Amiloride and sn-6 suppress audiogenic seizure susceptibility in genetically epilepsy-prone rats

Abstract

Aims: We have recently reported that amiloride, a potent and nonselective blocker of acid-sensing ion channels, prevents the development of pilocarpine-induced seizures and status epilepticus. Amiloride is also known to suppress the activity of Na+/Ca2+ and Na+/H+ exchangers that have been implicated in the pathophysiology of seizures. Here, we evaluated the effects of amiloride, SN-6 (a potent blocker of Na+/Ca2+ exchangers) and zoniporide (a potent blocker of Na+/H+ exchangers) on acoustically evoked seizures (audiogenic seizures, AGS) in genetically epilepsy-prone rats (GEPR-3s), a model of inherited generalized epilepsy. Methods: Male, six-week-old GEPR-3s were used. The GEPR-3s were tested for AGS susceptibility before and after treatment with various doses of amiloride, SN-6, and zoniporide (1, 3, 10, and 30 mg/kg; per os). Results: We found that pretreatment with amiloride and SN-6 markedly reduced the incidence and severity of AGS in the GEPR-3s. In contrast, administration of zoniporide only minimally reduced the incidence and severity of AGS in the GEPR-3s. A combination of noneffective doses of SN-6 and zoniporide also suppressed AGS susceptibility in the GEPR-3s. Conclusions: These findings suggest acid-sensing ion channels and the Na+/Ca2+ exchanger may play an important role in the pathophysiology of inherited AGS susceptibility in the GEPR-3s. © 2014 John Wiley & Sons Ltd.