Long-term benefits after treatment of traumatic brain injury with simvastatin in rats.
OBJECTIVE
This study was designed to investigate the long-term effects of simvastatin treatment after traumatic brain injury (TBI) in rats.


METHODS
Adult female Wistar rats (n = 24) were injured with controlled cortical impact and divided into 3 groups. The first 2 groups were treated with simvastatin (0.5 or 1.0 mg/kg) administered orally for 14 days starting 1 day after TBI. The third group (control) received phosphate-buffered saline orally for 14 days. Neurological functional outcome was measured with modified neurological severity scores performed 1 day before TBI; on days 1, 4, 7, 14 after TBI; and biweekly thereafter. All animals were sacrificed 3 months after TBI. Brain tissues of half of the animals were processed for preparation of paraffin-embedded sections for immunohistological studies. The remaining half were frozen for enzyme-linked immunosorbent assay studies for quantification of brain-derived neurotrophic factor (BDNF) in the hippocampus and cortex.


RESULTS
The results showed that both doses of simvastatin significantly improved functional outcome compared with the control, with no difference between the 2 doses. Simvastatin treatment of 1.0 mg/kg increased the number of morphologically intact neurons in the hippocampus, but treatment of 0.5 mg/kg had no significant effect. Enzyme-linked immunosorbent assay studies showed that 0.5 mg/kg simvastatin significantly increased BDNF levels within the hippocampus, but 1.0 mg/kg had no significant effect. Neither dose had any effect on BDNF levels within the cortex.


CONCLUSIONS
Simvastatin treatment provides long-lasting functional improvement after TBI in rats. It also enhances neuronal survival in the hippocampus and increases BDNF levels in the hippocampus secondary to simvastatin treatment.
Mahmood
Asim
A
Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan, USA. nsaam@neuro.hfh.edu
Goussev
Anton
A
Kazmi
Humaira
H
Qu
Changsheng
C
Lu
Dunyue
D
Chopp
Michael
M
D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006624:Hippocampus / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin