"Non-metabolic" and Proconvulsant Effects of Folic Acid and Reduced Folates

Going through some of these articles will help me learn about and remember some of this. There's this whole series of old articles that show epileptogenic effects of intracerebroventricular injections (injections into one of the ventricles in the brain) of folates. Here are some links to articles or old references, and there are many on this subject:

http://www.ncbi.nlm.nih.gov/pubmed/4402646

http://www.nature.com/nature/journal/v293/n5834/abs/293654a0.html
(pubmed id: http://www.ncbi.nlm.nih.gov/pubmed/6117018)

http://www.nature.com/nature/journal/v292/n5819/abs/292165a0.html
(pubmed id: http://www.ncbi.nlm.nih.gov/pubmed/6972487)

I haven't gotten the full texts of those, and I don't know what the extracellular concentrations of the folates were (in response to the injections). I have a feeling that high and supraphysiological, extracellular concentrations would be required to cause those effects, but it's worthwhile to be aware of all these possibilities.

This article shows that the proconvulsant effects can be limited or prevented by removal of the polyglutamate chain:

http://www.ncbi.nlm.nih.gov/pubmed/10528109

That type of result is sort of nonphysiological, because polyglutamylation of folates tends to trap them intracellulary and act as a "tether" to transfer folate-derived coenzymes between enzymes whose activity is coupled. One wouldn't expect to find high levels of polyglutamylated folate cofactors extracellularly. The authors also used extracellular concentrations of 300 micromolar (uM) to 30 millimolar (mM), and those are grossly-supraphysiological concentrations.

In most of the articles I've seen on the proconvulsant effects of folates, the folate is supposedly acting as an agonist or positive allosteric modulator of NMDA receptors or kainate receptors or other glutamate receptor subtypes. I think there are a lot of possibilities, though. These effects probably do occur, to some extent, at very high doses of folic acid or 5-methyltetrahydrofolate.

Nonetheless, large numbers of articles are similar to this one and show that folate depletion from the brain actually leads to increases in NMDA receptor activation, in part by increasing both homocysteine and the proconvulsant effects of homocysteine, and thereby produces excessive calcium influx into neurons and neuronal damage:

http://www.ncbi.nlm.nih.gov/pubmed/13678664

This article, below, has some interesting references on reports of sleeplessness or excessive arousal on high-dose folic acid, but this article doesn't make a convincing case for proconvulsant effects of folates at reasonable dosages (there's no information on concentrations under normal conditions, and the convulsant effects are mainly discussed in the context of animals with permeabilized blood-brain barriers or in patients with major neurological damage due to subacute combined degeneration):

http://jnnp.bmj.com/cgi/content/abstract/72/5/567

That article references some interesting articles, though, and the overall idea--that supraphysiological (>5-10 mg/d) doses of folic acid probably could produce proconvulsant effects--is valid. On page 569 of that article, though, the author makes the important point that folic acid can temporarily enhance cell proliferation, as evidenced by reticulocytosis (an acute increase in the numbers of immature red blood cells in the blood), in people with B12 deficiency but then worsen the situation in the longer term. I discussed that phenomena in a previous posting (http://hardcorephysiologyfun.blogspot.com/2008/12/methylfolate-trap.html), and it's the overall message of the article I linked to in that posting: (http://www.ncbi.nlm.nih.gov/pubmed/6974730?dopt=Abstract). It's a really important point.

I don't think folates exert their neuropsychiatric effects by acting in some selective way on dopaminergic, noradrenergic, or serotonergic neurotransmission. There's a tendency to attribute everything to those three neurotransmitter systems, but it doesn't make sense to me. To the extent that something like exogenous 5-methyltetrahydrofolate has a dopaminergic or noradrenergic effect, I think it's more likely to be the result of something like the modification of glycolysis and gluconeogenesis in astrocytes, the elevation of purine salvage in the basal ganglia (hypoxanthine-guanine phosphoribosyltransferase, a major purine salvage enzyme, is expressed at very high levels in the basal ganglia, and neurons in the basal ganglia have an extremely low capacity for de novo purine biosynthesis) in a way that would modify dopaminergic activity, or an enhancement of mitochondrial activity in dopaminergic or noradrenergic neurons (dopaminergic neurons and other groups of neurons in the basal ganglia have very high oxidative capacity and metabolic requirements) by increasing cerebral blood flow or purine salvage or decreasing the AICAR-mediated inhibition of mitochondrial activity, etc.