Increase in phosphorylation of Akt and its downstream signaling targets and suppression of apoptosis by simvastatin after traumatic brain injury.
OBJECTIVE
In their previous studies, the authors found that simvastatin treatment of traumatic brain injury (TBI) in rats had beneficial effects on spatial learning functions. In the current study they wanted to determine whether simvastatin suppressed neuronal cell apoptosis after TBI, and if so, they wanted to examine the underlying mechanisms of this process.


METHODS
Saline or simvastatin (1 mg/kg) was administered orally to rats starting on Day 1 after TBI and then daily for 14 days. Modified Neurological Severity Scores were used to evaluate the sensory motor functional recovery. Rats were killed at 1, 3, 7, 14, and 35 days after treatment, and brain tissue was harvested for terminal deoxynucleotidyl nick-end labeling (TUNEL) staining, caspase-3 activity assay, and Western blot analysis.


RESULTS
Simvastatin significantly decreased the modified Neurological Severity Scores from Days 7 to 35 after TBI, significantly reduced the number of TUNEL-positive cells at Day 3, suppressed the caspase-3 activity at Days 1 and 3 after TBI, and increased phosphorylation of Akt as well as Forkhead transcription factor 1, inhibitory-kappaB, and endothelial nitric oxide synthase, which are the downstream targets of the prosurvival Akt signaling protein.


CONCLUSIONS
These data suggested that simvastatin reduces the apoptosis in neuronal cells and improves the sensory motor function recovery after TBI. These beneficial effects of simvastatin may be mediated through activation of Akt, Forkhead transcription factor 1 and nuclear factor-kappaB signaling pathways, which suppress the activation of caspase-3 and apoptotic cell death, and thereby, lead to neuronal function recovery after TBI.
Wu
Hongtao
H
Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan, USA.
Lu
Dunyue
D
Jiang
Hao
H
Xiong
Ye
Y
Qu
Changsheng
C
Li
Bo
B
Mahmood
Asim
A
Zhou
Dong
D
Chopp
Michael
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D051858:Forkhead Transcription Factors / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020672:I-kappa B Proteins / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*; D015599:Trauma Severity Indices; D000071161:Forkhead Box Protein O1
D051858:Forkhead Transcription Factors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020672:I-kappa B Proteins; D009419:Nerve Tissue Proteins; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D019821:Simvastatin; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C496316:Nos3 protein, rat