Levosimendan exerts anticonvulsant properties against PTZ-induced seizures in mice through activation of nNOS/NO pathway: Role for KATP channel.

AIMS: Although approving new anticonvulsants was a major breakthrough in the field of epilepsy control, so far we have met limited success in almost one third of patients suffering from epilepsy and a definite and reliable method is yet to be found. Levosimendan demonstrated neuroprotective effects and reduced mortality in conditions in which seizure can be an etiology of death; however, the underlying neuroprotective mechanisms of levosimendan still eludes us. In the light of evidence suggesting levosimendan can be a KATP channel opener and nitrergic pathway activator, levosimendan may exert antiseizure effects through KATP channels and nitrergic pathway.

MAIN METHODS: In this study, the effects of levosimendan on seizure susceptibility was studied by PTZ-induced seizures model in mice.

KEY FINDINGS: Administration of a single effective dose of levosimendan significantly increased seizures threshold and the nitrite level in the hippocampus and temporal cortex. Pretreatment with noneffective doses of glibenclamide (a KATP channel blocker) and L-NAME (a non-selective NOS inhibitor) neutralize the anticonvulsant and nitrite elevating effects of levosimendan. While 7-NI (a neural NOS inhibitor) blocked the anticonvulsant effect of levosimendan, Aminoguanidine (an inducible NOS inhibitor) failed to affect the anticonvulsant effects of levosimendan. Cromakalim (a KATP channel opener) or l-arginine (an NO precursor) augmented the anticonvulsant effects of a subeffective dose of levosimendan. Moreover, co-administration of noneffective doses of Glibenclamide and L-NAME demonstrated a synergistic effect in blocking the anticonvulsant effects of levosimendan.

SIGNIFICANCE: Levosimendan has anticonvulsant effects possibly via KATP/nNOS/NO pathway activation in the hippocampus and temporal cortex.