Increased Antiseizure Effectiveness with Tiagabine Combined with Sodium Channel Antagonists in Mice Exposed to Hyperbaric Oxygen
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Hyperbaric oxygen (HBO2) is acutely toxic to the central nervous system, culminating in EEG spikes and tonic-clonic convulsions. GABA enhancers and sodium channel antagonists improve seizure latencies in HBO2 when administered individually, while combining antiepileptic drugs from different functional classes can provide greater seizure latency. We examined the combined effectiveness of GABA enhancers (tiagabine and gabapentin) with sodium channel antagonists (carbamazepine and lamotrigine) in delaying HBO2-induced seizures. A series of experiments in C57BL/6 mice exposed to 100% oxygen at 5 atmospheres absolute (ATA) were performed. We predicted equally effective doses from individual drug-dose response curves, and the combinations of tiagabine + carbamazepine or lamotrigine were tested to determine the maximally effective combined doses to be used in subsequent experiments designed to identify the type of pharmacodynamic interaction for three fixed-ratio combinations (1:3, 1:1, and 3:1) using isobolographic analysis. For both combinations, the maximally effective combined doses increased seizure latency over controls > 5-fold and were determined to interact synergistically for fixed ratios 1:1 and 3:1, additive for 1:3. These results led us to explore whether the benefits of these drug combinations could be extended to the lungs, since a centrally mediated mechanism is believed to mediate hyperoxic-induced cardiogenic lung injury. Indeed, both combinations attenuated bronchoalveolar lavage protein content by ~ 50%. Combining tiagabine with carbamazepine or lamotrigine not only affords greater antiseizure protection in HBO2 but also allows for lower doses to be used, minimizing side effects, and attenuating acute lung injury.
KeywordsAntiepileptic drugs CNS oxygen toxicity Drug synergy Isobolographic analysis Neuroprotection
This research was supported by the Office of Naval Research Grant N00014-15-1-2072 (to C. A. Piantadosi) and the Russian Academy of Sciences, Program 18, Project 0132-2018-0011 (to I. T. Demchenko).
Compliance with Ethical Standards
All animal procedures were approved independently by the Institutional Animal Care and Use Committee of Duke University and the Ethical Review Board of the Institute of Evolutionary Physiology and Biochemistry
Conflict of Interest
The authors declare that they have no conflict of interest.
The views expressed are those of H.G. Gasier and do not reflect the official position of the Uniformed Services University of the Health Sciences, United States Navy, or Department of Defense.
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