Thursday, August 21, 2008

Part 7 Excitotoxins, Neurodegeneration and Neurodevelopment

Part 7 Excitotoxins, Neurodegeneration and Neurodevelopment By Russell L. Blaylock, M.D

Special Functions of Ascorbic Acid

The brain contains one of the highest concentrations of ascorbic acid in the body. Most are aware of ascorbic acid's function in connective tissue synthesis and as a free radical scavenger. But, ascorbic acid has other functions that make it rather unique.

In man, we know that certain areas of the brain have very high concentrations of ascorbic acid, such as the nucleus accumbens and hippocampus. The lowest levels are seen in the substantia nigra.72 These levels seem to fluctuate with the electrical activity of the brain. Amphetamine acts to increase ascorbic acid concentration in the corpus striatum ( basal ganglion area) and decrease it in the hippocampus, the memory imprint area of the brain. Ascorbic acid is known to play a vital role in dopamine production as well.

One of the more interesting links has been between the secretion of the glutamate neurotransmitter by the brain and the release of ascorbic acid into the extracellular space.73 This release of ascorbate can also be induced by systemic administration of glutamate or aspartate, as would be seen in diets high in these excitotoxins . The other neurotransmitters do not have a similar effect on ascorbic acid release. This effect appears to be an exchange mechanism. That is, the ascorbic acid and glutamate exchange places. Theoretically, high concentration of ascorbic acid in the diet could inhibit glutamate release, lessening the risk of excitotoxic damage. Of equal importance is the free radical neutralizing effect of ascorbic acid.

There is now substantial evidence that ascorbic acid modulates the electrophysiological as well as behavioral functioning of the brain.74 It also attenuates the behavioral response of rats exposed to amphetamine, which is known to act through an excitatory mechanism.75 In part, this is due to the observed binding of ascorbic acid to the glutamate receptor. This could mean that ascorbic acid holds great potential in treating disease related to excitotoxic damage. Thus far, there are no studies relating ascorbate metabolism in neurodegenerative diseases. There is at least one report of ascorbic acid deficiency in guineas pigs producing histopathological changes similar to ALS.76

It is known that as we age there is a decline in brain levels of ascorbate. When accompanied by a similar decrease in glutathione peroxidase, we see an accumulation of h302 and hence, elevated levels of free radicals and lipid peroxidation. In one study, it was found that with age not only does the extracellular concentration of ascorbic acid decrease but the capacity of the brain ascorbic acid system to respond to oxidative stress is impaired as well.77

In terms of its antioxidant activity, vitamin C and E interact in such a way as to restore each others active antioxidant state. Vitamin C scavenges oxygen radicals in the aqueous phase and vitamin E in the lipid, chain breaking, phase. The addition of vitamin C suppresses the oxidative consumption of vitamin E almost totally, probably because in the living organism the vitamin C in the aqueous phase is adjacent to the lipid membrane layer containing the vitamin E.

When combined, the vitamin C is consumed faster during oxidative stress than vitamin E. Once the vitamin C is totally consumed, vitamin E begins to be depleted at an accelerated rate. N-acetyl-L-cysteine and glutathione can reduce vitamin E consumption as well, but less effectively than vitamin C. The real danger is when vitamin C is combined with iron. This is because the free iron oxidizes the ascorbate to produce the free radical dehydroxyascorbate. Alpha-lipoic acid acts powerfully to keep the ascorbate and tocopherol in the reduced state (antioxidant state). As we age, we produce less of the transferrin transport protein that normally binds free iron. As a result, older individuals have higher levels of free iron within their tissues, including brain, and are therefore at greater risk of widespread free radical injury.