Anticonvulsant effect of the calcineurin inhibitor ascomycin on seizures induced by picrotoxin microperfusion in the rat hippocampus

The potential in vivo anticonvulsant effect of calcineurin (protein phosphatase 2B) inhibitor ascomycin against seizures induced by intrahippocampal microdialysis of picrotoxin was examined in the present study. After establishing individual picrotoxin seizure thresholds, ascomycin was continually microperfused into the rat hippocampus through microdialysis probes at concentrations 10, 50 and 100 μM. No behavioral or electroencephalographic effects were observed during microperfusion of ascomycin alone. Low concentrations (10 μM) of ascomycin did not prevent picrotoxin seizures, however, 50 and 100 μM ascomycin showed antiepileptic effect, completely suppressing seizures in 41.7% and 75% of the animals studied respectively. Mean seizure duration and mean number of seizures were significantly reduced (P < 0.01) by microperfusion of 100 μM ascomycin. Calcineurin activity might be involved in the biochemical changes leading to picrotoxin-induced epileptic seizures. The present findings provide additional in vivo evidence of the involvement of phosphorylation/dephosphorylation mechanisms in the development of epileptic seizures, suggesting that calcineurin modulation may be a possible strategy in the search for new anticonvulsant drugs.