on January 27, 2005
Published online before print January 27, 2005, doi: 10.1161/01.ATV.0000157145.98200.55
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Submitted on January 8, 2004
Accepted on January 3, 2005
Rosuvastatin, but not Simvastatin, Provides End-Organ Protection in Stroke-Prone Rats by Antiinflammatory Effects
Luigi Sironi *;
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.
* To whom correspondence should be addressed. 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-
1, IL-1, 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.
Key words: inflammation • statins • rats • brain ischemia • proteome • rosuvastatin • simvastatin • stroke-prone rats
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