Increase in phosphorylation of Akt and its downstream signaling targets and suppression of apoptosis by simvastatin after traumatic brain injury - PubMed (original) (raw)

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

Hongtao Wu et al. J Neurosurg. 2008 Oct.

Abstract

Object: 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.

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Figures

Fig. 1

Fig. 1

The temporal profile of the NSS after TBI in saline- or simvastatin-treated rats. The score was significantly decreased in the simvastatin-treated group compared to the saline group from 7 days after treatment. These data demonstrate that simvastatin enhances the sensory-motor functional recovery after TBI. Data are represented as mean ± SD. * p < 0.05, ** p < 0.01, n = 8.

Fig. 2

Fig. 2

TUNEL staining for detection of the apoptotic cells. Representative pictures show the TUNEL-positive staining cells (brown) in the cortex, dentate gyrus and hippocampus CA1 area (a~l). Plots (m~o) show the statistical analysis of TUNEL-positive cell number in these areas. Treatment with simvastatin decreases the number of TUNEL-positive cells compared to saline. Scale bar = 50 µm (a,b,e,f,i,j), 100 µm (c,d,g,h,k,l). Data are represented as mean ± SD. * p < 0.05, n = 4/group.

Fig. 3

Fig. 3

Bar graphs show the activity of caspase-3. Simvastatin decreases the activity of caspase-3 at Days 1 and 3 after treatment compared to the saline group. As caspase-3 plays a key role in the process of cell apoptosis, inhibition of caspase-3 activity may result in suppression of apoptosis after TBI. Data are represented as mean ± SD. * p < 0.05, ** p < 0.01 vs. saline group, n = 4.

Fig. 4

Fig. 4

Representative Western blot and densitometry measurement of a) p-FOXO1, b) p-eNOS, and c) p-IκB in the cortex in rats treated with simvastatin (black bars) or saline (grey bars) after TBI (AU = arbitrary units). Data in the bar graphs are represented as mean ± SD. *p < 0.05. Simvastatin treatment significantly increases FOXO1 phosphorylation from Days 1 to 14 after treatment, eNOS phosphorylation at Days 3 and 7, and IκB phosphorylation at Days 3, 7 and 14. As FOXO1 and IκB are key factors of anti-apoptotic Akt signaling pathway, these data indicate simvastatin may reduce the neuronal cell apoptosis via activation of the above signaling factors.

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