title: Statins improve outcome in murine models of intracranial hemorrhage and traumatic brain injury: a translational approach.
abstract: 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.
authors.affiliation: Multidisciplinary Neuroprotection Laboratories, Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Fransisca
authors.initials: F
authors.lastname: Indraswari
authors.forename: Haichen
authors.initials: H
authors.lastname: Wang
authors.forename: Beilei
authors.initials: B
authors.lastname: Lei
authors.forename: Michael L
authors.initials: ML
authors.lastname: James
authors.forename: Dawn
authors.initials: D
authors.lastname: Kernagis
authors.forename: David S
authors.initials: DS
authors.lastname: Warner
authors.forename: Hana N
authors.initials: HN
authors.lastname: Dawson
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Laskowitz
mesh_terms: D000818:Animals; D001925:Brain Damage, Chronic / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D001930:Brain Injuries / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D005464:Fluorobenzenes / Q000494:pharmacology / Q000627:therapeutic use; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D020300:Intracranial Hemorrhages / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D000068718:Rosuvastatin Calcium; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D057170:Translational Research, Biomedical / Q000379:methods / Q000639:trends*; D016896:Treatment Outcome
chemical_list: D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018696:Neuroprotective Agents; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D019821:Simvastatin