NEUROPROTECTIVE EFFECTS OF SKF-10,047 IN CULTURED RAT CEREBELLAR NEURONS AND IN GERBIL GLOBAL BRAIN ISCHEMIA

Background and Purpose: Excitatory amino acids and their receptors are involved in mediating ischemic neuronal damage. The sigma-agonists are believed to interact with the N-methyl-D-aspartate receptor. Therefore, we studied the neuroprotective, hypothermic, and motor deficit effects of the sigma-agonist SKF 10,047 and the N-methyl-D-aspartate antagonist MK-801. Methods: Neuroprotective effects were compared using an in vitro ischemia model of cultured rat cerebellar granule cells and the gerbil model of global brain ischemia induced by 5 minutes of bilateral carotid artery occlusion followed by 7 days of reperfusion. Results: In vitro, (+)MK-801 protected against 100-mu-M glutamate with a 50% protective concentration of 30 nM, followed by (-)MK-801 (150 nM), cyclazocine (0.5-mu-M), (+)SKF 10,047 (3.3-mu-M), pentazocine (5-mu-M), and (-)SKF 10,047 (10-mu-M). In vivo, (+)SKF 10,047 pretreatment (60 mg/kg) or multiple postischemic treatments provided neuroprotection comparable with MK-801 pretreatment (10 mg/kg). When ischemic animals were administered the multiple dosing regimen of (+)SKF 10,047, no hypothermic effect was noted in the temporalis muscle over 4 hours' postischemia. Motor deficits monitored by a swing grid test showed that 50% recovery from (+)SKF 10,047 was 5.5 times faster than recovery from MK-801. Conclusions: These results are the first to report a hypothermia-free, in vivo neuroprotective effect of (+)SKF 10,047, a prototypical drug of the sigma-agonist class.