INFLUENCES OF GABA RECEPTOR SUBTYPES ON NEUROPROTECTIVE ACTION OF PROPOFOL USING MONGOLIAN GERBIL BRAIN ISCHEMIC MODEL

Abstract

S465 Introduction: It might be possible to explain that the neuroprotective mechanisms of intravenus anesthetics, relate to the potentiation of the gamma-amino butyric acid (GABA) neurons, since barbiturates and benzodiazepines (BZP) bind to the GABAa/BZP receptor complex and stimulate the Cl- influx to the neuronal cells. In the neurochemical studies, the physiological properties of GABA receptor subtypes in the central nervous system (CNS) have been identified. In particular, the different localization between GABAa and GABAb receptors in the neuronal system might be linked to their dissimilar physiological functions appeared in CNS. In this presentation, using the pathopharmacological techniques, we examined the neuroprotective effects of propofol on the brain ischemia of Mongolian gerbil and the functional role of GABA receptor subtypes on the neuroprotective mechanism of propofol. Materials and Methods: The male Mongolian gerbils (body weight; 50-80g) were anesthetized with 1.0% isoflurene and 70% N2O in O2. Each drug was injected intraperitoneal at 15 min before the treatment of ischemia. Under the anesthesia. the brain ischemia was induced by bilateral common carotid artery clamping (2VO) for 4 min. During brain ischemia and recovery from anesthesia, both temperatures of brain and body were kept at 37[degree sign]C by means of heating lamps. One week after ischemia, the ischemic animals were reanesthetized and perfusion-fixed with 4% formaldehyde, and these brains were dissected for the preparations of pathological estimations. The score of pathological estimation detected in the hippocampal CA1 area was divided for five grades depending on the severity. The following drugs were used in this experiment; propofol (25 and 50 mg/kg), muscimol (GABAa agonist; 0.5-4 mg/kg), bicuculline (GABAa antagonist; 5, 7.5 mg/kg), baclofen (GABAb agonist; 2, 4mg/kg) and phaclofen (GABAb antagonist; 1.5, 3mg/kg). Results: 1) One week after brain ischemia induced by a 4 min-2VO, more than 90 % of neuronal cells in CA1 region of hippocampus were injured, and the degenerated cells and vacuolarized cells were appeared in most cases. 2) The pretreatment of propofol significantly attenuated the brain injury induced by 2VO in a dose-dependent manner. The pretreatment of muscimol reduced the number of cell injury and improved the severe conditions in a dose-dependent manner, although this neuroprotection is less potent compared to that of propofol. However it was so hard to detect the significant neuronal protection after the pretreatment of baclofen. 3) The neuroprotecitive effects of propofol was attenuatedby the coadministration of bicuculline, but not phaclofen. Discussion: Our results indicate that propofol and GABAa receptor agonist suppress the severity of brain injury after 2VO, and then GABAa antagonists block these neuronal protections. These results, taken together with others [1,2,3] suggest that delayed neuronal death induced by ischemia may be partially modulated by the inhibition and/or attenuation of GABAa receptor activity and that the pharmacological mechanism of propofol may involve the potentiation of GABAa receptor.