Background and Purpose-Recent studies suggest that statins (3-hydroxy-3-met
hylglutaryl 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. Despit
e the growing body of evidence, however, the neuroprotective effect of stat
ins in stroke is still controversial. Herein, we studied whether a prophyla
ctic administration of simvastatin (Sim) provides significant protection ag
ainst 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 wi
th activated Sim (20 mg/kg) or an equivalent volume of vehicle. On postnata
l day 7, the rats were subjected to ligation of the right common carotid ar
tery, followed by 3 hours of hypoxia or by sham operation. The neuroprotect
ive effect of Sim was evaluated after the rats had achieved adulthood by us
ing a battery of behavioral tests and histological analysis.
Results-Sim-treated ischemic rats performed the circular water maze, the ra
dial arm maze, and the multiple-choice water maze significantly better than
did vehicle-treated ischemic rats. Furthermore, in contrast to the ischemi
c rats, hypoxia/ischemia-injured rats pretreated with Sim were not hyperact
ive at weaning and showed less behavioral asymmetry. Consistently, it was f
ound that brain damage was significantly attenuated.
Conclusions-These findings indicate that prophylactic administration of sta
tins may provide a potential neuroprotective strategy leading to an improve
ment in functional outcome in ischemic stroke. However, toxicity concern mu
st be addressed before these agents can be directed to the asphyxiated fetu
s or newborn.