic profile of astrocytes . Glucose is transported to astrocytes through GLUT1 transporter and then metabolized to lactate. Lactate is transported outside astrocytes and taken up by neurons by monocarboxylate transporters (MCTs). Intracellular lactate in neurons is oxidized to pyruvate and metabolized along the oxygen pathway. GLUT1: glucose transporter-1;MCT: monocarboxylate transporter; TCA: Krebs cycle; Pyr : pyruvate ; Lac: lactate. 2/20/2025 34

35. Neuron is an excitable cell It is capable of generating and conducting electrical impulse by temporarily reversing its membrane potential; Energy is needed for major functions of neurons : Excitation and Conduction, which are reflected in the unceasing electrical activity of Cerebral tissue; •Electrical energy is derived from chemical processes; •Energy consumption used for active transport of ions needed to sustain and restore membrane potentials discharged during excitation and conduction; • Thus, cerebral tissue requires constant supply of energy Why does cerebral tissue need energy? 2/20/2025 35

36. • Glucose is the major substrate for energy production in cerebral tissue; • Cerebral tissue utilizes glucose directly from arterial blood ; • About 0.1% Glycogen is stored in Cerebral tissue ; • Insulin is not required for uptake of glucose by cerebral tissue; • When blood glucose is low , Glycogen stored in brain is used to maintain cerebral metabolism for a very short duration ; What substrates are used for energy production in cerebral tissue? 2/20/2025 36

37. Apart from Glucose , Mannose can be used to sustain normal cerebral metabolism; Mannose easily crosses the blood–brain barrier (BBB), is converted to Fructose-6-Phosphate that enters the Glycolytic pathway; Mannose is not normally present in the blood and cannot therefore be considered as a substrate for cerebral energy metabolism; Fructose, Galactose , Lactate and Pyruvate have limited permeability across the BBB, therefore cannot directly serve as substrates for cerebral energy metabolism; Lactate and Pyruvate when formed within the BBB are useful metabolic substrates for cerebral metabolism; 2/20/2025 37

38. • Brain represents 2 to 3% of total body weight of an average adult, but utilizes 20 to 25% of the total Oxygen consumed by the whole organism; • In children up to 4 years of age , the brain utilizes about 50% of the total Oxygen consumed by the whole organism; • Cerebral tissue utilizes Oxygen more than other tissues; • Example, it utilizes about 20 times more Oxygen than muscle tissue at rest; How significant is O 2 supply to brain energy metabolism? 2/20/2025 38

39. Oxygen consumption varies throughout the brain: • Grey matter utilizes about twice more Oxy gen than White matter • Cerebral Oxygen consumption continues unabated day and night, • Sleep reduces cerebral Oxygen uptake by only 3%; • Amount of Oxygen stored in the brain is extremely small compared to the rate of utilization, • Brain requires continuous replenishment of its Oxygen via the circulation; • Consciousness is loss when Cerebral blood flow is interrupted; 2/20/2025 39

40. • Energy metabolism via Oxidative Phosphorylation • Maintenance of energy component in BBB • Impulse transmission (Ion pumps); • Signal transduction; • Functioning of specific enzyme systems: • Mixed Functional Oxygenases used in the biosynthesis of Neurotransmitters and other biologically active compounds; List some uses of O2 consumed by cerebral tissue? 2/20/2025 40

41. • Cerebral tissue contains : • Very high conc. of free amino acids compared to plasma; • Highest amount of free Glutamate, compared to any other mammalian tissue; • Some unusual amino acids: • Gamma- Aminobutyrate (GABA), • N-Acetyl- Aspartate and Cystathione . • GABA is an inhibitory neurotransmitter that acts by increasing the passage of Chloride ions through the Post-synaptic membrane of Neurons; • Glutamate is involved in several metabolic processes: Biosynthesis of GABA , Detoxification of Ammonia and as Neurotransmitter ; Briefly comment on the amino acid content in cerebral tissue 2/20/2025 41

42. Adenylate Deaminase reaction : Adenylate Deaminase AMP ================> IMP + NH 4 + ----------------------------------------------------------------------- Glutamate Dehydrogenase (GDH) reaction : • High conc. of Glutamate in blood causes Ammonia toxicity; • GDH catalyzes formation of Ammonia from Glutamate; GDH Glutamate + NAD + H 2 O α-KG+ NH 3 + NADH + H + {α- KG = α- Ketoglutarate ( α- Oxoglutarate )} How is Ammonia formed in cerebral tissue? 2/20/2025 42

43. Rate of urea formation in Cerebral tissue is too low to account for removal of Ammonia via Urea Cycle , Why? Mitochondrial N-Acetyl-Glutamate activated Carbamoyl-Phosphate Synthetase that catalyzes the first reaction in Urea cycle, is low or absent in Cerebral tissue; Two reactions are involved in removal of Ammonia from Cerebral tissue: How is Ammonia removed from Cerebral tissue? 2/20/2025 43

44. First is formation of Glutamate from Alpha- Oxoglutarate and Ammonia , by Glutamate Dehydrogenase (GDH) reaction: GDH α-KG+ NH 3 + NADH + H+ Glutamate + NAD + H 2 O ----------------------------------------------------------------------- Second is formation of Glutamine from Glutamate and Ammonia , by Glutamine Synthetase reaction: Glutamine Synthetase Glutamate + NH3 + ATP ======> Glutamine + ADP + Pi 2/20/2025 44

45. Concentration of Ammonia in Cerebral tissue is kept low when there is adequate supply of Alpha-Oxoglutarate Extensive utilization of Alpha-Oxoglutarate in Cerebral tissue, can deplete TCA cycle Intermediates and affects energy supply to the Brain, unless mechanisms to replenishing the intermediates are available Major mechanism is Anaplerotic (Filling-up) reaction; It involves formation of TCA cycle intermediates in cerebral tissue Anaplerotic reactions increase the concentrations of TCA cycle intermediates, allowing increased rate of oxidation of Acetyl CoA 2/20/2025 45

46. • Pyruvate Carboxylase reaction : formation of Oxaloacetate from Pyruvate using ATP and Biotin; • Some Transamination reactions; • Glutamate Dehydrogenase reaction to form Alpha-Oxoglutarate; • Succinyl-CoA formation from Isoleucine, Valine, Methionine, and Threonine ; Give examples of Anaplerotic reactions 2/20/2025 46

47. SOME FACTORS THAT CAN AFFECT CELEBRAL METABOLISM Oxygen and Glucose : Two major substrates required for normal energy metabolism Hypoxia and Ischaemia ; 2/20/2025 47

48. • After a brief period of hypoxia: • There is drastic slowdown in Oxidative Phosphorylation • Rate of Glycolysis is increased; • Lactic acid production is increased, which can consequently lead to intracellular acidosis; • These changes are due to the Pasteur effect; • Inhibition of Glycolysis in the presence of oxygen; • Pasteur effect reflects the increased energy yield obtained via Aerobic metabolism of glucose as compared to Anaerobic metabolism; How does hypoxia affect cerebral metabolism? 2/20/2025 48

49. Hypoxia causes an increase in Glucose utilization from cerebral blood stream, followed by a decrease in cerebral glucose concentration; Resulting is an increase in Lactic acid produc tion in cerebral tissue; Gradual increase in Spinal fluid Lactate level occurs during hypoxia; 2/20/2025 49

50. THANK YOU !!! 2/20/2025 50