title: Simvastatin improves clinical scores in a rabbit multiple infarct ischemic stroke model: synergism with a ROCK inhibitor but not the thrombolytic tissue plasminogen activator.
abstract: Statins have pleiotropic neuroprotective effects in the central nervous system. In this study, we assessed the pharmacological effects of simvastatin on measures of behavior in New Zealand white rabbits embolized using a suspension of small-sized blood clots. For these studies, simvastatin was administered up to 3 hours following embolization, and behavior was measured 48 hours following embolization to calculate the dose of emboli (P(50) in mg) that produces neurological deficits in 50% of the rabbits. A treatment is considered neuroprotective if it significantly increases the P(50) compared to control. Simvastatin treatment (20mg/kg, bolus subcutaneous injection) significantly improved clinical function and increased the P(50) by 143% when administered 1 hour following embolization but was ineffective at 3 hours. In combination studies with the thrombolytic, tissue plasminogen activator (tPA) using a standard intravenous dose of 3.3mg/kg (20% bolus, 80% infused), we found that simvastatin could be safely administered with tPA to improve clinical scores; however, the maximum behavioral improvement with the combination treatment was similar to either monotherapy alone, both of which significantly improved behavior (p<0.05). It has been proposed that Simvastatin neuroprotection may be related to a variety of signaling pathways including Rho-kinase (ROCK). To determine if a ROCK mechanism is involved in simvastatin-induced neuroprotection following embolic strokes, we used pharmacological intervention with the ROCK inhibitor, fasudil. When fasudil was administered 30 minutes before simvastatin (given at 1 hour), there was an additional significant (p=0.0217) synergistic increase in behavioral function. However, fasudil as a monotherapy did not affect behavioral function in embolized rabbits. The study suggests that there may be an interaction between simvastatin treatment and the ROCK signaling pathway that should be further explored. Our results suggest that simvastatin treatment may have clinical benefit when used alone or in the presence of tPA, but the therapeutic window using a single-dose regimen is narrow.
authors.affiliation: Department of Neurology, Cedars-Sinai Medical Center, 8730 Alden Drive, Thalians E216, Los Angeles, CA 90048, USA. Paul.Lapchak@cshs.org
authors.forename: Paul A
authors.initials: PA
authors.lastname: Lapchak
authors.forename: Moon Ku
authors.initials: MK
authors.lastname: Han
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D020520:Brain Infarction / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D008297:Male; D011817:Rabbits; D019821:Simvastatin / Q000627:therapeutic use*; D020521:Stroke / Q000150:complications; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D005343:Fibrinolytic Agents; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D019821:Simvastatin; D054460:rho-Associated Kinases; D010959:Tissue Plasminogen Activator; C049347:fasudil