Biochemistry of the Nervous System Lecture 1 PDF

DA 1218 BIOCHEMISTRY BIOCHEMISTRY OF THE NERVOUS SYSTEM LECTURE1 Pn. Mariati Abdul Rahman Dept. of Clinical Oral Biology Faculty of Dentistry. Ref: Medical Biochemistry J.W. Baynes & M.H. Dominiczak  NERVOUS SYSTEM C...

DA 1218 BIOCHEMISTRY BIOCHEMISTRY OF THE NERVOUS SYSTEM LECTURE1 Pn. Mariati Abdul Rahman Dept. of Clinical Oral Biology Faculty of Dentistry. Ref: Medical Biochemistry J.W. Baynes & M.H. Dominiczak  NERVOUS SYSTEM Central nervous system (CNS) – spinal cord and brain Peripheral nervous system (PNS)- all neural tissue outside the CNS (cranial & spinal nerves). CNS - Neural tissue, blood vessels and various connective tissue – provide physical protection and support. CNS – integrating, processing and coordinating sensory data and motor commands. Sensory data convey information about conditions inside/outside the body. Motor commands control/adjust activity of peripheral organs – skeletal muscle. Brain – higher functions- intelligence, memory, learning & emotion.  NERVOUS SYSTEM PNS – delivers sensory info. to CNS and carries motor commands to peripheral tissues and systems. Bundles of axon (nerve fibre) carry sensory info. and motor commands in the PNS – peripheral nerves. Cranial nerves Spinal nerves. Nervous system consist of two types of cells; neurons and neuroglia.  NEURON NEURON – structural & functional unit of the nerve tissue. Neurons have variety of shapes – multipolar (most common). Each multipolar neuron has a large cell body that is connected to a single elongated axon and several short, branched dendrites. Cell body contains a large nucleus with prominent nucleolus. Perikaryon- cytoplasm surrounding the nucleus. Axon – generate impulse & conducts them away from the cell body. appendage (projection) originated from perikaryon Dendrite – branched appendage from perikaryon Neuron processes that conveys messages (electrical impulse towards the cell body)  STRUCTURAL CLASSIFICATION OF Axon cannot be NEURONS Has two One process extends One axon, multiple differentiated processes/extensions. from cell body forming dendrites axon.  NEUROGLIA Cells that support and protect the neurons. Abundant and diverse, roughly half of the volume of the nervous system. CNS has 4 types of neuroglia Majoy type: Astrocyres (30%), oligodendrocytes (30%), microglia (30%). Minor type: Ependymal cells, brain endothelial cells PNS has 2 types of neuroglia Satellite cells and Schwann cells  NEUROGLIA ASTROCYTES A variety of functions. Maintain blood-brain barrier a semipermeable membrane separating the blood from the cerebrospinal fluid, and constituting a barrier to the passage of cells, particles, and large molecules. Repairing damaged neural tissue. Guiding neuron development Controlling interstitial environment – regulation of sodium & potassium ions, CO2, transportation of nutrients, ions & dissolved gases, controlling blood flow, absorbing & recycling of neurotransmitters & releasing chemicals to enhance or suppress communication across synapse terminals. ECF=interstitial fluid & blood plasma  NEUROGLIA OLIGODENDROCYTES – slender cytoplasmic extensions but smaller. Many oligodendrocytes cooperates in the formation of myelin sheath along the length of an axon – myelinated (forming a myelin sheath around a nerve to allow nerve impulses to move more quickly). White matter of the CNS. Unmyelinated axons not covered completely – part of the gray matter of CNS Function – structural organisation by tying clusters of axons together & improved functional performances of neurons by wrapping axons with myelin sheath.  NEUROGLIA MICROGLIA - least number & smallest neuroglia in CNS. Has many fine branches. Capable of migrating through neural tissue. EPENDYMAL CELLS have slender processes that branched Appear early in embryonic extensively & make direct contact development. with surrounding neural tissue. Function: produces CSF, with cilia Migrate to CNS as nervous that influences the direction of the system forms. CSF, distribution of NT & other messengers. Remains isolated in neural tissue to engulf cellular debris, waste products & pathogens.  NEUROGLIA (PNS) SATELLITE CELLS – regulate the environment around neurons, just like astrocytes. SCHWANN CELLS – myelinate only one segment of a single axon. A series of cells is required to enclose an axon along its entire length.  OVERVIEW OF NEURAL ACTIVITIES. ++++++++++++ -------------------- inside -------------------- ++++++++++++ Unequal positive & negative charges, kept apart by phospholipid membrane - All cells have a transmembrane potential potential difference also known as transmembrane that varies from moment to moment potential depending on the activities of the cell. Resting potential – transmembrane potential of a resting cell. All neural activities begin with a change in the resting potential of a neuron.  A typical stimulus produces a temporary, localized change in the resting potential. The effect which decreases with distance from stimulus is called a graded potential. If graded potential is sufficiently large, it produces action potential in the membrane of the axon. Action potential – electrical impulse that is propagated across the surface of an axon & does not diminish as it moves away from its source. The impulse travels along the axon to one or more synapse.  Synaptic activity – then produces graded potential in the cell membrane of post synaptic cell. Involves the release of neurotransmitters (NT) e.g. Acetylcholine (Ach) by the presynaptic cell. These compounds bind to receptors on post synaptic cell membrane, changing its permeability. Comparable to neuromuscular junction. Response of postsynaptic cell depends on what the stimulated receptors do & what other stimuli are influencing the cell at the same time.  