Simvastatin and atorvastatin improve behavioral outcome, reduce hippocampal degeneration, and improve cerebral blood flow after experimental traumatic brain injury

• Published in: Experimental neurology Vol. 206; no. 1; pp. 59 - 69
• Main Authors: Wang, Haichen, Lynch, John R., Song, Pingping, Yang, Hyuk-Jun, Yates, Robert B., Mace, Brian, Warner, David S., Guyton, John R., Laskowitz, Daniel T.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.07.2007; Elsevier
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Atorvastatin; Atorvastatin Calcium; Biological and medical sciences; Brain Edema - drug therapy; Brain Edema - etiology; Brain Edema - physiopathology; Brain Injuries - drug therapy; Brain Injuries - pathology; Brain Injuries - physiopathology; Brain Ischemia - drug therapy; Brain Ischemia - etiology; Brain Ischemia - physiopathology; Cerebral blood flow; Cerebrovascular Circulation - drug effects; Cerebrovascular Circulation - physiology; Chemotaxis, Leukocyte - drug effects; Chemotaxis, Leukocyte - physiology; Cognition Disorders - drug therapy; Cognition Disorders - etiology; Cognition Disorders - physiopathology; Cytokines - genetics; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Encephalitis - drug therapy; Encephalitis - etiology; Encephalitis - physiopathology; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Heptanoic Acids - pharmacology; Heptanoic Acids - therapeutic use; Hippocampus - drug effects; Hippocampus - pathology; Hippocampus - physiopathology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Injuries of the nervous system and the skull. Diseases due to physical agents; Interleukin 6; Male; Medical sciences; Mice; Mice, Inbred C57BL; Nerve Degeneration - drug therapy; Nerve Degeneration - etiology; Nerve Degeneration - physiopathology; Neurology; Neurons - drug effects; Neurons - metabolism; Nitric oxide; Pyrroles - pharmacology; Pyrroles - therapeutic use; Recovery of Function - drug effects; Recovery of Function - physiology; RNA, Messenger - drug effects; RNA, Messenger - metabolism; Simvastatin; Simvastatin - pharmacology; Simvastatin - therapeutic use; TNFα; Traumas. Diseases due to physical agents; Traumatic brain injury; Treatment Outcome; Interleukin 6; TNFα; Traumatic brain injury; Cerebral blood flow; Simvastatin; Nitric oxide; Atorvastatin; Prognosis; Leukocyte; Craniocerebral; Suppression; Central nervous system; Functional deficit; Cardiovascular disease; Intracranial pressure; Recruitment; Vascular disease; Surgery; Endothelial dysfunction; Degeneration; Cerebrovascular disease; Release; Subacute; Nervous system diseases; Pathophysiology; Intracranial hypertension; Rodentia; Cytokine; Inflammation; Statin derivative; Cerebral disorder; Blood flow; Vertebrata; Mammalia; Clinical management; Neuron; Treatment; Mouse; Animal; Evacuation; Central nervous system disease; Hematoma; Brain ischemia; Strategy; Hemodynamics; Head trauma; Cerebral edema; Hippocampus
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2007.03.031

The treatment of traumatic brain injury (TBI) remains limited, and aside from surgical hematoma evacuation, clinical management is largely supportive and directed toward management of cerebral edema and intracranial hypertension. Secondary neuronal injury caused by ischemia and the development of cerebral edema may occur in the subacute phase, with intracranial pressures often peaking in the first several days following injury. Because inflammation contributes significantly to the pathophysiology of cerebral ischemia and endothelial dysfunction underlies the development of cerebral edema, therapeutic strategies that target the post-traumatic inflammatory cascade and reduce endothelial dysfunction hold enormous potential to improve clinical outcomes after TBI. Statins inhibit inflammation by suppressing inflammatory cytokine release, and by interfering with multiple steps of leukocyte recruitment and migration into the CNS. In this study, we demonstrate that treatment with atorvastatin and simvastatin markedly reduced functional neurological deficits after traumatic brain injury in mice. These effects were accompanied by histological reduction in degenerating hippocampal neurons and suppression of inflammatory cytokine mRNA expression in brain parenchyma. Furthermore, statin treatment improved cerebral hemodynamics following head injury. Thus, the administration of statins may represent a viable therapeutic strategy in the acute treatment of closed head injury.