Convulsive seizures are due to abnormal synchronous and repetitive neuronal discharges in the central nervous system (CNS). Finding new therapeutics to overcome the side effects of the current drug therapies and to increase their effectiveness is ongoing. Orexin-A and orexin-B are brain neuropeptides originating from postero-lateral hypothalamic neurons. Studies show that orexins, through activation of OX1 and OX2 receptors, have excitatory effects in the CNS. Accordingly, this study was designed to evaluate the effect of OX1 receptor antagonist (SB-334867) on seizure- and anxiety-related behaviors of pentylenetetrazol (PTZ)-kindled rats. Kindling was induced by repeated intraperitoneal (IP) injections of PTZ (32 mg/kg) with two-day intervals for 24 days in male Wistar rats. Three groups received intracerebroventricular (ICV) injections of SB-334867 (2.5, 5, and 10 μg/rat) before PTZ injections. Two control groups received vehicle (2 μL/rat, ICV) and valproate (26 μg/rat, ICV) before PTZ injections. An extra group of control animals received saline both ICV and IP. Seizure-related behaviors were monitored for 30 min following PTZ administration. The anxiety-like behaviors were also assessed using elevated plus-maze in the first and last days of the study. The results revealed that ICV injection of SB-334867, mainly at the dose of 10 μg/rat, decreased the median of seizure stages, prolonged the latency and reduced the duration of different seizure stages, and reversed the PTZ-induced anxiety-like behaviors. Based on the presented results, it is suggested that pharmacological blockade of the OX1 receptor is a potential target in the treatment of seizure and concomitant anxiety disorders.

BackgroundCurrent antiepileptic drugs are not able to prevent recurrent seizures in all patients. Orexins are excitatory hypothalamic neuropeptides that their receptors (Orx1R and Orx2R) are found almost in all major regions of the brain. Pentylenetetrazol (PTZ)-induced kindling is a known experimental model for epileptic seizures. The purpose of this study was to evaluate the effect of Orx2 receptor antagonist (TCS OX2 29) on seizures and anxiety of PTZ-kindled rats.ResultsOur results revealed that similar to valproate, administration of 7 µg/rat of TCS OX2 29 increased the latency period and decreased the duration time of 3rd and 4th stages of epileptiform seizures. Besides, it significantly decreased mean of seizure scores. However, TCS OX2 29 did not modulate anxiety induced by repeated PTZ administration.ConclusionThis study showed that blockade of Orx2 receptor reduced seizure-related behaviors without any significant effect on PTZ-induced anxiety.