SEVO anaesthesia induced widespread apoptosis in infant rat brain. Co-administration of DEX (1 µg kg -1 ) provided significant protection, whereas DEX (5 µg kg -1 or higher) plus SEVO increased mortality. Our findings suggest that DEX could be an attractive therapeutic for future studies investigating its neuroprotective potential in a translational animal model.

Selective targeting of the ␣5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling. Am J Physiol Lung Cell Mol Physiol 308: L931-L942, 2015. First published February 6, 2015 doi:10.1152/ajplung.00107.2014The clinical need for novel bronchodilators for the treatment of bronchoconstrictive diseases remains a major medical issue. Modulation of airway smooth muscle (ASM) chloride via GABA A receptor activation to achieve relaxation of precontracted ASM represents a potentially beneficial therapeutic option. Since human ASM GABAA receptors express only the ␣4-and ␣5-subunits, there is an opportunity to selectively target ASM GABAA receptors to improve drug efficacy and minimize side effects. Recently, a novel compound (R)-) with allosteric selectivity for ␣5-subunit containing GABAA receptors has become available. We questioned whether this novel GABAA ␣5-selective ligand relaxes ASM and affects intracellular calcium concentration ([Ca 2ϩ ]i) regulation. Immunohistochemical staining localized the GABAA ␣5-subunit to human ASM. The selective GABAA ␣5 ligand SH-053-2=F-R-CH3 relaxes precontracted intact ASM; increases GABA-activated chloride currents in human ASM cells in voltage-clamp electrophysiology studies; and attenuates bradykinin-induced increases in [Ca 2ϩ ]i, store-operated Ca 2ϩ entry, and methacholine-induced Ca 2ϩ oscillations in peripheral murine lung slices. In conclusion, selective subunit targeting of endogenous ␣5-subunit containing GABAA receptors on ASM may represent a novel therapeutic option to treat severe bronchospasm.GABAA ␣5-subunit; SH-053-2=F-R-CH3; airway relaxation DESPITE A PRESSING CLINICAL need for novel bronchodilators in the treatment of asthma and other bronchoconstrictive diseases, only three drug classes are currently in clinical use as acute bronchodilators in the United States (methylxanthines, anticholinergics, and ␤-adrenoceptor agonists) (6). An emerging novel pathway to achieve bronchodilation involves modulating airway smooth muscle (ASM) chloride conductance via GABA A receptors to achieve relaxation of human precontracted ASM (15). Although there is legitimate concern that widespread activation of all GABA A receptors may lead to undesirable side effects (sedation, hypnosis, etc.), we have shown that human ASM cells express a limited repertoire of GABA A receptor subunits, with the ␣4-and ␣5-subunits the only ␣-subunits expressed, thereby allowing for potential selective pharmacological tissue specific receptor targeting to minimize side effects (18,33). Inhaled delivery of these selective compounds may also serve to obviate concerns of systemic effects. Concern regarding nonselective GABA A receptor activation is not limited to the airway. GABA A receptor ligands active in the central nervous system (CNS) can have many effects including anxiolytic, sedative, hypnotic, amnesic, anticonvulsant, and muscle relaxant effects. This motivated a search for benzodiazepine (BDZ) ligands that discriminate among the ␣-subunits of ...