pitavastatin and Subarachnoid-Hemorrhage

Statins have pleiotropic effects that are considered beneficial in preventing cerebral vasospasm and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (aSAH). Many studies using statins have been performed but failed to show remarkable effects. We hypothesized that a long-acting statin would be more effective, due to a longer half-life and stronger pleiotropic effects. Patients with aSAH were randomly assigned to a pitavastatin group (4 mg daily; n = 54) and a placebo group ( n = 54) after repair of a ruptured aneurysm. The primary efficacy end point was vasospasm-related delayed ischemic neurological deficits (DIND), and the secondary end points were cerebral vasospasm evaluated by digital subtraction angiography (DSA), vasospasm-related new cerebral infarctions, and outcome at three months. Severe cerebral vasospasms on DSA were statistically fewer in the pitavastatin group than in the placebo group (14.8% vs. 33.3%; odds ratio, 0.32; 95% confidence interval, 0.11-0.87, p = 0.042); however, the occurrence of DIND and new infarctions and outcome showed no statistically significant differences between the groups. The present study is the first to prove the definite, statin-induced amelioration of cerebral vasospasm on DSA. However, administration of any type of statin at the acute phase of aSAH is not recommended.

Topics: Adult; Aged; Aneurysm, Ruptured; Delayed-Action Preparations; Double-Blind Method; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intracranial Aneurysm; Male; Middle Aged; Quinolines; Subarachnoid Hemorrhage; Vasospasm, Intracranial

Accumulating results have disclosed that early brain injury (EBI) may play a major role in the determination of the outcome of aneurysmal subarachnoid hemorrhage (SAH) patients. This study is of interest to examine the efficacy of pitavastatin, a 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) inhibitor, on SAH-induced apoptosis.. A rodent double SAH model was employed. Pitavastatin was administered orally. CSF IL-1β, IL-6, IL-8 and TNF-α were measured (rt-PCR). Basilar arteries were harvested for C-Jun N-terminal kinase p46/p55 (cJNK (p46/p55)), matrix metallopeptidase-9 (MMP-9) (Western blot), caspase and Bcl-2 (rt-PCR) evaluation.. Pitavastatin reduced the bioexpression of cJNK p55 compared with the SAH groups. Cleaved caspase-9a was significantly reduced in the pitavastatin-preconditioned group compared with the SAH group (p > 0.05). IL-1β and TNF-α levels were reduced in the pitavastatin-preconditioned group. Pretreatment with pitavastatin significantly reduced activated MMP-9, capsase-9a and B-cell lymphoma 2(Bcl) mRNA.. Preconditioning with pitavastatin exerts its neuroprotective effect through the dual action of inhibiting cJNK(p46/p55) activation and reducing cleaved caspase-9a expression. Besides, the bioinhibition of MMP-9 may partially contribute to the neuroprotective effect. This study lends credence to the theory that statins, especially in the preconditioning status, may attenuate SAH-induced neuron apoptosis.

Topics: Animals; Apoptosis; Basilar Artery; Cytokines; Hydroxymethylglutaryl-CoA Reductase Inhibitors; JNK Mitogen-Activated Protein Kinases; Male; Neuroprotective Agents; Quinolines; Rats; Rats, Sprague-Dawley; Subarachnoid Hemorrhage

The Rho/Rho-kinase pathway is considered important in the pathogenesis of sustained smooth muscle cell contraction during cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). The aims of this study were to investigate whether combination treatment, with pitavastatin as an inhibitor of RhoA and fasudil as an inhibitor of Rho-kinase, prevents the cerebral vasospasm. SAH was simulated using the double-hemorrhage rabbit model, and pitavastatin, or fasudil, or both (combination treatment) were administrated. The basilar artery (BA) cross-sectional area only in the combination treatment group was statistically larger than in the SAH group (p<0.05). BA Rho-kinase, as measured by ELISA, was statistically reduced only in the combination treatment group compared with the SAH group (p<0.05). In the other two treatment groups, pitavastatin or fasudil treatment group showed larger BA cross-sectional areas and lower value for BA Rho-kinase, but there were no statistically significant differences compared with the SAH group. The expression of endothelial nitric oxide synthase (eNOS), evaluated by immunohistochemistry in the pitavastatin group and the combination group, was higher than in the SAH group. Results indicate that combination treatment could extensively prevent cerebral vasospasm due to the synergic effect of combining pitavastatin and fasudil on the Rho/Rho-kinase pathway and on eNOS.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Basilar Artery; Drug Combinations; Enzyme-Linked Immunosorbent Assay; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Nitric Oxide Synthase Type III; Quinolines; Rabbits; rho-Associated Kinases; Subarachnoid Hemorrhage; Vasospasm, Intracranial