AIMS: Kainic acid (KA), a rigid analog of the excitatory amino acid glutamate, has been widely used to create an excellent animal model for studying human temporal lobe epilepsy. A single injection of KA to rats induces long-lasting recurrent seizures and perhaps permanent biochemical and morphological changes in the brain which resemble the alterations found in patients with temporal lobe epilepsy. The purpose of this study was to elucidate the molecular mechanisms underlying the regulation of the long-term changes of two classes of opioid peptides, enkephalins and dynorphins, which are important neuromodulators regulating the seizure threshold in the hippocampus. ACCOMPLISHMENTS: Recently, we have demonstrated that a single injection of KA up- regulates proenkephalin mRNA and down-regulates prodynorphin mRNA in the rat hippocampus for at least one year. In addition, we observed permanent morphological changes in the hippocampus of KA-injected rats, i.e., mossy fiber sprouting. We hypothesized that these long-term biochemical and morphological changes may underlie the mechanism for the permanent changes in seizure threshold. To examine this possibility, we employed a pharmacological agent, scorpion venom (SV), which has been used for centuries in patients suffering from temporal lobe epilepsy in China, however, the modes of action of SV are not clear. Daily injections of SV to KA-treated rats for two to three weeks showed clear differences compared with the saline-treated control : 1) Reduced recurrent seizures. When KA-injected rats were challenged with second injections of subconvulsive doses of KA, most of saline - injected rats showed extensive convulsions, whereas SV-treated rats showed significantly reduced seizures. 2) Mossy fiber sprouting did not appear in SV-treated group. 3) SV injections prevented the up- regulation of the proenkephalin gene and down-regulation the prodynorphin gene in the hippocampus.These findings indicate that SV is an effective therapy for temporal lobe epilepsy.This study also demonstrate the utility of this pharmacological tool for further research on the mechanism of recurrent seizures. Experiments are underway to isolate the active principle(s) responsible for the anticonvulsive actions. Further studies ialong this line of research should provide insights into the etiology of temporal lobe epilepsy. - kainic acid, amino acid glutamate, opioid peptides, enkephalins, dynorphins, neuromodulators
