Cardiorespiratory Dysfunction Induced by Brainstem Spreading Depolarization: A Potential Mechanism for SUDEP
| Autor: | Pedro Lourenço Katayama |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Journal Club Apnea Mutation Missense Mice Transgenic Unexpected death Mice 03 medical and health sciences Epilepsy Calcium Channels N-Type 0302 clinical medicine Seizures Internal medicine Animals Medicine Sudden Unexpected Death in Epilepsy Potential mechanism Research Articles Cause of death Medulla Oblongata Human studies business.industry General Neuroscience Cortical Spreading Depression Depolarization Cardiorespiratory fitness medicine.disease Mice Inbred C57BL 030104 developmental biology Cardiology Female Brainstem business Excitatory Amino Acid Antagonists 030217 neurology & neurosurgery Brain Stem |
| Zdroj: | J Neurosci |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | Seizure-related apnea is common and can be lethal. Its mechanisms however remain unclear and preventive strategies are lacking. We postulate that brainstem spreading depolarization (SD), previously associated with lethal seizures in animal models, initiates apnea upon invasion of brainstem respiratory centers. To study this, we assessed effects of brainstem seizures on brainstem function and respiration in male and female mice carrying a homozygous S218L missense mutation that leads to gain-of-function of voltage-gated Ca(V)2.1 Ca(2+) channels and high risk for fatal seizures. Recordings of brainstem DC potential and neuronal activity, cardiorespiratory activity and local tissue oxygen were performed in freely behaving animals. Brainstem SD occurred during all spontaneous fatal seizures and, unexpectedly, during a subset of nonfatal seizures. Seizure-related SDs in the ventrolateral medulla correlated with respiratory suppression. Seizures induced by stimulation of the inferior colliculus could evoke SD that spread in a rostrocaudal direction, preceding local tissue hypoxia and apnea, indicating that invasion of SD into medullary respiratory centers initiated apnea and hypoxia rather than vice versa. Fatal outcome was prevented by timely resuscitation. Moreover, NMDA receptor antagonists MK-801 and memantine prevented seizure-related SD and apnea, which supports brainstem SD as a prerequisite for brainstem seizure-related apnea in this animal model and has translational value for developing strategies that prevent fatal ictal apnea. SIGNIFICANCE STATEMENT Apnea during and following seizures is common, but also likely implicated in sudden unexpected death in epilepsy (SUDEP). This underlines the need to understand mechanisms for potentially lethal seizure-related apnea. In the present work we show, in freely behaving SUDEP-prone transgenic mice, that apnea is induced when spontaneous brainstem seizure-related spreading depolarization (SD) reaches respiratory nuclei in the ventrolateral medulla. We show that brainstem seizure-related medullary SD is followed by local hypoxia and recovers during nonfatal seizures, but not during fatal events. NMDA receptor antagonists prevented medullary SD and apnea, which may be of translational value. |
| Databáze: | OpenAIRE |
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