Critical Molecular Targets for the Toxic Effects of Hyperbaric Oxygen and a Novel Pharmacological Approach for Preventing Acute Toxicity
Abstract
Experimental plan. Our preliminary studies have shown that certain drugs used for treating SE (vigabatrin, tiagabin, carbamazepin, valproic acid) delay or prevent O2 seizures under certain conditions, as do other agents (NOS inhibitors, propranolol, ascorbic acid and indomethacin). Our finding that seizures are associated with excessive sympathetic drive, potentiated by a disturbed Glutamate/GABA equilibrium, raises the possibility that both NMDA antagonists and GABA agonists, together with adjuvants such as beta-adrenergic blockers (propranolol) or agents that limit cerebral hyperemia (indomethacin), could be administered in combination to prevent oxygen seizures and protect the lung. As our first objective, drugs would be carefully selected, based on experience gained from our previous studies of CNS O2 toxicity as well as on the clinical literature for epilepsy. Up to two drugs from each category would be tested individually, in a program of animal experimentation, to determine the effects on neuronal excitation and the other pathophysiological responses to HBO2 defined above. Individual drugs would be screened quickly for their ability to prolong seizure latency in awake mice. For our second objective, the most effective individual drugs would be tested in pairs, chosen from separate categories listed in Appendix 2. Combinations known to be harmful or ineffective would not be used; whereas combinations that could provide useful synergies would be tested. For example, a Na-channel blocker could be combined with a voltage-sensitive Ca-channel inhibitor; or a glutamate receptor blocker with a GABA-T inhibitor. We anticipate that a maximum of three drugs would be effective in combination, so some groups of three would be also be tested. In our third objective, the most promising single drug or two- or three-drug combinations would be tested in instrumented animals so that appropriate physiological parameters could monitored to elucidate and confirm the mechanism(s) involved in the protective response. To determine the role of molecular targets in key brain regions, drugs would be delivered to striatum, hippocampus and hypothalamus by microdialysis in rats, and the effluent dialysate would be collected for analysis of markers of oxidative and nitrosative attack. Tissues samples would be analyzed postmortem for post-translational modification of critical molecular targets. We expect to be able to complete one objective per year in a three-year funding cycle.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 12, 2016
- Source ID
- N000141512072
Entities
People
- Claude Piantadosi
Organizations
- Duke University
- Office of Naval Research
- United States Navy