Sudden unexpected death in epilepsy is prevented by blocking postictal hypoxia

• Published in: Neuropharmacology 2023-06, Vol.231, p.109513-109513, Article 109513
• Main Authors: George, Antis G., Farrell, Jordan S., Colangeli, Roberto, Wall, Alexandra K., Gom, Renaud C., Kesler, Mitchell T., Rodriguez de la Hoz, Cristiane, Villa, Bianca R., Perera, Tefani, Rho, Jong M., Kurrasch, Deborah, Teskey, G. Campbell
• Format: Article
• Language: English
• Subjects: Animals; Breathing; Death, Sudden - etiology; Death, Sudden - prevention & control; Epilepsy; Epilepsy - complications; Epilepsy - drug therapy; Heart; Hypoxia; Hypoxia - complications; Mice; Seizures; Seizures - complications; Seizures - prevention & control; Spreading depolarization; Sudden Unexpected Death in Epilepsy - prevention & control; SUDEP
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2023.109513

Epilepsy is at times a fatal disease. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality in people with intractable epilepsy and is defined by exclusion; non-accidental, non-toxicologic, and non-anatomic causes of death. While SUDEP often follows a bilateral tonic-clonic seizure, the mechanisms that ultimately lead to terminal apnea and then asystole remain elusive and there is a lack of preventative treatments. Based on the observation that discrete seizures lead to local and postictal vasoconstriction, resulting in hypoperfusion, hypoxia and behavioural disturbances in the forebrain we reasoned those similar mechanisms may play a role in SUDEP when seizures invade the brainstem. Here we tested this neurovascular-based hypothesis of SUDEP in awake non-anesthetized mice by pharmacologically preventing seizure-induced vasoconstriction, with cyclooxygenase-2 or L-type calcium channel antagonists. In both acute and chronic mouse models of seizure-induced premature mortality, ibuprofen and nicardipine extended life while systemic drug levels remained high enough to be effective. We also examined the potential role of spreading depolarization in the acute model of seizure-induced premature mortality. These data provide a proof-of-principle for the neurovascular hypothesis of SUDEP rather than spreading depolarization and the use of currently available drugs to prevent it. •We tested the novel neurovascular theory of postictal brain dysfunction.•Seizures in brainstem breathing areas of awake mice are followed by severe hypoxia.•Postictal hypoxia is followed by cessation of breathing then heartbeat.•Ibuprofen and nicardipine delayed time to death in both acute and chronic models.•Pre-clinical evidence for the neurovascular theory of SUDEP is provided.