Medical countermeasures to chlorine exposure based on GABA(A) receptor targeting

University Of Wisconsin Milwaukee, Milwaukee WI

Investigators

Abstract

The proposed research will demonstrate the therapeutic efficacy of one or more gamma aminobutyric acid type A receptor (GABAAR) modulators in reducing acute lung injury (ALI) caused by inhaled chlorine. The research is significant because it supports the mission of the Chemical Countermeasures Research Program (CCRP) to address the nation's medical response capabilities during chemical emergencies. Deliberate or accidental release of chlorine represents a serious threat for civilians, chemical industry workers and people involved in transport and distribution of chemicals. Medical countermeasures for chlorine exposure can be employed early in a disaster situation when medical support does not exist. Hospitalized patients exposed to chlorine received supportive care such as humidified oxygen and inhaled beta agonists and corticosteroids. To address this need, we propose to investigate inhaled and injected GABAAR ligands that have been shown to reduce lung inflammation and bronchospasm. These compounds act selectively on GABAARs expressed on peripheral (non- CNS) tissues due to their inability to cross the blood brain barrier. Their mode of action is based on their ability to modulate intracellular chloride homeostasis by activating GABAARs. The safety of MIDD0301 has been demonstrated in rodent and non-rodent species. The long-term goal of this research is FDA approval of MIDD0301 with authorized use as a medical countermeasure for chlorine exposure. The objective is to compare the pharmacological effects of MIDD0301 with other agents that have been reported to alleviate symptoms caused by chlorine exposure. Our approach uses an established murine model of chlorine exposure testing in- life pulmonary and cardiovascular parameters as well as postmortem analysis of the lungs and bronchoalveolar lavage fluid. Our hypothesis is that the dual pharmacological effect of MIDD0301 (bronchodilation and anti- inflammation) will improve the recovery and survival of mice exposed to chlorine. The rationale is to develop a medical countermeasure for chlorine exposure that can be used with very limited medical support in extreme situations such as a terrorist attack or chemical plant accident. The Specific Aims (SA) are as follows. SA 1: Determine the therapeutic effects of nebulized MIDD0301 in chlorine exposed mice; SA 2: Determine the cellular GABAAR protein and gene expression after chlorine exposure; and SA 3: Determine the therapeutic effects of IM administered MIDD0301 in chlorine exposed mice. The results will inform the development of a novel small molecule based medical countermeasure for chlorine exposure and will validate a novel target (GABAARs) for alleviating acute lung injury caused by chlorine.