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Background and Purpose-Prophylactic administration of simvastatin has been shown to protect against brain damage and its long-lasting behavioral consequences in neonatal rats. To establish the drug treatment window, we evaluated the effectiveness of simvastatin administered at different intervals before and after stroke. Furthermore, we determined whether simvastatin affected endothelial nitric oxide synthase (eNOS) or inflammatory cytokines in brain tissue or cholesterol levels in serum. Methods-On postnatal day 7, male rats were subjected to hypoxia-ischemia (HI). The experiment included sham-operated controls and HI animals receiving daily saline or activated simvastatin (20 mg/kg) injections from postnatal day 1 to day 7 (HI-simvastatin 1-7 group), from postnatal day 4 to day 11 (HI-simvastatin 4 -11 group), or from postnatal day 7 to day 14 (HI-simvastatin 7-14 group). The neuroprotective effect of simvastatin was evaluated at adulthood by means of behavioral and histological analyses. Cytokines and eNOS expression were assessed by reverse transcriptasepolymerase chain reaction and Western blotting. Results-Animals in both the HI-simvastatin 1-7 and HI-simvastatin 4 -11 groups performed better than HI rats in either the T-maze or the circular water maze and showed significantly attenuated brain damage. Expression of interleukin-1␤ and tumor necrosis factor-␣ mRNA in cortex was significantly increased in HI but not in HI-simvastatin 1-7 animals. In the same brain area, simvastatin treatment did not affect the increase of eNOS expression observed after HI. Conclusions-These findings indicate that prophylactic but not delayed administration of simvastatin improves functional outcome in neonatal rat stroke. The reduced induction of cytokines suggests that the neuroprotective effect of simvastatin may be related to a dampening of the inflammatory response. (Stroke.

Background and Purpose-Recent studies suggest that statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) not only reduce the incidence of stroke by lowering cholesterol levels but may also exert neuroprotective effects via a mechanism not related to their lipid-lowering effect. Despite the growing body of evidence, however, the neuroprotective effect of statins in stroke is still controversial. Herein, we studied whether a prophylactic administration of simvastatin (Sim) provides significant protection against brain damage, and we sought to determine its long-lasting behavioral consequences in a neonatal model of hypoxia/ischemia. Methods-Newborn male rats were injected daily from postnatal days 1 to 7 with activated Sim (20 mg/kg) or an equivalent volume of vehicle. On postnatal day 7, the rats were subjected to ligation of the right common carotid artery, followed by 3 hours of hypoxia or by sham operation. The neuroprotective effect of Sim was evaluated after the rats had achieved adulthood by using a battery of behavioral tests and histological analysis. Results-Sim-treated ischemic rats performed the circular water maze, the radial arm maze, and the multiple-choice water maze significantly better than did vehicle-treated ischemic rats. Furthermore, in contrast to the ischemic rats, hypoxia/ischemia-injured rats pretreated with Sim were not hyperactive at weaning and showed less behavioral asymmetry. Consistently, it was found that brain damage was significantly attenuated. Conclusions-These findings indicate that prophylactic administration of statins may provide a potential neuroprotective strategy leading to an improvement in functional outcome in ischemic stroke. However, toxicity concern must be addressed before these agents can be directed to the asphyxiated fetus or newborn. Key Words: cerebral ischemia Ⅲ HMG-CoA reductase inhibitors Ⅲ neuroprotection Ⅲ newborn Ⅲ rats I schemic stroke is one of the leading causes of permanent disabilities and death in the elderly. Stroke also commonly occurs in the perinatal period and can have severe consequences on motor, cognitive, and behavioral functions that span the infant's lifetime. The mechanisms of hypoxia/ischemia (HI)-induced brain damage, the behavioral outcome, and the effect of potential pharmacological treatments during development can be studied in 7-day-old rats subjected to unilateral carotid artery ligation and exposure to a hypoxic environment for 2 to 3 hours. [1][2][3][4] In terms of brain development, this age of the rat is similar to that of near-term human babies. 5 In a recent study, we characterized the long-lasting behavioral alterations occurring in this model of neonatal HI and found that these animals, when adults, show behavioral asymmetry and deficits in performing spatial learning tasks. 4 Therefore, these behavioral abnormalities can be used as an end point to evaluate the efficacy of potential pharmacological treatments that may improve the consequences of a perinatal HI insult.Recent clinical studies have reported ...

Ethanol administration during the rat brain growth spurt triggers apoptotic neurodegeneration that appears to be mediated by caspase-3 activation. In order to gain more insight on the role of this caspase in ethanol-induced developmental neurotoxicity, we studied its expression and activity under different conditions of ethanol exposure during development. Furthermore, because of the cross-talk between caspase-3 and calpain we extended our study also at this protease. Ethanol was administered by gavage to rat pups as a singleday exposure on postnatal day (PN) 7 or from PN4 to PN10. Cleaved caspase-3 expression peaked in the cerebral cortex 12 h after ethanol treatment and returned to control values at 24 h. An identical pattern was found for caspase-3-like activity, that was increased only with the highest dose of ethanol tested (5 g/kg) and mostly in PN4. Repeated ethanol exposure, at a dose that was previously found to induce microencephaly, did not increase caspase-3 expression and activity although it decreased procaspase-3 expression and released mitochondrial cytochrome c. Repeated ethanol administration also increased calpain activity. These data show that acute and repeated ethanol administration differentially affect caspase-3 and calpain activity, suggesting that calpain activation may play a role in developmental neurotoxicity of ethanol.