Early-Onset Convulsive Seizures Induced by Brain Hypoxia-Ischemia in Aging Mice: Effects of Anticonvulsive Treatments

PLoS One. 2015 Dec 2;10(12):e0144113. doi: 10.1371/journal.pone.0144113. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Aging / physiology*
  • Animals
  • Anticonvulsants / administration & dosage*
  • Anticonvulsants / pharmacology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / physiopathology
  • Disease Models, Animal
  • Hippocampus / drug effects
  • Hippocampus / physiopathology
  • Hypoxia-Ischemia, Brain / complications*
  • Hypoxia-Ischemia, Brain / drug therapy
  • Hypoxia-Ischemia, Brain / pathology
  • Injections, Intraperitoneal
  • Lorazepam / administration & dosage
  • Lorazepam / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phenytoin / administration & dosage
  • Phenytoin / analogs & derivatives
  • Phenytoin / pharmacology
  • Seizures / epidemiology
  • Seizures / etiology*
  • Seizures / physiopathology
  • Seizures / prevention & control*

Substances

  • Anticonvulsants
  • Phenytoin
  • fosphenytoin
  • Lorazepam