title: Early-Onset Convulsive Seizures Induced by Brain Hypoxia-Ischemia in Aging Mice: Effects of Anticonvulsive Treatments.
abstract: Aging is associated with an increased risk of seizures/epilepsy. Stroke (ischemic or hemorrhagic) and cardiac arrest related brain injury are two major causative factors for seizure development in this patient population. With either etiology, seizures are a poor prognostic factor. In spite of this, the underlying pathophysiology of seizure development is not well understood. In addition, a standardized treatment regimen with anticonvulsants and outcome assessments following treatment has yet to be established for these post-ischemic seizures. Previous studies have modeled post-ischemic seizures in adult rodents, but similar studies in aging/aged animals, a group that mirrors a higher risk elderly population, remain sparse. Our study therefore aimed to investigate early-onset seizures in aging animals using a hypoxia-ischemia (HI) model. Male C57 black mice 18-20-month-old underwent a unilateral occlusion of the common carotid artery followed by a systemic hypoxic episode (8% O2 for 30 min). Early-onset seizures were detected using combined behavioral and electroencephalographic (EEG) monitoring. Brain injury was assessed histologically at different times post HI. Convulsive seizures were observed in 65% of aging mice post-HI but not in control aging mice following either sham surgery or hypoxia alone. These seizures typically occurred within hours of HI and behaviorally consisted of jumping, fast running, barrel-rolling, and/or falling (loss of the righting reflex) with limb spasms. No evident discharges during any convulsive seizures were seen on cortical-hippocampal EEG recordings. Seizure development was closely associated with acute mortality and severe brain injury on brain histological analysis. Intra-peritoneal injections of lorazepam and fosphenytoin suppressed seizures and improved survival but only when applied prior to seizure onset and not after. These findings together suggest that seizures are a major contributing factor to acute mortality in aging mice following severe brain ischemia and that early anticonvulsive treatment may prevent seizure genesis and improve overall outcomes.
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Justin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Chiping
authors.initials: C
authors.lastname: Wu
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Jessie
authors.initials: J
authors.lastname: Peng
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Nisarg
authors.initials: N
authors.lastname: Patel
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Yayi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Gao
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.|Neurology Unit, Department of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Salman
authors.initials: S
authors.lastname: Aljarallah
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.|Department of Surgery (Neurosurgery), University of Toronto, Toronto, Ontario, Canada.
authors.forename: James H
authors.initials: JH
authors.lastname: Eubanks
authors.affiliation: Department of Neuroscience, University of Lethbridge, Lethbridge, Alberta, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: McDonald
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.|Departments of Medicine (Neurology), University of Toronto, Toronto, Ontario, Canada.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
mesh_terms: D017668:Age of Onset; D000375:Aging / Q000502:physiology*; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D020925:Hypoxia-Ischemia, Brain / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D007274:Injections, Intraperitoneal; D008140:Lorazepam / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010672:Phenytoin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D012640:Seizures / Q000453:epidemiology / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D000927:Anticonvulsants; D010672:Phenytoin; C043114:fosphenytoin; D008140:Lorazepam