1. Brain metabolism & Neurotransmitters
Reference: Devlin Ch 23
Selective reading!
MOHAMAD NUSIER, M.D., Ph.D.

2. Discuss the biochemical and molecular aspects of:
Brain metabolism
Neurotransmitters
Related disorders

3. Objectives
Know the major source for brain energy and what limits its supply
Know the main aspects of metabolic pathways for neurotransmitters: acetylcholine, dopamine, norepinephrine, epinephrine, serotonin, glutamate, and GABA.
Know how neurotransmitters are degraded and inactivated
Know major neuropeptides and how they act

4. Aspects of Brain Metabolism
Carbohydrate Metabolism
Amino Acids Metabolism
Lipid Metabolism

5. Key points
Brain is command center: always functioning and requires a large amount of energy to keep it operational
Glucose is the main source for energy (80 g/day). 25% of total body glucose consumption
TCA cycle functions at near maximum capacity
Glycolysis functions at 20% capacity
Ketone bodies in starvation but CAN NOT REPLACE GLUCOSE

6. Key points Why brain needs energy?
Maintain ionic gradients across the plasma membranes
Various storage and transport processes
Synthesis of neurotransmitters
Synthesis of other cellular components

7. Key points
Lipids are used in brain to maintain membrane integrity rather than in metabolic roles

8. Key points
Brain proteins are rapidly turned over (degraded) than other body proteins (Why…….?)

9. Carbohydrate Metabolism
Normally, the brain energy source is aerobic oxidation of glucose
Brain glycogen stores are small (about 1/10th of muscle)

10. Carbohydrate Metabolism
Glucose crosses Blood Brain Barrier (BBB) by facilitated diffusion (insulin-independent)
Therefore, brain is very susceptible to hypoglycemia

11. Carbohydrate Metabolism
During prolonged starvation (> 48 h) and in neonate, ketone bodies can be used as brain energy source
When ketone bodies levels in blood are high, specific transporters are upregulated

12. Under ordinary conditions
The basic substrate for brain energy metabolism is glucose
Brain glucose levels depend on:
Blood glucose levels
Uptake across BBB

13. Glycogen levels vary and depends on plasma glucose levels; thus,
Brain is very susceptible to hypoglycemia
Glucose crosses BBB and taken up by brain cells by a specific transporters (Glut 1 & Glut 3)
Glut 1: expressed by glial cells
Transport glucose into the endothelial cells of the barrier
Glut 3: located on neurons facilitate glucose transport from ECF into neurons

14. Amino Acid Metabolism
LNAA: Large Neutral Amino Acids (phenylalanine, leucine, tyrosine (catecholamine precursor!), isoleucine, valine, tryptophan (serotonin precursor!), methionine, histidine, L-DOPA) are transported across BBB
Via a single AA-transporter L-system transporter
L stands for (leucine preferring)

15. Amino Acid Metabolism
They compete for entry with one another
Thus, elevated levels of, say, phenylalanine as in phenylketonuria (PKU) affect brain supplies of other essential amino acids

16. Amino Acid Metabolism
Small neutral AAs (GABA, glycine, alanine, proline):
Have restricted entry: otherwise they change neurotransmitters content
Synthesized in brain
Some are transported out via A-system carrier
A stands for (Alanine preferring)

17. Vitamins have specific transporters through the BBB as in most tissues

18. Amino Acid Metabolism Basic and acidic AAs
Glutamate & aspartate are both transmitters & metabolic intermediates
They are synthesized in the brain, but are also transported across BBB (slow)

19. In the brain, there is a relatively high content of glutamate, aspartate, glutamine, and GABA
In addition, tyrosine and tryptophan are precursors for several neurotransmitters and thus are of extreme importance

20. Dietary sources of brain amino acids are very important and may regulate the levels of neurotransmitters in the brain

21. Since tyrosine and tryptophan are each precursors for neurotransmitters (catecholamines and serotonin, respectively), their uptake into the brain is important

22. Both amino acids (tyrosine and tryptophan) share the same brain uptake system which is for large neutral amino acids (LNAA) such as tryptophan, tyrosine, phenylalanine, isoleucine, and valine

23. Diets which contain proteins result in lower brain levels of tryptophan because most dietary proteins contain less tryptophan than other LNAA which can then compete for the uptake carrier

24. Carbohydrate diets stimulate insulin secretion which lowers the plasma level of all the LNAA except for tryptophan
Thus, tryptophan uptake is facilitated resulting in higher brain levels and increased synthesis of serotonin
Sweets (chocolate …….good mood?)

25. Lipid Metabolism
Lipids store energy as triglycerides, but NOT in the BRAIN (almost no triglycerides there)
Lipids function as messengers (steroid hormones, eicosanoids)

26. Lipids are structural membrane components, especially important in myelin
Major ones include cerebroside (a sphingolipid) and cholesterol
A number of diseases result from genetic defects in sphingolipid degradation. Many have neurologic consequences, including Niemann-Pick, Gaucher's, Tay-Sachs.

27. The brain is one of the richest portions of the body in total lipid content; approximately half the dry weight of white matter and 1/3 of the gray matter of the human brain is lipid
The brain lipids are comprised of three major categories:
Cholesterol
Sphingolipids
Glycerophospholipids

28. Triglycerides and free fatty acids constitute only a very small percent
The lipids are incorporated into membrane structures and are especially rich in myelin
Cholesterol is the only sterol in the brain in significant amounts

29. Lipid synthesis Most lipids are synthesized in the brain
Exceptions: essential ones (linoleic & linolenic acid) are taken up by specific transporters
Very long-chain fatty acids are synthesized in brain important for myelin formation