ABSTRACT. One postulated final common pathway lead- MATERIALS AND METHODSing to neuronal death after hypoxic-ischemic insults is an increase in intracellular calcium concentrations. We exExperimental preparation. The 21-d-old Wistar rats were anamined the effect of pretreatment with flunarizine, a ,,+ aesthetised with a 2% halothane/02 mixture. In each rat one cium channel antagonist known to pass the blood brain carotid artery was exposed and ligated with 6.0 silk sutures. The barrier, on the behavioral and histologic changes after an rats were removed from anaesthesia and then received, by intrahypoxic-ischemic insult in the infant rat. The 21-d-old rats peritoneal injection, either flunarizine (Janssen Pharmaceutica, were subjected to unilateral carotid ligation, then to 2 h of Beers% Belgium), 30 mg/kg or an equal volume of the diluent, hypoxia. They were pretreated with either flunarizine (30 10% ethanol, 1.5 ml/kg, given in equally divided doses. The first mg,kg, intraperitoneally) or with an equal volume of dose was given immediately after surgery, the second immedidiluent. After 5 days of observation they were killed for ately before the hypoxia2 later. histology. Acute behavioral abnormalities wereEach rat was next subjected to an h~~o x i c environment of 8% in more controls than treatment animals, 52 vs 11% ( p < 0 2 and 2% COz [to prevent hypocapnia induced vasospasm 0.002). Cerebral injury was almost entirely confined to the (2411, maintained at 37" C, for 120 min. The pups were then ligated side and was significantly worse in the control rats. returned to their cages, with their litter mates. Daily after the ~~1 1 thickness cortical infarction was noted in 56% of hypoxia each rat was behaviorally tested by a blind, independent controls (n = 27) vs 4% of flunarizine-treated rats (n = observer (LB), who scored each for the presence of five possible 24), (p < O.OO1). Mean and maximum damage scores for abnormalities: fits, absence of startle response, abnormal turning, all areas assessed including cortex, corpus striaturn, tllal-impaired righting, and impaired response to tail pinch (23, 25). amus, amygdala, and h~ppocampus were improved mark-On the day of death a further scoring for residual abnormalities edly in treatment rats (p < 0 . 0 0~) . These observations was made. The presence of definite unilateral weakness was confirm that flunarizine, when given prophylactically, has scored as 2, whereas other behavioral problems such as excessive a neuroprotective effect against hypoxic-ischemic injury in or reduced activity or persistent piloerection were scored as 1. the developing brain. (Pediatr Res 25:573-576). Death was by the injection of pentobarbital. These experiments were approved by the Animal Ethical Committee of the University of Auckland. Pilot study. This study included the two main groups. 1 ) Flunarizine pretreated, with ligation and hypoxia, the treatment Perinatal hypoxic-ischemic encephalopathy is associated with group (n = 5). 2) Ethanol pretreated, with ligation and hypoxia, a signi...