Metabolism in Brain (2024/2025) PDF

MBBS 240 (CNS MODULE/MED209 Year 2 (2024/2025) METABOLISM IN BRAIN, NEUROPROTECTION BY B1, B6, B12 & VISUAL CYCLE Assoc. Prof. Dr. Sharaniza Ab. Rahim Dept. of Biochemistry & Molecular Medicine Faculty of Medicine, UITM 11 NOV 2024 SPECIFIC LE...

MBBS 240 (CNS MODULE/MED209 Year 2 (2024/2025) METABOLISM IN BRAIN, NEUROPROTECTION BY B1, B6, B12 & VISUAL CYCLE Assoc. Prof. Dr. Sharaniza Ab. Rahim Dept. of Biochemistry & Molecular Medicine Faculty of Medicine, UITM 11 NOV 2024 SPECIFIC LEARNING OUTCOME Describe major function of the brain and its component Outline the major metabolic pathways available for energy production State the main types of substances used by the brain for energy production Discuss the role of neurons and glial cells in the brain Describe the types of inhibitory and excitatory neurotransmitters and associated pathologies Explain the biochemical functions of vitamin B1, B6 and B12 Describe the biochemical functions of vitamin A with regards to visual cycle  Overview of Brain Metabolism GLUCOSE AS CONSTANT PRIMARY FUEL ENERGY SUPPLY Main energy source with Requires continuous ketones and amino acids as supply for its function such as cognition, memory alternative fuel HIGH ENERGY and homeostasis DEMAND Accounts for 20% energy despite only 2% of body mass  Composition of the Brain Consist of Grey matter (40%) and White matter (60%) Cells are mainly present in the grey matter and nerve axons are mainly present in the white matter. Cells: neurons and glial cells Considerable amount of protein and complex lipid (plasmanogens, gangliosides and glycospingolipids) High turnover rate of proteins Lipids are integrated in the phospholipid membranes enveloping brain cells and neurons 50% of neurons plasma membrane weight is composed of decohexanoic acid (DHA) Arachidonic acid also abundant in the neuron’s plasma membrane Brain Cells Structural and functional unit Neurons Does not have centrosome Cannot undergo division Supporting cells Glial Occupy spaces between neurons 5 types Cells ⚬ Astrocytes ⚬ Ependymal cells: lin cavities of brain and spinal cord ⚬ Microglia: immune cells ⚬ Oligodendrocytes: CNS ⚬ Schwann cells: PNS  Glucose Metabolism in the Brain Consume 25% of total body glucose ATP essentials for synaptic transmissions and membrane potential Glucose enters neurons and astrocytes equally Pentose shunt accounts for less than 5% of glucose utilization in adult brain. Astrocytes regulate glucose availability and convert it into lactate - shuttle to neurons for alternative fuel Fasting/starvation: Ketones are used but less efficient Astrocytes and other glia cells: small amount of glycogen for very short-term source energy for neurons Glucose Metabolism in Brain GLUT-1: mediates the facilitated diffusion of glucose through the blood brain barrier. GLUT-1: stable energy supply even during low blood glucose level GLUT-3: transports glucose inside the neuron. The glycolytic and TCA cycle pathways are responsible for metabolism of most of the glucose entering brain cells. Net yield of 2 ATP is obtained from glycolysis and another 30 from oxidative metabolism of one molecule of glucose; which is less than the theoretical maximum because of proton leaks. The pentose phosphate shunt pathway generates NADPH for use in management of oxidative stress and in fatty acid and cholesterol biosynthesis Amino Acid Metabolism in the Brain Brain needs amino acids for the synthesis of neurotransmitters. Large amino acids eg. leucine, phenyl alanine, tyrosine, isoleucine, valine, tryptophan, methionine, histidine enter the CSF rapidly via a leucine preferring system carrier. Small amino acids eg. alanine, glycine, proline and GABA are transported via alanine preferring system carrier. Certain proteins such as insulin, transferrin, insulin like growth factors cross the BBB by receptor mediated transcytosis.  Lipid Metabolism in Brain Only essential fatty acids can cross the BBB (linoleic, linolenic acid), enter the brain and are elongated or desaturated. Brain generally synthesizes its own lipids eg. cholesterol, fatty acids, glycosphingolipids and phospholipids. Very long chain fatty acids are synthesized in the brain and forms myelin sheath. Schwan cells produce the myelin sheath in the PNS. Impulse Transmission Neurotransmitter Chemical substances act as the mediator for the transmission of nerve impulses from one neuron to another one through a synapse. Criteria: Found in neuron Produced by a neuron Release by a neuron Act on a target area and produce biological effect Inactivated after its action (destroyed by enzymes, engulfed by astrocytes, re- uptake by pre-synaptic axon terminal) Neurotransmitter Classification Excitatory Inhibitory Acetylcholine Gamma amino butyric acid (GABA) Glutamate Glycine Aspartate Serotonin Norepinephrine Norepinephrine (GI, urinary bladder) Epinephrine Epinephrine Histamine Dopamine Nitric oxide  Acetylcholine Excitatory in nature and works at neuromuscular junction, at synapses in the ganglia of the visceral motor system and at a variety of sites within the central nervous system Synthesized from acetyl coenzyme A and choline in a reaction catalyzed by choline acetyltransferase Two main classes of Ach receptors nicotinic and muscarinic receptors The NAchRs are ligand gated ion channels MAchRs belong to the superfamily of G protein coupled receptors that activate ionic channels via a second messenger cascade Destroyed by acetylcholinesterase  Alzheimer’s Disease Selective loss of neurons that synthesise acetylcholine Lower levels of this neurotransmitter causes gradual deterioration of memory, language and motor functions. Also due