Neuroprotective properties of propofol and midazolam, but not pentobarbital, on neuronal damage induced by forebrain ischemia, based on the GABAA receptors

Background: The mechanism of the neuroprotective effects of propofol was compared to two other types of intravenous (i.v.) anesthetics (i.e., benzodiazepine; midazolam and barbiturate; pentobarbital) using Mongolian gerbils focusing on GABA receptor subtypes. Methods: Neuronal injury was induced by a 4-min occlusion of the common carotid arteries followed by reperfusion. One week after occlusion, animals were transcardially perfused for histochemistry. Neuronal death in four brain regions was evaluated by direct visual counting of acidophilic neurons. Results: Seven days after this ischemic episode, severe neuronal injury was measured in the hippocampal CA1 area (>98% of total cells damaged) and parietal cortex (>35%). Also lateral thalamus and caudate putamen were damaged but to a lesser extent (about 10%). The neuronal injury in these areas was significantly attenuated by propofol, midazolam and the GABAA agonist, muscimol, intraperitoneally administered 15 min prior to ischemia. This neuroprotective property however, was lacking with pentobarbital and GABA(B) agonist baclofen. Concomitant pretreatment with subthreshold doses of propofol and muscimol significantly reduced the amount of cell death induced by brain ischemia. On the other hand, pretreatment with the GABA(A) antagonist bicuculline significantly inhibited the neuroprotective effects of propofol. However, a GABA(B) antagonist, phaclofen, was without effect on neuronal damage and on neuronal protection of propofol. Conclusion: These results indicate that activation of GABA(A) receptors, which include the specific binding subunits for propofol and midazolam, but not pentobarbital, plays a role in the inhibition of neuronal death induced by brain ischemia.