Anticonvulsant and adverse effects of avermectin analogs in mice are mediated through the gamma-aminobutyric acid(A) receptor

Twenty-five avermectin analogs were assessed in a mouse seizure model. The ED50 against pentylenetetrazole-induced tonic seizures ranged from 0.48 mg/ kg (L-676,893) to >160 mg/kg (L-685,869) cf. 0.26 mg/kg for diazepam. Altho ugh avermectins are without acute toxic effects, they have been historicall y shown to have relative low LD50 values in mammals. The mechanisms involve d in the anticonvulsant effect and the toxicity were investigated. A series of avermectin analogs displaced [H-3]ivermectin binding to rat brain membr anes and recombinant GABA(A) receptors (alpha1 beta3 gamma2-subtype) with t he same affinities, strongly suggesting that [H-3]ivermectin labels the GAB A(A) receptor in rodent brain. Avermectins, which were anticonvulsant, were also potent inhibitors of [H-3]ivermectin binding in rat brain. However, t he rank order for anticonvulsant activity did not parallel the rank order f or affinity at the [H-3]ivermectin site and it was reasoned that avermectin s may have differential affinity or efficacy at subtypes of the GABA(A) rec eptor. All the active compounds tested potentiated the effects of GABA at r ecombinant GABA(A) receptors in oocytes and at native cortical GABA(A) rece ptors and the efficacy of avermectins at the GABA(A) receptor correlated be st with their anticonvulsant potency. Although avermectins weakly inhibited [H-3]strychnine binding in rat spinal cord, and inhibited glycine response s on primary cultured cortical neurons, activity at glycine receptors did n ot correlate with either anticonvulsant activity or toxicity. Because both anticonvulsant activity and toxicity correlated best with activity at GABA( A) receptors, it is unlikely that these effects can be separated, which may contraindicate the potential use of avermectins as anticonvulsants.