A multidisciplinary study of folic acid neurotoxicity: Interactions with kainate binding sites and relevance to the aetiology of epilepsy

Folic acid has been injected unilaterally into the amygdaloid complex of awake chronically implanted rats, or in rats under anaesthesia. Clinical, electrographic and metabolic changes (estimated by means of the 2-deoxyglucose method) have been studied in relation to subsequently demonstrated neuropathology using Fink-Heimer and Nissl stains. The observations are compared to the corresponding effects of intra-amygdaloid application of kainic acid.Major differences were noted between the folate and the kainate induced seizure/brain damage syndrome. Thus: (a) folate produced essentially stereotypies, alternating with myoclonic unilateral jerks of head and limbs. In contrast, limbic motor seizures which are characteristically produced by kainic acid, were extremely rare, (b) Folate did not produce the preferential and sequential electrographic activation of limbic structures as observed after kainate. (c) 2-Deoxyglucose autoradiography revealed an enhanced metabolic activity in the injected amygdala and in the overlying piriform and entorhinal cortices. The most conspicuous rise in labelling, however, occurred in the entire fronto-parietal cortex (ipsilaterally) up to the cingulate region, as well as in the ventral thalamic complex and the globus pallidus, i.e. in structures which are not labelled after kainate treatment. (d) Some extent of local damage was observed 1–8 days after the injection; distant from the injection site, we found massive anoxic-ischemic type of damage in the superficial layers of the fronto-parietal cortex, a complete necrosis of the piriform lobe and neuronal cell loss in the ventral thalamus and several extrapyramidal structures. The full range of limbic damage associated with kainate was never produced by folate. The CA3 region of the hippocampus, most susceptible to kainate, was only mildly affected by folate.These differences between kainate and folate prompted us to re-evaluate the recently reported high affinity of folates for kainic acid membrane binding sites. We found that folic acid competed only very weakly with ³H]kainic acid for binding sites on striatal, cortical, hippocampal, amygdaloid and cerebellar membranes. It is thus concluded, that folate is not a good candidate for an endogenous kainate-like substance. We propose intracerebral injections of folic acid as a useful tool to study the vulnerability of brain structures to anoxic-ischemic conditions.