POSTISCHEMIC TREATMENT WITH CALPAIN INHIBITOR MDL-28170 AMELIORATES BRAIN-DAMAGE IN A GERBIL MODEL OF GLOBAL-ISCHEMIA

The newly-developed calpain inhibitor, MDL 28170 penetrates the blood- brain barrier and inhibits brain cysteine protease activity after syst emic administration. This experiment was initiated to determine if the calpain inhibitor, MDL 28170 could, by these actions, reduce neuronal damage in an animal model of global cerebral ischemia in the gerbil. The calpain inhibitor, MDL 28170 (50 mg/kg), was initiated at 0.5 and 3 h of recirculation following 5min of global ischemia. Animals subjec ted to ischemia but without treatment or with vehicle treatment served as controls. Evaluation by light microscopy was carried out on paraff in-embedded brain sections of gerbils which were sacrificed 7 days pos t-operatively. The results show that the calpain inhibitor, MDL 28170, protects against cortical neuronal damage even if the treatment is de layed until 3 h after reperfusion. However, the neuroprotective effect of this agent is less pronounced in the hippocampal CA1 sector. The r esults suggest that calpain-mediated proteolysis plays an important ro le in neuronal death due to ischemia, However, additional mechanisms b y which an increased intracellular calcium concentration leads to neur onal death may exist. (C) 1998 Elsevier Science Ireland Ltd.