Amiloride enhances the anticonvulsant action of various antiepileptic drugs in the mouse maximal electroshock seizure model

Abstract

Accumulating evidence indicates that amiloride (a potassium-sparing diuretic) exerts the anticonvulsant action in various in vivo and in vitro experiments. Therefore, the objective of this study was to assess the influence of amiloride on the protective action of numerous conventional and second-generation antiepileptic drugs [AEDs: carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), topiramate (TPM), and valproate (VPA)] against maximal electroshock (MES)-induced seizures in mice. Results indicate that amiloride [up to 100 mg/kg, intraperitoneally (i.p.), at 30, 60, and 120 min before the test] neither altered the threshold for electroconvulsions, nor protected the animals against MES-induced seizures in mice. Moreover, amiloride (75 and 100 mg/kg, i.p., 120 min prior to the test) significantly enhanced the anticonvulsant effects of all studied AEDs, except for LTG, by reducing their ED(50) values in the MES test. In contrast, amiloride at 50 mg/kg (i.p.) had no significant effect on the antielectroshock action of the tested AEDs in mice. Estimation of total brain AED concentrations revealed that amiloride (75 mg/kg) significantly increased total brain concentrations of CBZ, OXC, and PB, but not those of LTG, TPM, and VPA in mice. In conclusion, one can ascertain that the potentiation of the antiseizure action of TPM and VPA by amiloride in the MES test and lack of any pharmacokinetic interactions between drugs, make the combinations of amiloride with TPM and VPA of pivotal importance for epileptic patients.

International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na+Channel

“…Because inhibitory interneurons in hippocampus display higher ASIC current amplitudes than pyramidal neurons it is possible that the interneuron-mediated inhibition ended the seizures (Ziemann et al, 2008). Observations of seizure inhibition by high concentrations ASIC and ENaC Function and Pharmacology of amiloride (Ali et al, 2006;N'Gouemo, 2008;Luszczki et al, 2009) appear to contradict the role of ASIC1a in seizure termination. Because of its hydrophilic nature, amiloride is expected not to cross the blood-brain barrier, and it is currently not clear whether it reaches the brain or whether it exerts anti-seizure effects by other mechanisms.…”

Ion Channels as Drug Targets in Central Nervous System Disorders

“…One of them showed that acidsensing ion channel 1a (ASIC1a) activation enhances neuronal excitability in the hippocampus and neocortex, indicating that ASIC1a might play a role in the generation and maintenance of epileptic seizures [292]. Other publication mentioned that ASICs' inhibitor -amiloride neither altered the threshold for electroconvulsions, nor protected the animals against MES-induced seizures in mice but amiloride administered 75 and 100 mg/kg, i.p., 120 min prior to the test significantly enhanced the anticonvulsant effects of carbamazepine, oxcarbamazepine and phenobarbital, by reducing their ED 50 values in the MES test [291]. On the other hand, there was also established that seizures reduce extracellular pH.…”

Effect of nifedipine, imipramine and sertraline on the antidepressant-like actions of furosemide in forced swim (FST) and tail suspension (TST) tests models of depression in mice

“…The mice were injected intraperitoneally (i.p.). The doses of drugs were chosen from previous studies (Eraly et al, 2006;Luszczki et al, 2003;Cryan et al, 2004;Kosuda et al, 1997;Hesdorfffer et al, 2001;Mogilnicka et al, 1987).…”