rate limiting enzyme in glycolysis is PFK (phoshofructokinase); products are pyruvate or lactate
oxidative phosporylation of glucose leads to production of a total of 38 ATP (2 from TCA and 2 from glycolysis)
glycogen stores in brain are 1/3 of those in skeletal muscle
therefore requires continuous flow of blood.
glial cell glucose stores last 5 min; unconscious after 8 sec of no blood flow
rate of consumption depends on rate of metabolism, which is controlled by ADP
10 % of tissue is mitochondrial (less than cardiac but more than most other tissues)
Maintaining the ionic gradients through rest and activity is critical and is done by the Na/K ATPase
ADP controls the rate of metabolism; ADP mainly produced by the action of Na+/K+ ATPase (40% of CNS metabolism)
Na+/K+ ATPase
maintains membrane potential in brain under conditions of small resting leak and action potential ion flux
in brain, extracellular space is small, so the outward flux of K+ significantly changes extracellular K+ concentration
ATPase produces ADP, which removes the limitation on PFK and the mitchondrial respiratory chain which burns substrate against O2 thus making ATP and consuming O2 and glucose.
if ox/phos is blocked but glycolisis continues (i.e. ischemia), then lactate and pyruvate build up
glucose and O2 have to be delivered on a moment by moment basis because stores are low and the workload is high
What is the workload of the brain tissue?
Osmotic Component
: mainly ion transport discussed above and axoplasmic transport which is relatively small
blocking the Na+/K+ ATPase cuts the resting waking metabolic activity of brain in half to the Minimum
Biosynthetic Component
: homeostatic; manufacture of maintenance proteins
most all of the electrical activity of brain is stopped by barbiturate coma which cuts metabolic activity to minimum
resting wake metabolism of brain is twice this level
cocaine can stimulate brain to maximum electrical activity which is 5 fold that of the minimum.
Brain Blood flow and Consumption of O2
Systemic
: blood flow to the brain needs to be kept constant, independent of fluctuations in systemic pressure
Autoregulation
facilitates this mechanism Cerebral Blood Flow
CBF remains constant around normal MAP (mean arterial pressure) mg/100g/min
extreme high or low fluctuations cause CBF to fluctuate according to Ohm’s Law V=IR ~ P = FR therefore F=P/R
the mechanism of auto regulation is mediated by control of arterial diameter
Myogenic:
when musculature of arteries are stretched they tend to contract by means of stretch-sensitive Ca++ channels
Neurogenic:
sympathetic neurons provide tone by modulating diameter of arteries via a receptors (norepinephrine transmitter)
MAP < 50
Þ hypotensive syncope. MAP > 150 (break through pressure) Þ hemorrhage (found in chronic HTN, so treating HTN drops incidence of strokes; Chronic HTN shifts the curve to the right.)
Intrinsic:
Even though O2 consumption remains same over 24 hours for the whole brain, within brain it is quite variable
long exposure of neurons to O2 is toxic, so exposure is minimized by a heterogeneous distribution of blood flow in space and time. This is the basis of functional MRI, which lights up the O2 to localize functional areas.
control due to various local factors: K+ flux (K+ is vasodilator), H+, CO2, NO, adenosine
neurogenic vasoconstriction/dilation mechanism from Nucleus locus ceruleus acts like adrenal gland of brain by ending on small blood vessels and capillaries and releasing NE in fight or flight to dilate vessels via b receptors
Monroe-Kellie Doctrine
: total volume of blood, spinal fluids and brain tissue in cranium must remain constant.
Blood Brain Barrier (BBB)
– another way of separating the systemic from the intrinsic.
systemic blood circulation can tolerate greater fluctuation in composition than brain can therefore BBB protects brain milieu
primarily a function of the endothelial cells of the brain which have tight junctions instead of fenestrae
prevents water-soluble diffusion, thus requiring special transport for ions, glucose, amino acids, etc.
Carrier-mediated facilitated diffusion
of glucose means flux depends on # of and affinity of carrier protein; therefore carrier is saturable and follows Michealis-Menton mechanics
lipid soluble substances can cross: CO2, O2, H2O
[K+] in brain is 3 mmol but 4.5 in systemic circulation. If this level rises in brain then the membrane potential is reduced and makes the cell more excitable
Þ seizure; therefore must be tightly controlled by tight junctions and Na/K ATPase.
astrocyte (glial cells) foot processes cover 98% of capillaries and induce the endothelial cells to form tight junctions
astrocytes also contain enzymes that detox lipid soluble molecules as they diffuse through BBB
area that do not have BBB: Pineal, posterior pituitary, Area postrema, supra optic crest, Subfornical organ