Biochemistry-Brain Metabolism Disorders Flashcards
What is responsible for the majority of glucose consumption by the brain?
Na/K ATPase. This maintains the electrolyte balance of the brain.
Astocyte-Neuron Lactate Shuttle and Glutamante-Glutamine shuttle.
Glucose -> Glutamate -> Secretory vesicle -> Fuses w/membrane -> Synaptic cleft -> Binds to Metabotropic, Na+ and Ca2+ receptors -> Glutamate/Na+ secondary active transport into astrocyte -> Glutamine -> Neuron -> Glutamate
Where does the neuron get the majority of its energy?
Lactate produced by the astrocyte.
Where does glutamate come from?
Alpha-ketoglutarate and Glutamine. Note that NH4+ accumulation will shift equilibrium towards glutamine and glutamine will pile up.
What is hypoxia’s effect on the brain?
Glutamte excitotoxicity
What is responsible for 1/3 of mountain climbers hallucinating as they approach the summit of mount Everest?
Mild hypoxia w/ PaO2 of 25-40 mmHg. At this PaO2, ATP levels are maintained by increased cerebral blood flow, however, neurotransmitter synthesis is impaired and thus cognitive function is impaired.
What PaO2 will likely result in coma?
Less than 20 mmHg. This is where people experience acute hypoxia. At this level blood is only about 20% saturated with oxygen.
What are 4 common causes of hypoxia?
High altitude, severe anemia, cyanide and CO poisoning.
Why does a PaO2 < 20 mmHg cause such severe neurological deficits?
As PaO2 decreases, so does the amount of ATP. Less ATP means less Na/K ATPase causing osmotic swelling that allows Ca2+ to flow into the cell. Ca2+ activates phospholipases (loss of membrane), opens MPTP (loss of proton gradient in mitochondria) and activates NO synthase (ROS formation).
What are agents that stimulate increased permeability of the mitochondria so it loses its gradient?
Ca2+, P and ROS all activate the MPTP
What happens to NO levels as Ca2+ levels increase? Why is this a bad thing?
Too much NO is made from arginine by NO synthase. If too much NO is made it is routed into formation of many RNOS.
How does hypoxia cause glutamate excitotoxicity?
Decreased ATP levels decrease astrocyte ability to uptake Glutamate in the synaptic cleft. Opening of the NMDA receptor allows for continuous flow of Na+ and Ca2+ into the cell. Then Ca2+ wreaks its havoc.
What blood glucose level is kind of a target for beginning of subtle neurological signs? What is the most common cause of hypoglycemic encephalopathy?
2mM. Insulin overdose most often takes you below this level. Going below this level decreases NT synthesis and causes you to feel sweating, palpitations, anxiety, hunger, confusion, lethargy, seizures, coma and even brain death.
What happens at levels of 1mM glucose and below?
ATP levels are depleted
What 3 metabolic reactions are most affected in patients with nutritional deficiency or in alcoholics?
1) Pyruvate dehydrogenase reaction by Thiamine Pyrophosphate 2) Alpha-ketoglutarate dehydrogenase by Thiamine Pyrophosphate 3) Alpha-ketoacid dehydrogenase for branched chain amino acids. Note that despite getting plenty of glucose for fuel, patients cannot use it as a fuel.
Dry beriberi
Peripheral neuropathy deficiency
Wet beriberi
Cardiovascular problems from thiamine deficiency
Wernicke-Korsakoff Syndrome
Brain damage from thiamine deficiency
Why do you give a patient with beriberi IV thiamine injection?
The patient cannot absorb oral thiamine because alcohol causes gastritis and inhibits nutrient absorption.
Why does liver failure cause encephalopathy?
The liver is responsible for converting the toxic NH4+ to non-toxic urea. When ammonia builds up glutamine piles up in the neurons and astrocytes. Astrocyte mitochondria then converts glutamine to glutamate and NH3 -> NH3 increased ROS and cell permeability to Ca2+ -> MPTP opens -> ATP loss -> Cell death
