Mechanisms of Neuroprotection by Vitamin B6: Potential Involvement of the Malate-Aspartate Shuttle

This article [Geng et al., 1995: (http://www.ncbi.nlm.nih.gov/pubmed/8848291)] is interesting, and the authors found that the neuroprotective effects of pyridoxine (vitamin B6) in cultured neurons were evidently dependent, in part, on the PLP (pyridoxal 5'-phosphate, or coenzymated pyridoxine) mediated increases in the activities of one or more transaminase enzymes. Geng et al. (1995) found that the pyridoxine-mediated neuroprotection could be blocked by the GABA-A receptor antagonist picrotoxin or by ifenprodil, an antagonist at the polyamine binding site on the NR2B subunit of the NMDA receptor (more specifically, for polyamine-sensitive epsilon2 NMDA receptors, containing NR1A and NR2B subunits) [Gallagher et al., 1996: (http://www.jbc.org/cgi/content/full/271/16/9603) (http://www.ncbi.nlm.nih.gov/pubmed/8621635?dopt=Abstract)]. Polyamines can either inhibit or activate NMDA receptors, and the effects of polyamines (such as spermidine, spermine, putrescine, N-acetylspermidine, etc.) depend on the extracellular (synaptic) concentration of glycine (Gallagher et al., 1996). Pyridoxine could increase glycine availability by increasing the activities of the cytosolic or mitochondrial serine hydroxymethyltransferase (cSHMT or mtSHMT) enzymes in neurons, but PLP is a cofactor for ornithine decarboxylase [Hillary et al., 2003: (http://www.ncbi.nlm.nih.gov/pubmed/12686127)]. Ornithine decarboxylase is one of the rate-limiting enzymes required for polyamine biosynthesis. The pyridoxine probably stimulated polyamine biosynthesis. Geng et al. (1995) speculated that the GABAergic neuroprotection had occurred through a PLP-induced increase in glutamic acid decarboxylase activity.

The involvement of aminotransferase enzymes in the neuroprotection is really interesting, and Geng et al. (1995) suggested that the additional, exogenous pyridoxine had activated PLP-dependent aminotransferase enzymes that normally maintain the malate-aspartate shuttle. The malate-aspartate shuttle normally maintains the activities of the mitochondrial tricarboxylic acid cycle enzymes, and inhibition of the malate-aspartate shuttle per se inhibits mitochondrial ATP production (http://hardcorephysiologyfun.blogspot.com/2009/01/cytosolic-redox-state-and-tca-cycle.html). That's a really interesting mechanism, and the effects of pyridoxine on mitochondrial activity tend to get overlooked. It's strange, because there's evidence that the mitochondrial damage to the liver in pyridoxine deficiency, referred to as fatty liver disease [Inubushi et al., 2005: (http://www.ncbi.nlm.nih.gov/pubmed/16179747)], is potentially more severe than the damage produced by depletion of other cofactors (pyridoxine depletion has been said to produce "florid cirrhosis," preceded by the mitochondrial injury that characterizes fatty liver disease) [Lumeng et al., 1974: (http://www.ncbi.nlm.nih.gov/pubmed/4359937)]. The inhibition of the malate-aspartate shuttle, by an adequate pool of PLP, could be one mechanism that would help explain the mitochondrial damage that occurs in pyridoxine deficiency. Almost all of the B-vitamins have been shown to produce fatty liver in animals and, directly or indirectly, in humans as well. But the effects of pyridoxine on mitochondrial activity have been really overlooked. The neglect and lack of awareness of those effects is probably a result, in part, of the capacity of pyridoxine to produce peripheral neuropathy at doses larger than 150-200 mg/d in the long term. There must be some mechanism for that neuropathy, but no one knows what it is.