A novel oxazolidinone derivative PH192 demonstrates anticonvulsant activity in vivo in rats and mice

Abstract

The pharmacotherapeutic management of seizure disorders with currently available medications is not optimal due to side effects and failure of some patients to respond to all available medications. As such there is the need to develop new antiseizure drugs by looking at new chemical classes of compounds. We recently screened, in vitro, a new class of compounds, the oxazolidinones, for actions in the brain that may indicate potential for antiseizure activity. A few compounds were identified with such a potential. Here we tested whether one of these lead compounds, PH192, will exhibit in vivo antiseizure activity using chemically- and electrically- induced seizures models in mice and rats. Out of 5 compounds tested, all of them had minimal neurotoxicological effects in mice, with PH192 being the best, with comparable efficacy (ED₅₀) and toxicity (TD₅₀) to only levetiracetam. Intraperitoneal (IP) pretreatment with PH192 produced a dose-dependent protection of mice from seizures induced using the 6 Hz stimulation protocol with an estimated ED₅₀ of 34.5 mg/kg in mice and about 90 mg/kg in rats and a neurotoxic dose >500 mg/kg in mice, yielding a calculated neuro (protective) index of >14.7. When pretreated with 100 mg/kg PH192 for 30 min, about 75% of mice were protected from 6 Hz-induced seizures. When rats were pretreated for 30 min with PH192, 66.6% of rats were protected from seizures induced using the 6 Hz stimulation protocol while 83.3% were protected using the maximal electroshock (MES) stimulation protocol. Pentylenetetrazole (PTZ) injection at 50, and 100 mg/kg produced stage 5 seizures in all rats. Thirty minutes IP pretreatment of rats with 100 mg/kg PH192 protected 80% of rats from the PTZ-induced seizures, a level of protection similar to that obtained with a reference antiepileptic drug (AED) phenytoin (40 mg/kg), that is used clinically for the treatment of various seizure disorders. The results of these studies indicate that PH192 protects against both chemically- and electrically-induced seizures with little central nervous system side effects. This suggests that the oxazolidinone pharmacophore has potential for discovering new antiepileptic drugs with possibly minimal central side effects.

Keywords: Anticonvulsant; Antiepileptic; Antiseizure; In vivo; Oxazolidinones; PH192.