Levosimendan exerts anticonvulsant properties against PTZ-induced seizures in mice through activation of nNOS/NO pathway: Role for K ATP channel Maziar Gooshe a,b,c,d , Mohammad Tabaeizadeh a,b , Ali Reza Aleyasin a,b , Payam Mojahedi a,b , Keyvan Ghasemi a,b,c,d , Farbod Yousefi a,b , Ali Vafaei a,b , Hossein Amini-Khoei a,b,e , Shayan Amiri a,b , Ahmad Reza Dehpour a,b,c, ⁎ a Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran b Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran c Brain and Spinal Injury Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran d Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran e Department of Physiology and Pharmacology, School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran abstract article info Article history: Received 18 September 2016 Received in revised form 7 November 2016 Accepted 8 November 2016 Available online 14 November 2016 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 condi- tions 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 K ATP channel opener and nitrergic pathway activator, levosimendan may exert antiseizure effects through K ATP channels and nitrergic pathway. Main methods: In this study, the effects of levosimendan on seizure susceptibility was studied by PTZ-induced sei- zures 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 K ATP channel blocker) and L-NAME (a non-selective NOS inhibitor) neutralize the anticonvul- sant and nitrite elevating effects of levosimendan. While 7-NI (a neural NOS inhibitor) blocked the anticonvul- sant effect of levosimendan, Aminoguanidine (an inducible NOS inhibitor) failed to affect the anticonvulsant effects of levosimendan. Cromakalim (a K ATP channel opener) or L-arginine (an NO precursor) augmented the an- ticonvulsant 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 K ATP /nNOS/NO pathway activation in the hip- pocampus and temporal cortex. © 2016 Elsevier Inc. All rights reserved. Keywords: Seizure Levosimendan PTZ K ATP channels Nitrergic system 1. Introduction With a prevalence of 1–2%, epilepsies undoubtedly impose a major burden upon patients and societies [1]. Despite major breakthroughs in the field of epilepsy research, anti-seizure medications do not provide sufficient seizure control in almost one-third of patients suffering from epilepsy [2,3]. Thus, investigation on new evidence-based therapeutical strategies is mandatory, and neuropharmacology can be a promising field for this purpose. Levosimendan is a novel pyridazinone-dinitrile derivate, well-known for positive inotropic effects through enhancing the sensitivity between Ca +2 and myofilaments and inhibiting the phosphodiesterase III activity [4]. Some studies suggest possible impact of calcium sensitizers including levosimendan on CNS, demonstrated as central symptoms such as head- aches, vertigo, flushing, and nausea [5]. Recent studies demonstrated that levosimendan can improve the survival rates in calcium channel blockers (CCBs) toxicity, which partly might be through seizure reduction as a common consequence of CCB toxicity [6–8]. Life Sciences 168 (2017) 38–46 ⁎ Corresponding author at: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran. E-mail addresses: Dr.mgooshe@gmail.com (M. Gooshe), Dehpour@yahoo.com (A.R. Dehpour). http://dx.doi.org/10.1016/j.lfs.2016.11.006 0024-3205/© 2016 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Life Sciences journal homepage: www.elsevier.com/locate/lifescie