title: Rosuvastatin, but not simvastatin, provides end-organ protection in stroke-prone rats by antiinflammatory effects.
abstract: 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
  
  
  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-beta1, IL-1beta, and tumor necrosis factor-alpha 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.
authors.affiliation: Department of Pharmacological Sciences, University of Milan, Italy. luigi.sironi@unimi.it
authors.forename: Luigi
authors.initials: L
authors.lastname: Sironi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Gianazza
authors.forename: Paolo
authors.initials: P
authors.lastname: Gelosa
authors.forename: Uliano
authors.initials: U
authors.lastname: Guerrini
authors.forename: Elena
authors.initials: E
authors.lastname: Nobili
authors.forename: Anita
authors.initials: A
authors.lastname: Gianella
authors.forename: Benedetta
authors.initials: B
authors.lastname: Cremonesi
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Paoletti
authors.forename: Elena
authors.initials: E
authors.lastname: Tremoli
mesh_terms: D000209:Acute-Phase Proteins / Q000276:immunology; D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects / Q000276:immunology; D018932:Chemokine CCL2 / Q000235:genetics; D005464:Fluorobenzenes / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D019007:P-Selectin / Q000235:genetics; D011507:Proteinuria / Q000188:drug therapy / Q000276:immunology; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D000068718:Rosuvastatin Calcium; D019821:Simvastatin / Q000494:pharmacology*; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D020521:Stroke / Q000188:drug therapy* / Q000276:immunology; D013449:Sulfonamides / Q000494:pharmacology*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014657:Vasculitis / Q000188:drug therapy* / Q000276:immunology
chemical_list: D000209:Acute-Phase Proteins; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019007:P-Selectin; D011743:Pyrimidines; D012333:RNA, Messenger; D017673:Sodium Chloride, Dietary; D013449:Sulfonamides; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D000068718:Rosuvastatin Calcium; D019821:Simvastatin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat