Orexin-A differentially modulates electrically evoked hippocampal epileptiform activity in rats via site-specific mechanisms

The hippocampus is a critical brain region for learning and memory, but also a common site for seizure initiation in epilepsy. Current anticonvulsant therapies often have systemic side effects or fail to control seizures in all patients, highlighting the need for novel, targeted approaches. The orexinergic system, involving neuropeptides Orexin-A and Orexin-B and their receptors (OX1R, OX2R), plays a key role in arousal and neuromodulation, with emerging evidence suggesting its involvement in seizure susceptibility and control. This study explores how exogenous orexins might modulate epileptiform activity in the CA1 field, addressing a gap in understanding their direct anticonvulsant potential.

Electrophysiological experiments were conducted in anesthetized rats. Bipolar electrodes were stereotaxically implanted into the CA1 region of the hippocampus to induce epileptiform activity via high-frequency electrical stimulation (HFES). Orexin-A and Orexin-B (10 μg/10 μl) were administered either intracerebroventricularly (into the lateral ventricle) or applied directly to the frontal cortex. The primary endpoints were the duration of electrically evoked epileptiform discharges (EEDs) and the incidence of high-amplitude population spikes during these EEDs. Control animals received no orexin administration, serving as a baseline for HFES-related changes.

Intracerebroventricular administration of Orexin-A significantly reduced the duration of EEDs within 20 minutes of application. This route also abolished the progressive prolongation of epileptiform discharges that was observed in control animals following HFES. In contrast, cortical application of Orexin-A selectively reduced the incidence of high-amplitude (7-10 mV) population spikes during EEDs, without affecting the overall duration of the epileptiform activity itself. Neither cortical nor intraventricular administration of Orexin-B produced significant changes in evoked epileptiform activity in the CA1 field, suggesting a specific role for Orexin-A and potential involvement of OX1 receptor signaling. The distinct effects observed after cortical versus intraventricular administration of Orexin-A indicate site-specific mechanisms of action. Intraventricular effects were predominantly induced via direct activation of hippocampal orexinergic receptors, while cortical application modulated cortico-hippocampal mechanisms.

Intracerebroventricular Orexin-A significantly reduced the duration of electrically evoked epileptiform discharges within 20 minutes and abolished HFES-related prolongation.