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...

Perinatal asphyxia is associated with an increased risk of cerebral palsy and significant mortality. We investigated the use of flunarizine, a calcium antagonist and MK-801, an excitatory amino acid antagonist, in preventing the sequelae of severe hypoxic/ischemic insults. Flunarizine was neuroprotective in the infant rat subjected to unilateral carotid ligation and 2 h of hypoxia. Preliminary analysis of experiments in a novel model of cerebral ischemia in the fetal sheep suggests that prophylactic treatment with flunarizine greatly modified the outcome after 30 min of total ischemia. Treatment with MK-801 prevented post-ischemic seizures. The background to these developments is outlined and future prospects considered.

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1 The aim of this study was to examine the cholinoreceptor population in the rat costo-uterine muscle. 2 The nicotinic cholinoreceptor agonists nicotine and DMPP, and the ganglionic muscarinic cholinoreceptor stimulant McNeil A-343, had no effects upon isolated preparations of this tissue. 3 Acetylcholine was more potent than carbachol and approximately equipotent with methacholine (the mean EC50 values were 7.0, 6.3 and 6.7 respectively) in producing contractions of the preparation; each was a full agonist. The potencies of carbachol and methacholine were similar in preparations taken from animals in oestrus and in dioestrus. 4 Atropine competitively antagonised the effects of carbachol and methacholine, the pA2 values were 9.37 and 9.41 respectively. The pA2 value for pirenzepine with carbachol as the agonist was 6.69. 5 Pilocarpine produced phasic contractions of the tissue (EC50 value = 4.17), and competitively antagonised the effects of carbachol with a pA2 value of 5.26. The anticholinesterase, physostigmine, produced only a small potentiation of the effects of acetylcholine. 6 It is concluded that the cholinoreceptors which mediate contraction of the rat costo-uterine muscle are muscarinic, homogeneous in nature and unaffected by fluctuating levels of ovarian hormones occurring during the oestrous cycle. The consequences of inhibition of cholinesterase activity in isolated preparations of the tissue are minimal.

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