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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:598.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Rosuvastatin, but not Simvastatin, Provides End-Organ Protection in Stroke-Prone Rats by Antiinflammatory Effects

Luigi Sironi; Elisabetta Gianazza; Paolo Gelosa; Uliano Guerrini; Elena Nobili; Anita Gianella; Benedetta Cremonesi; Rodolfo Paoletti; Elena Tremoli

From the Department of Pharmacological Sciences (L.S., E.G., P.G., U.G., E.N., A.G., B.C., R.P., E.T.), Centre for Excellence on Neurodegenerative Diseases, (L.S., E.G., R.P., E.T.), Proteomic and Protein Structure Study Group (E.G.), University of Milan; and Monzino Cardiologic Center IRCCS (E.T.), Milan, Italy.

Correspondence to Luigi Sironi, Dipartimento di Scienze Farmacologiche, Università degli Studi di Milano, Via Balzaretti 9, I-20133 Milano, Italy. E-mail luigi.sironi{at}unimi.it

Objective— Brain abnormalities, preceded by a systemic inflammation, develop in spontaneously hypertensive stroke-prone rats (SHRSP). In this model, we investigated whether the hydrophilic statin, rosuvastatin, influences the development of inflammation associated with brain abnormalities. Because differences in hydrophilicity/hydrophobicity contribute to the differences in statin pharmacology, we also evaluated the effects of simvastatin, a lipophilic molecule

Methods and Results— SHRSP, fed a high-salt diet, were treated long-term with vehicle or rosuvastatin (1 and 10 mg/kg per day). Brain abnormalities developed after 40±5 days and after 60±5 days of salt loading, in vehicle-treated and in rosuvastatin-treated (1 mg/kg per day) SHRSP, respectively. After 100 days of treatment, no damage was detectable in 30% of the rats treated with the highest dose of the drug. In comparison with vehicle-treated SHRSP, rosuvastatin treatment attenuated the transcription of monocyte chemoattractant protein-1, transforming growth factor-ß1, IL-1ß, and tumor necrosis factor- in the kidney, and of P-selectin in brain vessels and increased the transcription of endothelial nitric oxide synthase mRNA in the aorta. Urinary excretion of acute-phase proteins increased with time in vehicle-treated animals but remained negligible in drug-treated animals. These effects are independent of changes in physiological parameters. Treatment of SHRSP with simvastatin (2 to 20 mg/kg per day) did not exert any protective effect.

Conclusions— Rosuvastatin attenuates inflammatory processes associated with cerebrovascular disease.

Stroke-prone rats have brain abnormalities preceded by the development of systemic inflammation. In this animal model, rosuvastatin, a hydrophilic statin, attenuates the release of inflammatory mediators and delays the appearance of brain damage. In the same model, simvastatin, a lipophilic statin, fails to exert any beneficial effect.

Key Words: inflammation • statins • rats • brain ischemia • proteome • rosuvastatin • simvastatin • stroke-prone rats

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