Increased Antiseizure Effectiveness with Tiagabine Combined with Sodium Channel Antagonists in Mice Exposed to Hyperbaric Oxygen.


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.





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Publication Info

Demchenko, Ivan T, Sergei Yu Zhilyaev, Olga S Alekseeva, Alexander I Krivchenko, Claude A Piantadosi and Heath G Gasier (2019). Increased Antiseizure Effectiveness with Tiagabine Combined with Sodium Channel Antagonists in Mice Exposed to Hyperbaric Oxygen. Neurotoxicity research, 36(4). pp. 788–795. 10.1007/s12640-019-00063-5 Retrieved from

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Claude Anthony Piantadosi

Professor Emeritus of Medicine

Dr. Piantadosi's laboratory has special expertise in the pathogenic mechanisms of acute organ failure, particularly acute lung injury (ALI), with an emphasis on the molecular regulatory roles of the physiological gases— oxygen, carbon monoxide, and nitric oxide— as they relate to the damage responses to acute inflammation. The basic science focuses on oxidative processes and redox-regulation, especially the molecular mechanisms by which reactive oxygen and nitrogen species transmit biological signals involved in the maintenance of energy metabolism and mitochondrial health, but also contribute to pathogenesis and to the resolution of tissue injury.

Clinically, ALI and the related syndrome of multiple organ failure has a high mortality, which is related to the host inflammatory response, but is not well understood scientifically; thus, the laboratory is devoted to understanding these mechanisms in the context of the host response to relevant but well-controlled experimental manipulations including hyperoxia, bacterial infections, toxic drugs, and cytokine/chemokine signals. The approach relies on animal models, mainly transgenic and knockout mice, and cell models, especially lung and heart cells to evaluate and understand the physiology, pathology, and cell and molecular biology of the injury responses, to test independent and integrated mechanisms, and to devise interventions to prevent damage.

Apart from the lung, significant work is devoted to understanding damage to the heart, brain, liver, and kidney caused by these immune mechanisms, specifically emphasizing the role of mitochondria, key targets and sources of oxidative damage. This damage compromises their ability to support energy homeostasis and advanced cellular functions, and impacts on the important roles these organelles play in cell death by apoptosis and necrosis as well as in the resolution of cellular damage and inflammation.


Heath Gasier

Associate Professor in Anesthesiology

I am a physiologist who joined Duke University in 2019 after retiring from military service. My research has focused on understanding how oxidant stress impacts cellular and systems physiology. Initially, I studied in humans how hyperbaric oxygen (HBO2) within the therapeutic range and high altitude influence nitric oxide production, antioxidant defenses, tissue oxygenation and muscle performance. This work sparked my interest in redox biology and led me to train under Dr. Claude A. Piantadosi at Duke University. Here, I began to study in mice and rats the impact of extreme HBO2 on the central nervous system (CNS). The objectives were to identify in rodents the origin and mechanisms of CNS oxygen toxicity, and test targeted pharmacological intervention strategies. It was during this time that I became interested in heme oxygenase 1 (HO-1). During my final military assignment, I continued to work on HBO2 and CNS oxygen toxicity related research (pharmacological intervention) and initiated new studies examining how HO-1 induction influences musculoskeletal health in diet-induced obesity. These studies led to follow-on work aimed at determining the mechanisms of HO-1 induction and mitochondrial dynamic regulation in an in vitro model of diet-induced obesity. In addition, I was involved in research aimed at understanding how antioxidants influence skeletal muscle mitochondrial dynamics in rodents and cells exposed heat stress and extreme high altitude.

Since returning to Duke University, I continue to conduct research focused on understanding how oxidant stress induced by HBO2 and obesity influences mitochondrial dynamic regulation in the brain, lung and skeletal muscle. I am now studying how sarcopenia and gender influence these responses. I am also involved (Co-I) in research testing the efficacy of a home-based high intensity interval training program in COVID-19 critical illness and early parenteral nutrition in abdominal trauma victims. In both of these studies, my efforts will be directed towards measuring inflammation and mitochondrial quality control responses to the interventions, which are linked to HO-1 activation.

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