Brain Metabolism PDF

BRAIN METABOLISM By: Dr. Safinaz Hamdy El Khoulany Lecturer of Medical Biochemistry and Molecular Biology Brain  Nerve signal transmission Signal Opening of ion channels in axon membrane Influx of sodium and efflux of p...

BRAIN METABOLISM By: Dr. Safinaz Hamdy El Khoulany Lecturer of Medical Biochemistry and Molecular Biology Brain  Nerve signal transmission Signal Opening of ion channels in axon membrane Influx of sodium and efflux of potassium When action potential reaches the axon terminal Synaptic vesicles release the neurotansmitter into the synaptic cleft Who will clean that up ? & Who will pay for it ?  clean How neurons get ATP? Or Where the energy comes from We have to pay for 1 ATP molecule HOW THE CELL (BRAIN) GETS ENERGY FROM GLUCOSE ? Glucose (6C) 2 Pyruvate (3C) Lactate (3C) Or Oxygen crosses Transport of glucose to the BBB by brain via blood vessels in diffusion which BBB is present Glucose is able to cross BBB by GLUT-1 1- Eating Carbohydreares(polymers) 2- Digestion Liver, Pancreas and other 3- Absorption of Glucose endocrine glands maintain 4- Excess glucose is stored steady blood glucose in Liver Under physiological conditions, substances may cross the BBB Brain energy  alternative substrates Starvation or ketogenic diet  brain  vital to the proper functioning of all organs of the body, special priority is given to its fuel needs. To provide energy, substrates must cross (the “blood-brain barrier”). glucose  The primary fuel for the brain. Hypoglycemia (40 mg/100 ml), cerebral function is impaired. Severe and irreversible brain damage may occur. During fasting  ketone bodies  Sources of energy for the brain: There are alternative substrates for glucose like : 1- Glutamate 2- Lactate 3- Ketone bodies Brain, unlike heart and skeletal muscles can’t use fatty acids as a source of energy because fatty acids bound to albumin can’t cross BBB. Glucose: Primary fuel. 25% of total body glucose (120g). The constant consumption regardless the activity state. Continuous supply No storage of triglycerides Very small capacity to store glycogen. Glucose enters the brain through astrocytes by GLUT-1 (independent on insulin). Glucose  glycolysis ATP  GLUTAMATE Non essential amino acid The most abundant excitatory neurotransmitter  Glutamate doesn’t cross BBB and thus, must be synthesized by the in neurons from local precursors ( glutamine ) released by glial cells  Glutamate is also synthesized from α-ketoglutaric acid (citric acid cycle) by AST. Thus, some of glucose metabolism in neurons can be used for glutamate synthesis  Vesicles Post synaptic neurons receptors Removal by ( the excitatory amino acid transporters (EAATs)  Glutamate-Glutamine cycle Fate of Glutamate in the glial cells Glutamine  neurons into glutamate In this way synaptic terminals cooperate with glial cells to maintain an adequate supply of the neurotransmitter Glutamate receptors: -3 types of Ionotropic receptors -3 types of metabotropic receptors -3 types of Ionotropic receptors non-selective cation channels deploarizing the post synaptic neuron (excitatory response) -3 types of metabotropic receptors  activate G protein  interacts with ion channels (excitatory or inhibitory action)  Glutamate as an energy source: Hypoglycemia. Hypoglycemia leads to decrease of glycolysis and decreased conversion of glucose to lactate which leads to use of Glutamate as a substitute for glucose as a source of energy. Part of glutamate is transaminated to a-ketoglutarte by AST α-ketoglutarate enter TCA cycle  THE ABSORPTIVE (fed) STATE  two- to four-hour period after ingestion of a normal meal.  Increases in plasma glucose, amino acids, and triacylglycerols (TAG) occur.  Insulin release and a decreased release of glucagon.  elevated insulin to glucagon ratio  Anabolic period characterized by increased synthesis of TAG and glycogen (fuel stores), and protein.  All tissues use glucose as a fuel. A. Carbohydrate metabolism in brain: No significant stores of glycogen and is, therefore, completely dependent on the availability of blood glucose B. Fat metabolism in brain: No significant stores of TAG Fatty acids bound to albumin do not efficiently cross the blood-brain barrier.  FASTING  If no food is ingested.  inability to obtain food, the desire to lose weight rapidly, or clinical situations in which an individual cannot eat, for example, because of trauma, surgery, cancer, or burns.  plasma levels of glucose, amino acids, and TAG fall,  decline in insulin secretion and an increase in glucagon release.  The decreased insulin to glucagon ratio  catabolic period characterized by degradation of TAG, glycogen, and protein.  2 aims : 1) adequate plasma levels of glucose to sustain energy metabolism of the brain, red blood cells, and other glucose-requiring tissues. 2) mobilize fatty acids from adipose tissue, and the synthesis and release of ketone bodies from the liver, to supply energy to all other tissues.  BRAIN IN FASTING During the first days of fasting:  use glucose as a fuel.  hepatic gluconeogenesis from glucogenic precursors, such as amino acids from proteolysis and glycerol from lipolysis. In prolonged fasting (greater than 2–3 weeks):  plasma ketone bodies  elevated levels, and replace glucose  This reduces the need for protein catabolism for gluconeogenesis Thus, ketone bodies spare glucose and, thus, muscle protein. The metabolic changes that occur during fasting ensure that all tissues have an adequate supply of fuel molecules.  Energy metabolism within neurons and astrocytes - 1 2 Glucose+++++++astrocytes ++ Neurones Glucose Glycolysis pyruvate AcetylcoA—TCA Lactate Astrocytic reuptake of Glutamate through symport +++Na +++Na/K ATPase GlutamateGlutamine Need ATP -ATPglycolysis++glucose uptakemore lactate and more ATP 2 processes in astrocytes need ATP: 1) Na+ / K+ pump 2) Conversion of the uptaken Glutamate into Glutamine Mechanisms helping in protection from oxidative stress and apoptosis in neurons  Reactive oxygen species (ROS)  They are formed from the partial reduction of molecular oxygen  These compounds are formed continuously : -as by-products of aerobic metabolism -through reactions with drugs and environmental toxins - when the level of antioxidants is diminished all creating the condition of oxidative stress. Dangers: 1- They can cause serious chemical damage to DNA, proteins, and unsaturated lipids, and can lead to cell death. 2- They have been implicated in a number of pathologic processes, including reperfusion injury, cancer, inflammatory disease,and aging.  NADPH PROVIDES THE REDUCING EQUIVALENTS REQUIRED BY THE PROTECTIVE MECHANISMS THAT MINIMIZE THE TOXIC POTENTIAL OF ROS 1- Reduced glutathione, a tripeptide- thiol present in most cells, can chemically detoxify hydrogen peroxide 2- The cell regenerates reduced glutathione in a reaction catalyzed by glutathione reductase, using NADPH as a source of reducing equivalents. Thus, NADPH indirectly provides electrons for the reduction of hydrogen peroxide 3- Pentose phosphate pathway for their supply of NADPH  Brain consumes 20% of body energy Neurons consumes Astrocytes consumes 70-80 % of brain energy 20-30% of brain energy Glycolysis to form Glycogenesis and form Pyruvate Lack storage of Lactate from Glycogenolysis from Lactate as it glycogen (But can store has LDH 1 Pyruvate as it has LDH 5 small amounts of glycogen Low level of Fructose 2,6 bisphosphate ( the key stimulator of glycolysis)