SYNAPTIC ACTIVITY Nerve impulse – movements of electrical events from one location to another in the form of action potentials along axons. At a synapse between two neurons, the impulse passes from presynaptic neuron to postsynaptic neuron. Two types Electrical synapses Chemical synapses  ELECTRICAL SYNAPSES Location: in CNS & PNS but are extremely rare. Present in some areas of the brain, in the eye & in at least one pair of PNS ganglia. The presynaptic & postsynaptic membrane are locked together at gap junctions. Changes in the transmembrane of one cell will produce local currents that affect the other cell as if they share a common membrane. As a result – the electrical synapse propagate action potentials quickly & efficiently from one cell to the next.  CHEMICAL SYNAPSES Far more dynamic because cells are not directly coupled. E.g. an action potential that reaches an electrical synapse will always be propagated to the next cell. But for a chemical synapse, the arriving action potential may or may not release enough NT to bring the postsynaptic neuron to threshold (limit). Other factors may intervene, making the postsynaptic cell more or less sensitive to the arriving stimuli.  CHEMICAL SYNAPSES Most abundant type of synapse. Most synapse between neurons & communication between neurons and other types of cells involve chemical synapse Normally occur in one direction: from presynaptic membrane to postsynaptic membrane.  NEURONS 3 significant features of neurons; 1. Length 2. Many interconnections 3. Do not divide post partum Because of the great length  1m, nucleus is quite far from the synaptic terminal. Nucleus – source of synthesis of neurotransmitter. Ability to transport material to & fro are crucial. Anterograde transport – from nucleus synapse (forward) Retrograde transport – from synapse nucleus (backwards)  METABOLISM IN THE BRAIN Carbohydrate (CHO) metabolism In a 70kg man, mass of brain is about 1.5kg , yet this relatively small mass(2.1%) received 15% of cardiac output & 20% of total oxygen & 25% of total glucose utilization of the body at rest. CHO are substrates for oxidative metabolism. Glucose is the only major fuel removed from the cerebral blood flow. Carbohydrate (CHO) metabolism In order to understand- study the effect of hypoglycaemia (abnormal decrease of sugar in the blood). Subjects are given high doses of insulin (which can lead to convulsions). Recovery by injection of glucose is rapid, intravenous glucose acts within 30 secs. Used as a shock therapy for treatment of certain psychoses. Glucose may also be required for metabolic processes not related to energy provision.  LIPID METABOLISM Brain is rich in lipids. Synthesis of lipid components – cholesterol, glycerophospholipids & sphingolipids. Sphingolipids are build up from sphingosine, acylated to form ceramide & then linked to short chains of CHO residues in the form of gangliosides i.e. with 1 or more N- acetylneuraminic acid (sialic acid) residue.  LIPID METABOLISM Biosynthesis & catabolic pathway are generally similar to those found in other organs. Deficiencies in specific catabolic enzymes tends to accumulate certain spingolipids – sphingolipidoses. 1881 – this disease was recorded by Tay in England. 1887 – by Sachs in USA This condition is now called Tay-Sachs disease. Reason was not known until 1965, when a related condition called ‘Gaucher’s disease’ was caused by deficiency of -glucosidase with the accumulation of glucocerebroside.  METABOLIC DISEASE CHARACTERISED BY INABILITY TO DEGRADE SPHINGOLIPIDS Disease Major accumulation of Enzyme defects Sphingolipids Tay-Sachs Ganglioside Hexosaminidase A Niemann- Sphingomyelin Sphingomyelinase Pick Gaucher Ceramide glucoside -glucosidase (glucocerebrocide) Krabbe Ceramide galactoside -galactosidase (galactocerebrocide) Fabry Ceramide trihexoside -galactosidase  AMINO ACID METABOLISM Major part of amino acid & protein metabolism occurring in the brain is similar to other tissue, but discussion only on some important distinctions. [glutamate] & its derivatives aspartate are present in higher conc in the brain. This forms >2/3 of free amino nitrogen in the brain.  AMINO ACID METABOLISM N-acetylaspartate – occurs only in the brain with conc of 2-3X more than aspartic acid. Low conc at birth, rise to adult level during development. Aspartate + acetyl SCoA N-acetylaspartate. May function as reservoir for acetyl group of source for synthesis of special protein. Amino acid transport system in the brain capillaries. For synthesis of proteins of CNS and NTs. L1 (large & neutral aa) – essential: Leu, Phe – catecholamine precursor, Ile, Val, Met,Trp –serotonin precursor, Semi-essential: Histidine Non-essential: Tyrosine (Catecholeamine precursor) Non-essential aa transporters (the alanine, serine & cysteine (ASC) & alanine preferring system (A) y+ (cationic) amino acid transporters -Lysine, Arg & Ornithine. Sodium-dependent excitatory aa transporter 1 (EAAT1), EAAT2 and EAAT3 at abluminal side of BBB – remove glutamate.  The mechanism of brain protein synthesis are identical in other tissues Studies of labelled proteins showed that they move from the nerve cell through the axon in 2 major waves, rapid flow & slow flow. Rapid flow: moves at the rate of several hundred mm per day, Most protein moves much slower – slow flow- several mm per day.  UTILIZATION OF KETONE BODIES Acetoacetate & 3-hydroxybutyrate can also be a source of energy. Normal circumstances, when ample glucose is available & levels of ketone bodies in plasma is very low, the brain does not use ketone bodies. However, during starvation, when glycogen storage is exhausted & gluconeogenesis cannot supply sufficiently & rapidly, ketone bodies will be used by the brain. Although ketone bodies may replace glucose as energy-yielding substrate, it will not replace glucose required by the brain for other requirement i.e. synthesis of NT.  METABOLISM PROCESSES IN BRAIN TISSUE Krebs cycle +++ Glycogenesis + Glycogenolysis + Glycolysis + Oxidation – fatty acid - Ketogenesis - Ketone bodies - (well fed) +++ (starvation) Lipogenesis - Gluconeogenesis + (starvation)