Neurotoxic action of methyltetrahydrofolate in rat cerebellum unrelated to direct activation of kainate receptors

Abstract

Kainic acid is a potent neuroexcitant with neurotoxic properties—its infusion into the cerebellar cortex of rat and hamster selectively destroys inhibitory neurones^1–3. Electrophysiological⁴ and neurochemical⁵ data indicate that kainate is unlikely to act through the predominant type of receptor for L-glutamate. Thus, kainate may interact either with a specific subclass of glutamate receptor or with receptors for an unidentified endogenous neuroexcitant. Recently, it was reported that the pteroylmonoglutamate compound, methyltetrahydrofolate (MTHF), is a potent inhibitor of ³H-kainate binding to rat cerebellar membranes, while not influencing the binding of L-glutamate, and exhibits an activity approximately 1/10th of that of kainate itself⁶. As MTHF, like kainate, has convulsive properties^7,8, we have investigated the possibility that this substance also exhibits neurotoxic effects. Here, we report that 2 weeks after intracerebellar injections of MTHF (250 nmol) there was a substantial loss of Purkinje cells and a reduction in associated markers for functions mediated by γ-aminobutyric acid (GABA). However, the time course of degeneration after MTHF was much slower than with kainate, and in contrast to kainate and other neurotoxic amino acids, MTHF did not increase the levels of cyclic GMP in cerebellar slices. A direct effect of MTHF on receptors for kainate therefore seems unlikely.