The Neuroprotective Actions of a Calcium Channel Antagonist, Flunarizine, in the Infant Rat

Abstract

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...

Platelet-Activating Factor Is an Important Mediator in Hypoxic Ischemic Brain Injury in the Newborn Rat

“…Flunarizine crosses the blood brain barrier and is relatively selective for the cerebral circulation, having little effect on the heart or systemic vasculature [19]. Several studies confirmed that flunarizine has a neuroprotective effect against hypoxic-ischemic injury [17][18][19][20]. Although the most direct explanation for the overall neuroprotective action of flunarizine is inhibition of calcium uptake by neurons, the mechanism of these protective effect is unclear.…”

“…Previous experimental studies showed that calcium channel blockers reduced ischemic neuronal damage in the brain [17,18]. Flunarizine is a lipid-soluble calcium antagonist known to pass the blood-brain barrier inhibiting depolarization-induced uptake of calcium [19].…”

Some Animal Models for the Study of Perinatal Asphyxia

“…and after recov ery'. exposure to 8%Oi for 3.5 h [50]: varying mod ifications of this model [56][57][58][59]61 ] In 7-day rat pups both CCA ligated, and exposed to hypoxia as above [54] Breathing hypoxic gas mixtures [60] tions. following which changes in the fetal car diovascular status and the central nervous system were systematically evaluated.…”

Possible Neuroprotective Properties of Flunarizine Infused after Asphyxia in Fetal Lambs Are Not Explained by Effects on Cerebral Blood Flow or Systemic Blood Pressure

“…(Pediatr Res 34: 379-384, 1993) Abbreviations rCBF, regional cerebral blood flow FHR, fetal heart rate Pa, arterial blood pressure Pv, venous blood pressure [02]a, arterial oxygen content Paco2, arterial carbon dioxide tension post-1, postasphyxia 1; time = 90 min post-2, postasphyxia 2; time = 180 min properties in various experimental setups. Newborn and infant rats, pretreated with the class IV calcium channel blocker flunarizine (2) and submitted to hypoxic-ischemic insults, had less brain damage compared with nontreated controls (3)(4)(5). Flunarizine treatment after induction of cortical damage in adult rats improved brain function and reduced infarct size (6).…”