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(Stroke. 2003;34:2007.)
© 2003 American Heart Association, Inc.

Original Contributions

Prophylactic but Not Delayed Administration of Simvastatin Protects Against Long-Lasting Cognitive and Morphological Consequences of Neonatal Hypoxic-Ischemic Brain Injury, Reduces Interleukin-1ß and Tumor Necrosis Factor- mRNA Induction, and Does Not Affect Endothelial Nitric Oxide Synthase Expression

Walter Balduini, PhD; Erika Mazzoni, PhD; Silvia Carloni, PhD; Maria Grazia De Simoni, PhD; Carlo Perego; Luigi Sironi, PhD Mauro Cimino, PhD

From the Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino, Urbino (W.B., E.M., S.C., M.C.); Istituto di Ricerche Farmacologiche "Mario Negri," Milano (M.G. De S., C.P.); and Dipartimento di Scienze Farmacologiche, Università degli Studi di Milano, Milano (L.S.), Italy.

Correspondence to Dr Walter Balduini, Istituto di Farmacologia e Farmacognosia, Università di Urbino, via S. Chiara 27, 61029 Urbino (PS), Italy. E-mail balduini{at}uniurb.it

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 transcriptase-polymerase 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-1ß 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.

Key Words: cerebral ischemia • HMG-CoA reductase inhibitors • neuroprotection • newborn • rats

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