Statins improve outcome in murine models of intracranial hemorrhage and traumatic brain injury: a translational approach.

Published

Journal Article

Traumatic brain injury (TBI) and intracerebral hemorrhage (ICH) are leading causes of neurological mortality and disability in the U.S. However, therapeutic options are limited and clinical management remains largely supportive. HMG-CoA reductase inhibitors (statins) have pleiotropic mechanisms of action in the setting of acute brain injury, and have been demonstrated to improve outcomes in preclinical models of ICH and TBI. To facilitate translation to clinical practice, we now characterize the optimal statin and dosing paradigm in murine models of ICH and TBI. In a preclinical model of TBI, mice received vehicle, simvastatin, and rosuvastatin at doses of 1 mg/kg and 5 mg/kg for 5 days after the impact. Immunohistochemistry, differential gene expression, and functional outcomes (rotarod and Morris water maze testing) were assessed to gauge treatment response. Following TBI, administration of rosuvastatin 1 mg/kg was associated with the greatest improvement in functional outcomes. Rosuvastatin treatment was associated with histological evidence of reduced neuronal degeneration at 24 h post-TBI, reduced microgliosis at day 7 post-TBI, and preserved neuronal density in the CA3 region at 35 days post-injury. Administration of rosuvastatin following TBI was also associated with downregulation of inflammatory gene expression in the brain. Following ICH, treatment with simvastatin 1 mg/kg was associated with the greatest improvement in functional outcomes, an effect that was independent of hemorrhage volume. Clinically relevant models of acute brain injury may be used to define variables such as optimal statin and dosing paradigms to facilitate the rational design of pilot clinical trials.

Full Text

Duke Authors

Cited Authors

  • Indraswari, F; Wang, H; Lei, B; James, ML; Kernagis, D; Warner, DS; Dawson, HN; Laskowitz, DT

Published Date

  • May 1, 2012

Published In

Volume / Issue

  • 29 / 7

Start / End Page

  • 1388 - 1400

PubMed ID

  • 22233347

Pubmed Central ID

  • 22233347

Electronic International Standard Serial Number (EISSN)

  • 1557-9042

Digital Object Identifier (DOI)

  • 10.1089/neu.2011.2117

Language

  • eng

Conference Location

  • United States