Noradrenaline and Seizures: A Perspective on the Role of Adrenergic Receptors in Limbic Seizures.

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 β- adrenergic receptors (AR). Since autophagy is related to seizure threshold, this perspective questions whether modulating β-AR focally within the anterior piriform cortex affects limbic seizures.

Objective: In this perspective, we analyzed a potential role for β-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 microinfusing within AT either a β-AR agonist (salbutamol) or a β-AR antagonist (butoxamine) 5 minutes before bicuculline.

Results: β-AR stimulation fully prevents limbic seizures induced by bicuculline micro-infusion in AT. Conversely, antagonism at β-AR worsens bicuculline-induced seizure severity and prolongs seizure duration, leading to self-sustaining status epilepticus. These data indicate a specific role for β-AR as an anticonvulsant in AT.

Conclusion: 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 β-AR may be related to the stimulation of the autophagy pathway. Recent literature and present data draw a perspective where β-AR stimulation while stimulating autophagy mitigates limbic seizures, focally within AT. The mechanism linking β-AR to autophagy and seizure modulation should be extensively investigated.