Use of Glutamine in Chemotherapy-Induced Neuropathy; GABAergic Symptoms and Glutamate Depletion in Pyridoxine-Induced Neuropathy?

The authors of this article [Wang et al., 2007: (http://theoncologist.com/cgi/content/full/12/3/312) (http://www.ncbi.nlm.nih.gov/pubmed/17405895)] used 30 grams/d of L-glutamine to help prevent chemotherapy-induced peripheral neuropathy. There's a whole series of articles on this, and it's interesting. I don't know what the mechanism would be, but glutamine might just increase the pool of tricarboxylic acid (TCA) cycle intermediates in the neurons. This reminds me of that article showing that glutamic acid could prevent peripheral neuropathy induced by an excess of vitamin B6 (pyridoxine) (http://hardcorephysiologyfun.blogspot.com/2009/01/clues-to-mechanisms-of-excessive.html), and I'm thinking that the peripheral neuropathy that occurs in response to high doses of vitamin B6 might well be metabolic. The authors [Arkaravichien et al., 2003: (http://www.ncbi.nlm.nih.gov/pubmed/12909271)] of that article, discussing the prevention of pyridoxine-induced peripheral neuropathy with glutamic acid, attributed the prevention to glutamatergic mechanisms (i.e. an increase in glutamate storage and release), and that could be part of the mechanism. The activity of glutamic acid decarboxylase (GAD, an enzyme that converts glutamate to GABA) is thought to be very sensitive to pyridoxine intake (PLP availability) and to increase more than the activity of GABA transaminase [an enzyme that converts GABA into succinate semialdehyde and is another vitamin B6-derived-cofactor (PLP)-dependent enzyme] in response to an increase in PLP availability. As the dosage of pyridoxine is increased into the "peripheral-neuropathy-inducing" range of long-term dosages (125-150 or more mg/d), one would expect to see more GABAergic effects (sedation, slowing of mental function, depression, etc.).

PLP is a cofactor for over 100 enzymes, though. But GAD activity is known to increase more than other PLP-dependent enzymes' activities do, as the dosage of vitamin B6 is increased. The increases in GAD activity are evidently a result of the loose binding of PLP (in comparison to the binding of PLP to GABA transaminase and other PLP-dependent enzymes) to one of the isoforms of GAD that's expressed in the brain [Martin et al., 1991: (http://www.ncbi.nlm.nih.gov/pubmed/1685767)]. Increases in the transaminase enzymes that are PLP-dependent would produce really complicated effects on aspartate and glutamate [and on the activities of TCA cycle enzymes, by maintaining the flux of substrates through the enzymes whose activities sustain the malate-aspartate shuttle: (http://hardcorephysiologyfun.blogspot.com/2009/01/mechanisms-of-neuroprotection-by.html)], for example, and those changes could interact with the increases in GAD activity and conceivably lead to peripheral neuropathy. But PLP is also a cofactor for glycogen phosphorylase, and increases in the vitamin B6 intake tend to increase glycogenolysis. Vitamin B6 is used in McArdle's disease (a glycogen storage disease) to promote glycogenolysis, and that effect of vitamin B6 could be a double-edged sword and interfere with blood sugar regulation or even lead, in concert with other PLP-dependent changes, to astrocyte glycogen depletion (and produce some degree of peripheral neuropathy by increasing the frequencies of efferent discharges from primary afferent neurons, with the action potentials or inflammatory changes originating at the central terminals of the primary afferent neurons, etc.). PLP bound to glycogen phosphorylase in skeletal muscles turns over really slowly and is tightly-bound, but I think that's not necessarily relevant to the issue of peripheral neuropathy (sensitivity to pyridoxine status doesn't correlate inversely with the tightness of bound PLP to all PLP-dependent enzymes, just with GAD). Peripheral neuropathy due to an excess of pyridoxine tends to develop gradually, but I'm just saying that there's not going to be a magic, cut-off dosage that won't produce any neuropathic changes but will produce purely "therapeutic" or desirable effects. The mechanisms leading to neuropathy are, in my opinion, going to be present at a low level at lower dosages. In any case, I think that some of those GABAergic effects of high dosages of vitamin B6 should be viewed as being, in my opinion, "pre-neuropathic."