The orexin pathway is not involved in the attenuation of limbic seizures by des-acyl ghrelin

Purpose: Once considered inactive, des-acyl ghrelin is now implicated in a number of biological functions. Unlike ghrelin, des-acyl ghrelin is unable to activate the ghrelin receptor and recently one study implied that intracerebroventricular des-acyl ghrelin administration affected food intake via the orexin pathway. Recently, des-acyl ghrelin has been proposed to have beneficial effects on limbic seizures. In this study, we further characterised the role of des-acyl ghrelin in seizures using the focal pilocarpine model for limbic seizures.
Method: In this study we used the in vivo rat model for pilocarpine-induced limbic seizures. Intrahippocampal administration of des-acyl ghrelin, the dual orexin receptor antagonist almorexant, or co-administration of des-acyl ghrelin and almorexant was performed in rats for two hours prior subsequent administration of pilocarpine directly in the hippocampus. Rats were monitored following pilocarpine perfusion, and seizure behavior grades were evaluated according to a modified Racine's scale.
Results: We noted that while des-acyl ghrelin attenuated pilocarpine-induced limbic seizures at different concentrations, almorexant did not affect seizure severity. To determine whether des-acyl ghrelin utilizes the orexin pathway for its anticonvulsant effect, des-acyl ghrelin was co-administered with almorexant. Dual orexin receptor blockade did not prevent des-acyl ghrelin's anticonvulsant effect.
Conclusion: We confirmed that des-acyl ghrelin attenuates limbic seizures and established that the orexin pathway is not involved. This is also first evidence that simultaneous antagonism of hippocampal orexin receptors does not affect seizure severity. This study highlights the need of identifying the mechanism of action of des-acyl ghrelin in epileptic seizures.