Abstracts

RATIONALE: Several lines of evidence suggest an important role for gap junctional mediated communication in the generation of seizures. Electrotonic coupling via gap junctions mediates fast oscillatory synchronization and blockage of gap junctional communication inhibits epileptiform activity in various [italic]in vitro[/italic] models of epilepsy. Moreover, fast oscillations have been observed at the onset of seizures in humans suffering from epilepsy (1). Long chain n-alcohols, in particular heptanol and octanol, have been shown to uncouple gap junctions (GJ) possibly by interfering with the Vm-sensitive gating mechanism of GJ channels (2). Besides the uncoupling effect of GJs, octanol has been shown to inhibit both sodium and calcium channels and to be a positive modulator of GABA[sub]A[/sub] receptors (3, 4). Heptanol is generally considered to be more specific as a gap junctional blocker (1). Biological effects of nonanol have not previously been described. We investigated the anticonvulsant effects of heptanol, octanol and nonanol in mice models of epilepsy.
METHODS: The alcohols were tested in pentetrazole (PTZ) threshold and maximal electroshock threshold (MEST) tests in mice. Furthermore, effects against PTZ (35 mg/kg)- induced myoclonic and clonic convulsions were assessed in PTZ-kindled mice. All doses that were used were below those that produced motor impairment in the rotarod test.
RESULTS: Heptanol, octanol and nonanol significantly raised the threshold at 700 mg/kg when tested in the MEST and PTZ-threshold. At 350 mg/kg heptanol, 29% and 43% mice were protected against myoclonic and clonic convulsions, respectively. At 700 mg/kg, 0% and 29% were protected against myoclonic and clonic convulsions, respectively. At 700 mg/kg octanol, 43% and 57% were protected against myoclonic and clonic convulsions, respectively. At 175 mg/kg nonanol, 57% and 33% were protected against myoclonic and clonic convulsions, respectively.
CONCLUSIONS: These results show that heptanol, octanol and nonanol possess anticonvulsive properties in mice models of epilepsy. However, additional studies are required in order to clarify whether these effects can be ascribed to uncoupling of gap junctions or other pharmacological activities.

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