Sirtuin 1 alleviates neuroinflammation-induced apoptosis after traumatic brain injury

Abstract

Sirtuin 1 (SIRT1) plays a very important role in a wide range of biological responses, such as metabolism, inflammation and cell apoptosis. Changes in the levels of SIRT1 have been detected in the brain after traumatic brain injury (TBI). Further, SIRT1 has shown a neuroprotective effect in some models of neuronal death; however, its role and working mechanisms are not well understood in the model of TBI. This study aimed to address this issue. SIRT1-specific inhibitor (sirtinol) and activator (A3) were introduced to explore the role of SIRT1 in cell apoptosis. Results of the study suggest that SIRT1 plays an important role in neuronal apoptosis after TBI by inhibiting NF-κB, IL-6 and TNF-α deacetylation and the apoptotic pathway sequentially, possibly by alleviating neuroinflammation.

Keywords: NF-κB; neuroinflammation; neuronal apoptosis; sirtuin 1; traumatic brain injury.

FIGURE 1

Expression of SIRT1 in the brain cortex after TBI. Western blot analysis shows the expression of SIRT1 at 6, 12, 24, 48 and 72 h after TBI; *P < .05, ***P < .001 vs. Sham group

FIGURE 2

Effects of sirtinol on the expression of SIRT1 (A, B, D) and inflammatory factor (B, C) 24 h after TBI. Bars represent mean ± SD. *P < .05, **P < .01, ***P < .001 vs. Sham group; ^# P < .05, ^## P < .01 vs. TBI + vehicle group

FIGURE 3

Effects of sirtinol on neuronal survival 24 h after TBI (A, B) The apoptotic index was determined by the TUNEL assay 1 d after TBI. (C) Brain water content and neurological function were assessed after TBI. Data represent mean ± SD, *P < .05, **P < .01, ***P < .001 vs. Sham group; ^# P < .05, ^### P < .001 vs. TBI + vehicle group

FIGURE 4

Effects of sirtinol on the SIRT1 and apoptotic protein expression after TBI. A, Representative photomicrographs of caspase‐3 staining in the experimental groups. B, Effects of sirtinol on the apoptotic pathway, including the levels of cleaved caspase‐3 Bax and Bcl‐2. Bars represent mean ± SD. *P < .05, **P < .01 and ***P < .001 vs. Sham group; ^# P < .05, ^## P < 0.001vs. TBI + vehicle group

FIGURE 5

Effects of A3 on the SIRT1 expression and neuroinflammation 24 h after TBI. A, Representative Immunohistochemical staining to detect A3 on the expression of SIRT1. B, The levels of SIRT1, NF‐кB, TNF‐α and IL‐6 were significantly increased after TBI and were evidently decreased by the A3 treatment. Arrows point to SIRT1‐positive neurons. Data represent mean ± SD, **P < .01, ***P < .001 vs. Sham group; ^# P < .05 vs. TBI + vehicle group

FIGURE 6

Effects of A3 on apoptosis, brain oedema and neurological function 24 h after TBI. (A, E) Representative photomicrographs of TUNEL staining in the experimental groups. (B, C, F) A3 treatment significantly decreased the Bax protein levels, but increased the Bcl‐2 protein levels compared with those in the TBI + vehicle group. (D, G) Impaired brain oedema and neurological behaviour decreased significantly after A3 administration, compared with those in the TBI + vehicle group. Data represent mean ± SD, *P < .05, **P < .01, ***P < .001 vs. Sham group; ^# P < .05, ^## P < .01 vs. TBI + vehicle group