Failure of folic acid derivatives to mimic the actions of kainic acid in brain in vitro or in vivo.
The ability of three derivatives of folic acid, N-5-methyltetrahydrofolic acid (MTHF), tetrahydrofolic acid (THF) and dihydrofolic acid (DHF) to mimic the actions of kainic acid (KA) in a number of in vitro and in vivo systems known to be sensitive to KA was examined. None of the three folate derivatives at 100 microM concentration significantly inhibited the specific binding of [3H]-KA to striatal membranes although 2 microM L-glutamate produced a 40% inhibition. None of the three folate derivatives stimulated the formation of cyclic GMP in cerebellar slices incubated in vitro although KA (0.5 mM) increased cyclic GMP levels by 2.5-fold. Whereas intrahippocampal injection of 2.3 nmoles of KA produces prolonged abnormalities of the EEG, limbic-type seizures and a characteristic pattern of neuronal degeneration in the hippocampal formation and related structures, intrahippocampal injection of a 100-fold greater dose of THF caused only minor and transient EEG abnormalities, no overt seizures and a highly restricted lesion. Whereas intrastriatal injection of 5.6 nmoles of KA caused a profound reduction in the specific activities of choline acetyltransferase and glutamate decarboxylase, markers for striatal intrinsic cholinergic and GABAergic neurons, 50-fold greater doses of MTHF did not affect either enzyme although this high dose of THF did cause a significant 33% reduction in choline acetyltransferase activity. These findings support the suggestion that THF may have weak neurotoxic effects in brain but indicate that the actions of this compound and the related MTHF and DHF are not mediated through KA-specific receptors.
D000818:Animals; D001921:Brain / Q000187:drug effects*; D002531:Cerebellum / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D004569:Electroencephalography; D005071:Evoked Potentials / Q000187:drug effects; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects; D007608:Kainic Acid / Q000378:metabolism / Q000633:toxicity*; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D011759:Pyrrolidines / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000187:drug effects; D018092:Kainic Acid Receptors; D013763:Tetrahydrofolates / Q000633:toxicity*
D006152:Cyclic GMP; D005492:Folic Acid; D007608:Kainic Acid; D018377:Neurotransmitter Agents; D011759:Pyrrolidines; D011956:Receptors, Cell Surface; D018092:Kainic Acid Receptors; D013763:Tetrahydrofolates; C010920:dihydrofolate; C030371:5,6,7,8-tetrahydrofolic acid; C005984:5-methyltetrahydrofolate