Efficacy of retigabine in ameliorating the brain insult following sarin exposure in the rat.

BACKGROUND

Sarin is an irreversible organophosphate cholinesterase inhibitor. Following toxic signs, an extensive long-term brain damage is often reported. Thus, we evaluated the efficacy of a novel anticonvulsant drug retigabine, a modulator of neuronal voltage gated K channels, as a neuroprotective agent following sarin exposure.

METHODS

Rats were exposed to 1 LD or 1.2 LD sarin and treated at onset of convulsions with retigabine (5 mg/kg, i.p.) alone or in combination with 5 mg/kg atropine and 7.5 mg/kg TMB-4 (TA) respectively. Brain biochemical and immunohistopathological analyses were processed 24 h and 1 week following 1 LD sarin exposure and at 4 weeks following exposure to 1.2 LD sarin. EEG activity in freely moving rats was also monitored by telemetry during the first week following exposure to 1.2 LD and behavior in the Open Field was evaluated 3 weeks post exposure.

RESULTS

Treatment with retigabine following 1 LD sarin exposure or in combination with TA following 1.2 LD exposure significantly reduced mortality rate compared to the non-treated groups. In both experiments, the retigabine treatment significantly reduced gliosis, astrocytosis and brain damage as measured by translocator protein (TSPO). Following sarin exposure the combined treatment (retigabine+ TA) significantly minimized epileptiform seizure activity. Finally, in the Open Field behavioral test the non-treated sarin group showed an increased mobility which was reversed by the combined treatment.

CONCLUSIONS

The M current modulator retigabine has been shown to be an effective adjunct therapy following OP induced convulsion, minimizing epileptiform seizure activity and attenuating the ensuing brain damage.