title: Antiepileptic drugs prevent seizures in hyperbaric oxygen: A novel model of epileptiform activity.
abstract: Breathing oxygen at sufficiently elevated pressures can trigger epileptiform seizures. Therefore, we tested the hypothesis that pre-treatment with FDA-approved antiepileptic drugs could prevent seizure onset in hyperoxia at 5 atmospheres absolute. We selected drugs from two putative functional categories, Na+-channel antagonists and GABA enhancers, each administered intraperitoneally at four doses in separate groups of C57BL/6 mice. The drugs varied in efficacy at the doses used. Of the five tested Na+-channel antagonists, carbamazepine and lamotrigine more than tripled seizure latency compared to values seen in vehicle controls. Primidone, zonisamide and oxcarbazepine were less effective. Of the four GABA reuptake inhibitors, tiagabine and vigabatrin also increased seizure latency by more than three times control values; valproic acid was less effective, and the GABA synthesis promoter gabapentin was intermediate in effectiveness. We infer that Na+-channel function and GABA neurotransmission may be critical targets in the pathophysiology of CNS O2toxicity. Because these essential components of neuronal excitation and inhibition are also implicated in the pathogenesis of other seizure disorders, including generalized epilepsy, we propose that, at some level, common pathways are involved in these pathologies, although the initiating insults differ. Furthermore, hyperoxic exposures are not known to cause the spontaneously-recurring seizures that characterize true clinical epilepsy. Nonetheless, experimental studies of hyperbaric oxygen toxicity could provide new insights into molecular mechanisms of seizure disorders of various etiologies. In addition, the neuropathology of hyperbaric oxygen is particularly relevant to the hypothesis held by some investigators that oxidative stress is an etiological factor in clinical epilepsies.
authors.affiliation: Center for Hyperbaric Medicine and Environmental Physiology, Duke University Medical Center, Durham, NC, United States; Department of Anesthesiology, Duke University Medical Center, Durham, NC, United States; Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia.
authors.forename: Ivan T
authors.initials: IT
authors.lastname: Demchenko
authors.affiliation: Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia.
authors.forename: Sergei Yu
authors.initials: SY
authors.lastname: Zhilyaev
authors.affiliation: Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia.
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Moskvin
authors.affiliation: Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia.
authors.forename: Alexander I
authors.initials: AI
authors.lastname: Krivchenko
authors.affiliation: Center for Hyperbaric Medicine and Environmental Physiology, Duke University Medical Center, Durham, NC, United States; Department of Anesthesiology, Duke University Medical Center, Durham, NC, United States; Department of Medicine, Duke University Medical Center, Durham, NC, United States.
authors.forename: Claude A
authors.initials: CA
authors.lastname: Piantadosi
authors.affiliation: Center for Hyperbaric Medicine and Environmental Physiology, Duke University Medical Center, Durham, NC, United States; Department of Anesthesiology, Duke University Medical Center, Durham, NC, United States. Electronic address: barry.w.allen@duke.edu.
authors.forename: Barry W
authors.initials: BW
authors.lastname: Allen
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000188:drug therapy / Q000378:metabolism; D058805:GABA Uptake Inhibitors / Q000494:pharmacology; D006931:Hyperbaric Oxygenation; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D012640:Seizures / Q000378:metabolism / Q000517:prevention & control*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D058805:GABA Uptake Inhibitors; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D005680:gamma-Aminobutyric Acid
keywords: Antiepileptic drugs; CNS oxygen toxicity; Epileptiform seizures; Nitric oxide; Oxidative stress; Reactive oxygen and nitrogen species