Perspective on mTOR-dependent Protection in Status Epilepticus

Biagioni, Francesca; Celli, Roberta; Giorgi, Filippo Sean; Nicoletti, Ferdinando; Fornai, Francesco

doi:10.2174/1570159x19666211005152618

Cited by 2 publications

(1 citation statement)

References 20 publications

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“…In fact, β 2 -AR, which may alter seizure susceptibility through a variety of mechanisms, including ion channels modulation [ 21 ], also induces autophagy when required [ 20 ]. This mechanism was recently shown to be a pivot in modulating seizures focally induced by micro-infusions of the GABA-A antagonist bicuculline within AT [ 22 ]. Therefore, this article sheds a perspective on joining the anticonvulsant role of NA with the autophagy pathway and its potential effects in modulating seizures.…”

Section: Resultsmentioning

confidence: 99%

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

Biagioni

Celli

Puglisi‐Allegra

et al. 2023

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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.

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Section: Resultsmentioning

confidence: 99%

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

Biagioni

Celli

Puglisi‐Allegra

et al. 2023

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Enhancing glymphatic fluid transport by pan-adrenergic inhibition suppresses epileptogenesis in male mice

Sun,

Peng,

et al. 2024

Nat Commun

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Epileptogenesis is the process whereby the previously normally functioning brain begins to generate spontaneous, unprovoked seizures. Status epilepticus (SE), which entails a massive release of neuronal glutamate and other neuroactive substances, is one of the best-known triggers of epileptogenesis. We here asked whether pharmacologically promoting glymphatic clearance during or after SE is beneficial and able to attenuate the subsequent epileptogenesis. We induced SE in adult male mice by intrahippocampal kainic acid (KA) infusion. Acute administration of a cocktail of adrenergic receptor antagonists ( p ropranolol, p razosin, and a tipamezole: PPA), enhanced glymphatic flow and effectively reduced the severity of spontaneous seizures in the chronic phase. The PPA treatment also reduced reactive gliosis and inhibited the loss of polarized expression of AQP4 water channels in the vascular endfeet of astrocytes. Administration of PPA after cessation of SE (30 hours post KA) also effectively suppressed epileptogenesis and improved outcome. Conversely, mice with constitutively low glymphatic transport due to genetic deletion of the aquaporin 4 (AQP4) water channel showed exacerbation of KA-induced epileptogenesis. We conclude that the pharmacological modulation of glymphatic fluid transport may represent a potential strategy to dampen epileptogenesis and the occurrence of spontaneous seizures following KA-induced SE.

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Perspective on mTOR-dependent Protection in Status Epilepticus

Cited by 2 publications

References 20 publications

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

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

Enhancing glymphatic fluid transport by pan-adrenergic inhibition suppresses epileptogenesis in male mice

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