Increase in phosphorylation of Akt and its downstream signaling targets and suppression of apoptosis by simvastatin after traumatic brain injury

Object. In their previous Studies, the authors found that simvastatin treatment of traumatic brain injury (TBI) in rats had beneficial effects oil 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 oil Day I 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 clays 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 I and 3 after TBI, and increased phosphorylation of Akt as well as Forkhead transcription factor 1, inhibitory-kappa B, and enclothelial 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-kappa 13 signaling pathways, which suppress the activation of caspase-3 and apoptotic cell death, and thereby, lead to neuronal function recovery after TBI.