to protein misfolding or proteopathy and accumulation of abnormally folded A-beta proteins (amyloid protein) Also considered due to abnormal aggregation of the tau protein (microtubule associated protein expressed in neurons)  Myasthenia Gravis Autoimmune disease. Muscle weakness due to decreased neuromuscular signal transmission Nearly 90% of these patients have antibodies to the acetylcholine receptor located on the postsynaptic membrane of neuromuscular junction The antibodies destroy them and reduce the number of receptors on the postsynaptic membrane. Acetyl cholinesterase inhibitors: neostigmine, improve muscle function by inhibiting cholinesterase that degrades acetyl choline in the motor end plate  Catecholamines Biologically active amines containing a cathechol or 3,4 dehydroxy benzene group Dopamine, norepinephrine and epinephrine. Action of catecholamine neurotransmitters are terminated by reuptake into the presynaptic neuron by specific transporter proteins. Inside the neuron, these neurotransmitters are either repackaged into synaptic vesicles or metabolized. Catechol-O-methyltransferase and monoamine oxidase metabolize them. The end product of dopamine metabolism is homovanillic acid, Norepinephrine and epinephrine metabolise to 3-methoxy- 4-hydroxymandelic acid. Increase level of norepinephrine/epinephrine found in pheochromocytoma patients.  Dopamine Secreted by the nerve endings of: – Hypothalamus – Basal ganglia – Retina Action is terminated by its reuptake into the presynaptic neuron by a specific transporter. Deficiency of dopamine occurs in the brain stem, particularly in the midbrain, where there is a marked loss of Substantia Nigra cells. Substantia Nigra cells play important role in eye movement, motor movement and learning. This disease leads to slowness, stiffness and tremor. L-DOPA is transformed into dopamine in the dopaminergic neurons by dopa decarboxylase. Only 5 10% of L dopa crosses the BBB. The remaining L DOPA is often metabolized to dopamine elsewhere, causing a wide variety of side effects including nausea, vomiting, stiffness.  Parkinson’s Disease Deficiency of dopamine in the brain stem, particularly in the midbrain, Marked loss of Substantia Nigra Cells. This disease leads to slowness, stiffness and tremor. Treated by administration of DOPA analogs (L-Dopa). L-DOPA is transformed into dopamine in the dopaminergic neurons by dopa decarboxylase. Only 5-10% of L-DOPA crosses the blood brain barrier. Remaining L-DOPA is often metabolized to dopamine elsewhere, causing a wide variety of side effects including nausea, vomiting, stiffness.  Serotonin Also known as 5-hydroxy tryptamine (5-HT). Synthesized from tryptophan. Large amount of serotonin is found in enterochromatin cells of GIT. Small amount is found in platelets and nervous system. It is secreted in: – GIT – Hypothallamus – Cerebellum – Spinal cord – Retina – Lungs – Platelet  Glutamate and Glutamine Glutamate: syntesised from α- ketoglutarate Glutamate is converted to glutamine by the glutamine synthase in the astroglial cells. In excitatory neurons, glutamine is converted to glutamate and packaged in synaptic vesicles. Gamma Amino Butyric Acid (GABA) Glutamine is converted to glutamate and then to GABA Repackaged in synaptic vesicles. GABA is low in some epileptic patients NEUROPROTECTION BY VITAMIN B1, B6 & B12 Vitamin B1 (Thiamine) Active form: Thiamine pyrophosphate (TPP) Sources: Liver, egg, cereal, wheat (non-refined), rice (non-refined), meat, nuts Co-factors in biochemical pathways to produce ATP Plays important role in transmission of nerve impulse Its required for activation of ion transport in neural tissue – donating phosphate for phosphorylation of one of the proteins in the nerve membrane Na+ transport channel (regulate sodium channel). Deficiency: Beri-beri (peripheral neuropathy, muscular degeneration/weakness) and Wernicke- Korsakoff Neurodegeneration  Vitamin B6 (Pyridoxine) Active form: Pyridoxal phosphate Associated with metabolism of amino acid – Transamination – Decarboxylation – Methionine cycle  Vitamin B12 (Cyanocobalamine/Cobalamine) Active form: Methylcobalamin and 5- deoxyadenosylcobalamin Only biochemical reactions depends on it 1. Methionine cycle 2. Isomerisation of methylmalonyl CoA to Succinyl CoA Methyl malonyl CoA from degradation of amino acids, cholesterol, odd chain fatty acids and pyrimidines (T and U) Deficiency: Demyelination of nerves and neuronal degeneration Due to fatty acid synthesis required for myelin formation  Retina: rods and cones cells Vitamin A Component of visual pigments of rods and cones Human eyes has 10 million rods and 5 million cones Rods involved in dim light vision Cones involved in bright light and colour vision  Wald’s Visual Cycle 2 main events: 1. Regeneration of rhodopsin 2. Bleaching of rhodopsin and generation of nerve impulse 1. Rhodopsin generation – Rhodopsin (visual pigment) consists of 11-cis retinal bound to opsin – Exposure to light split it to all-trans retinal and opsin – It will esterified to cis retinal and combined with opsin to regenerate rhodopsin to complete the cycle.  Wald’s Visual Cycle 2. Bleaching of rhodopsin and generation of nerve impulse – Opsin activates regulatory protein transducin – Transducin-GDP complex activates phosphodiesterase – This initiates guanine nucleotide amplification cascade – Generation of nerve impulse  Textbooks 1. Marks, D.B., Marks, A.D. & Smith, C.M. (2022). Basic Medical Biochemistry: A clinical approach (6th edition), Williams THANK YOU and Wilkins co. Baltimore. 2. Champe, P.C. & Harvey, R. A. (2017). Biochemistry (Lippincott’s illustrated reviews) (7th edition), J.B. Lippincott Co.