Published Online
on June 26, 2003

A more recent version of this article appeared on August 1, 2003

This Article Full Text (PDF) All Versions of this Article: 34/8/2007    most recent 01.STR.0000080677.24419.88v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Balduini, W. Articles by Cimino, M. Search for Related Content PubMed PubMed Citation Articles by Balduini, W. Articles by Cimino, M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CHOLESTEROL Related Collections Animal models of human disease Growth factors/cytokines Acute Cerebral Infarction Behavioral Changes and Stroke Neuroprotectors

Submitted on March 21, 2003
Accepted on March 27, 2003

Prophylactic but Not Delayed Administration of Simvastatin Protects Against Long-Lasting Cognitive and Morphological Consequences of Neonatal Hypoxic-Ischemic Brain Injury, Reduces Interleukin-1 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; and 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.

^* To whom correspondence should be addressed. 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-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.

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

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