Y.-Q. Pei

Chemical models of epilepsy with some reference to their applicability in the development of anticonvulsants

This paper reviews chemical models of epilepsy and their relevance in the identification and characterization of anticonvulsants. For each convulsant we discuss possible modes of administration, clinical type(s) of seizures induced, proposed mechanism(s) of epileptogenesis and, where available, responsiveness of the induced seizures to anticonvulsants. The following compounds are reviewed: pentylenetetrazol, bicuculline, penicillin, picrotoxin, beta-carbolines, 3-mercaptopropionic acid, hydrazides, allylglycine; the glycine antagonist strychnine; gamma-hydroxybutyrate; excitatory amino acids (glutamate, aspartate, N-methyl-D-aspartate, quisqualate, kainate, quinolinic acid); monosubstituted guanidino compounds, metals (alumina, cobalt, zinc, iron); neuropeptides (opioid peptides, corticotropin releasing factor, somatostatin, vasopressin); cholinergic agents (acetylcholine, acetylcholinesterase inhibitors, pilocarpine); tetanus toxin; flurothyl; folates; homocysteine and colchicine. Although there are a multitude of chemical models of epilepsy, only a limited number are applied in the routine screening of potential anticonvulsants. Some chemical models have a predictive value with regard to the clinical profile of efficacy of the tested anticonvulsants. Some chemical models may contribute to a better understanding of possible mechanisms of epileptogenesis.

N-Methyl-d-aspartate receptors contribute to guanidinosuccinate-induced convulsions in mice

Increased levels of the endogenous convulsant guanidinosuccinate (GSA) might contribute to the epileptic symptomatology presenting in patients with renal failure. Little is known, however, about the underlying epileptogenic mechanism of guanidinosuccinate-induced convulsions. In this paper, we present pharmacological evidence for a direct excitatory action of this compound. In particular, the close involvement of N-methyl-D-aspartate (NMDA) receptors in the pathogenesis of GSA-induced generalized convulsions is suggested. GSA potentiated NMDA-induced convulsions significantly, but not L-glutamate- or kainate-induced convulsions. Conversely, and in addition, NMDA receptor antagonists, like D(-)-2-amino-5-phosphonovalerate, CGP 37849 [DL)-(E)-2-amino-4-methyl-5-phosphono-3-pentenoate] or ketamine (but not kynurenate), blocked the convulsions induced by i.c.v. injection of GSA dose dependently whereas anti-epileptic drugs, like carbamazepine, diazepam, phenobarbital or valproate, only abolished the tonic extension phase of these convulsions. Thus, NMDA receptors appear to be involved, at least partly, in GSA-induced convulsions.

Behavioral toxicity of guanidinosuccinic acid in adult and young mice

Guanidinosuccinic acid (GSA), a guanidino compound found to be greatly increased in uremia, was administered by intraperitoneal (i.p.) injection to adult albino mice and to young mice 7, 14 and 21 days old. Epileptogenic and toxic properties were assessed and GSA brain levels following i.p. injection were determined. In adult mice, GSA induced long-lasting generalized clonic and clonic-tonic convulsions in a dose-dependent manner with a CD50 (and 95% confidence interval) of 363 (287-458) mg/kg (n = 35), and an LD50 of 579 (445-756) mg/kg. The CD50 of GSA corresponded with a brain concentration of 56 nmol/g tissue. Electrocorticographic recording in five adult mice revealed epileptiform discharges (spikes, spike-waves, and polyspike-waves) which appeared concomitant with the convulsions. When young mice were i.p. injected with a (for adults) subconvulsive dose of GSA (250 mg/kg), an age-dependent decrease was noted in GSA-induced convulsions and in the resulting brain concentration. The presented findings suggest that GSA could be an important uremic toxin which could contribute to the epileptic symptomatology in uremia.