ReviewNeuroprotective Effect of Simvastatin in Stroke: A Comparison Between Adult and Neonatal Rat Models of Cerebral Ischemia
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INTRODUCTION
Clinical trials demonstrated that 3-hydroxy-3-methylglutaril coenzyme A reductase inhibitors or statins exert beneficial effects when used as stroke prophylactic agents (Byington et al., 2001, Gil-Nunez and Villanueva, 2001, Vaughan et al., 2001). These studies showed that statins reduce the incidence of both first and secondary events by 25–30%; prevention is believed to be achieved mainly through their activity on blood vessel wall function. However, in addition to exerting
THE NEONATAL AND ADULT MODELS OF CEREBRAL ISCHEMIA
The pharmacological properties of simvastatin in experimental stroke have been evaluated by using several rodent models of cerebral ischemia (Ginsberg and Busto, 1989, Vannucci et al., 1999). Over the past years, numerous investigators have described the basic mechanisms involved in tissue injury, as well as specific therapeutic interventions, and have highlighted homologies and differences between hypoxia/ischemia (H/I) in neonates, middle cerebral artery occlusion (MCAO) in the adults, and
EFFECT OF PRE- AND POST-ISCHEMIA SIMVASTATIN ADMINISTRATION ON INFARCT SIZE
The effect of simvastatin was evaluated in both the neonatal and the adult experimental models. In the H/I model, ischemia was induced at PN7 and the drug (20 mg/kg) was injected daily (s.c.) either before (from post-natal day 1 to post-natal day 7; Sim 1–7), before and after (from post-natal day 4 to post-natal day 11; Sim 4–11) or after the ischemic insult (from post-natal day 7 to post-natal day 14; Sim 7–14). This last group received the first dose immediately after the period of hypoxia.
THERAPEUTIC WINDOW OF SIMVASTATIN IN THE MCAO MODEL
In light of the clinical relevance that the protective effect of statins might play in acute stroke, we sought to investigate the therapeutic window of the post-ischemic neuroprotective action of simvastatin in adult rats undergoing MCAO. Fig. 3 shows that a single injection of simvastatin (20 mg/kg) was able to prevent the progression of ischemic damage if given soon after MCAO. Indeed, this strong beneficial effect of the acute dose of simvastatin was observed when the drug is administered
EFFECT OF PRE- AND POST-ISCHEMIA SIMVASTATIN ADMINISTRATION ON eNOS ACTIVATION
There is consistent evidence indicating that augmentation of eNOS activity has beneficial effects in adult stroke, whereas deletion of the gene further exacerbates damage (Sironi et al., 2003, Endres et al., 2004). Indeed, adult mice lacking eNOS develop larger cerebral infarctions, while enhanced NO production by administration of the eNOS substrate l-arginine increases cerebral blood flow in the area of the ischemic insult and confers neuroprotection (Dalkara et al., 1994, Endres et al., 1998
CONCLUSIONS
Experimental investigations carried out on animal models of cerebral ischemia have further emphasized the beneficial role of statins in stroke. Nevertheless, the molecular mechanisms underlying this protective action still remain far from being completely understood and may differ according to the type of insult (global, focal, transient or permanent) and to the stage of brain development. Indeed, the intrinsic vulnerability of the immature brain differs from that of the adult because the
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