Study of Synergistic Anticonvulsant Effects of Pregabalin/Nimodipine and Pregabalin/Amlodipine on Acute and Chronic Seizure Models in Mice

Abstract

After stroke epilepsy is the second most common neurological disorder. It occurs due to abnormal neuronal discharge. It is characterized by unprovoked and recurrent seizures which are known as epileptic seizures. Clinically it is manifested in variety of ways from minor physical convulsions to severe tonic-clonic seizures with or without loss of consciousness. Status epilepticus is an acute exacerbation of common epilepsies and life threatening medical emergency, it must be treated or else it may cause serious damage to the brain and even death in many cases. For the management of epilepsy, the antiepileptic drugs, including second and third generations have extensively widened the choice of the drugs for the physicians; however, the efficacy and the antiseizure effects of these drugs are not satisfactory. There is limited choice of drugs for the management of status epilepticus. Keeping these challenges in mind the present study was carried out to investigate the synergistic anti-seizure/antiepileptic effects of combined regimens of Pregabalin with Amlodipine (PGB/AML) and Pregabalin with Nimodipine (PGB/NMD ) on acute and kindled models of epilepsy in mice. Current research suggests that calcium influx in neurons plays important role in the genesis of seizures, therefore, the calcium antagonists have potential to be used as anticonvulsants. Anti-seizure actions of PGB can be augmented/potentiated or modified if given in combination with calcium channel inhibitors AML and NMD.The rationale for selecting this combination was based on facts that AML and NMD have synergistic anti seizure effects s on PGB and calcium channel blockers have inhibitory effects on voltage-gated calcium channel blockers. we designed the working hypothesis for the present study stating that the in combination-therapies AML and NMD would potentiate and enhance the anti-seizure effects of PGB by their inhibitory and modulating effects on the calcium channels of the CNS. We examined and analyzed the combination therapy from multiple dimensions both in acute model of seizures as well as in kindled model of epileptogenesis.Our proposed hypothesis that anti-seizure actions of PGB can be augmented or modified if given in combination with AML and NMD had been substantiated by our results. The Combination regimens we employed in the instant experimental animal study were novel and demonstrated significant seizure protection. Our study has established that in both in-vivo models of seizures the combined regimens have demonstrated synergism between PGB and both calcium channel blockers (AML and NMD) incrasing the latent periods, reducing the duration of seizures and increasing the mortality protection in mice.. We are inclined to hold that PGB:AML and PGB:NMD provided synergistic antiseizure effects in both seizure models. PGB:AMLin acute as well as in kindled modelsprovidedupto 100 percent seizure protection and complelety abolished the generation of seizures at the doses of 5055mg/kg of PGB with 12.5-15 mg/kg of AML(fifth and sixth doses)comparable to reference drugsVPT, PHT and DZ. PGB:NMD provided 100 percent seizure protectionat the dose of 55mg/kg of PGB with 15 mg/kg (sixth dose) only in Kindled model of seizure. PGP:AML demonstrated more efficacious and potent anti seizure effects as compared to PGB:NMD. We presume that both the calcium channel blockers exhibited their anti seizure effects by potentiating the antiseizure effects of PGB in both combined regimens.In the light of present study the major advantage of combination therpy would be that low doses of PGB could be employed that would be atleast six times in potency to its individual effects, thus reducing the doses of the PGB.The combination regimens broader spectrum of antiepileptic usage as compared to ther AEDs is another advantage. This study has provided some basic ground-work guidelines for the future clinical use of combination therapies of PGB with AML and NMD in various forms of epilepsies both for the short term management in conditions like status epilepticus and non epilepticus seizures as well as for the long term management of epilepsy. AML and NMD deserves attention from a clinical point of view, as a potentially favorable drugs that could be applied in epileptic patients treated with PGB, who additionally requires calcium channel antagonist for reasons other than epilepsy such as hypertensive patients. Though, presently intravenous/ parenteral preparations of PGB is not available, however, it can be hoped that in near future the the availability of PGB parenteral formulations would provide alternate treatment options as combination therapies with calcium antagonist for the management of acute seizures