Differential neuroprotective effects for three GABA-potentiating compounds in a model of hypoxia-ischemia

Clomethiazole (CMZ) is a GABA(A)-potentiating compound; however, it is unclear whether this mode of action is responsible for its neuroprotective effects in animal models of ischemia. This study compared the neuroprotective efficacies of muscimol and midazolam, two potent GABA(A)-potentiating compounds, to that of CMZ in a model of hypoxia-ischemia (H-I). To establish a neuroprotective profile for CMZ, CMZ (60, 95, or 125 mg kg-1, i.p.) was administered to post-natal day 25 male rats at numerous post-hypoxic time points and the rats were sacrificed 1 or 4 weeks later. Varying degrees of histological protection were evident when CMZ was administered 1, 2, or 3 h post-hypoxia with the 125 mg kg-1 dose producing complete histological protection if administered 3 h post-hypoxia. To determine whether midazolam or muscimol could match the protection provided by CMZ administered 3 h post-hypoxia, H-I rats received varying doses of these compounds 3 h post-hypoxia and were sacrificed 1 week later. Under identical conditions, no dose of muscimol or midazolam provided equivalent neuroprotection to that provided by CMZ. In fact, muscimol showed no neuroprotective ability whatsoever. Thus, CMZ, administered as late as 3 h post-hypoxia, was able to completely prevent H-I-induced cell death while a full dose range of other GABA-potentiating agents did not. Such direct comparison of these compounds in this model suggests the mechanism underlying the protective effects of CMZ may not rely solely on GABA(A)-potentiating properties. Elucidation of a novel mechanism of action for CMZ may expose new therapeutic targets in stroke treatment.