Noradrenaline and seizures: a perspective on the role of adrenergic receptors in limbic seizures

Abstract

Background: Noradrenergic fibers originating from the locus coeruleus densely innervate limbic structures including the piriform cortex, which is the limbic structure with the lowest seizure threshold. Noradrenaline (NA) modulates limbic seizures, while stimulating autophagy through β2-adrenergic receptors (AR). Since autophagy is related to seizure threshold, this perspective questions whether modulating β2-AR focally within the anterior piriform cortex, affects limbic seizures. Objective: In this perspective we analyzed a potential role for β2-AR as an anticonvulsant target within the anterior piriform cortex, area tempestas (AT). Methods: We developed this perspective based on current literature on the role of NA in limbic seizures and autophagy. The perspective is also grounded on preliminary data obtained by micro-infusing within AT either a β2-AR agonist (salbutamol) or a β2-AR antagonist (butoxamine), 5 minutes before bicuculline. Results: β2-AR stimulation fully prevents limbic seizures induced by bicuculline micro-infusion in AT. Conversely, antagonism at β2-AR worsens bicuculline-induced seizure severity and prolongs seizure duration, leading to self-sustaining status epilepticus. These data indicate a specific role for β2-AR as anticonvulsant in AT. Conclusions: NA counteracts limbic seizures. This relies on various receptors in different brain areas. The anterior piriform cortex plays a key role in patients affected by limbic epilepsy. The anticonvulsant effects of NA through β2-AR may be related to the stimulation of the autophagy pathway. Recent literature and present data draw a perspective, where β2-AR stimulation while stimulating autophagy mitigates limbic seizures, focally within AT. The mechanism linking β2-AR to autophagy and seizure modulation should be extensively investigated.