SIRT2 inhibition exacerbates neuroinflammation and blood-brain barrier disruption in experimental traumatic brain injury by enhancing NF-κB p65 acetylation and activation

Abstract

Sirtuin 2 (SIRT2) is a member of the sirtuin family of NAD(+) -dependent protein deacetylases. In recent years, SIRT2 inhibition has emerged as a promising treatment for neurodegenerative diseases. However, to date, there is no evidence of a specific role for SIRT2 in traumatic brain injury (TBI). We investigated the effects of SIRT2 inhibition on experimental TBI using the controlled cortical impact (CCI) injury model. Adult male mice underwent CCI or sham surgery. A selective brain-permeable SIRT2 inhibitor, AK-7, was administrated 30 min before injury. The volume of the brain edema lesion and the water content of the brain were significantly increased in mice treated with AK-7 (20 mg/kg), compared with the vehicle group, following TBI (p < 0.05 at 1 day and p < 0.05 at 3 days, respectively). Concomitantly, AK-7 administration greatly worsened neurobehavioral deficits on days 3 and 7 after CCI. Furthermore, blood-brain barrier disruption and matrix metalloproteinases (MMP)-9 activity increased following SIRT2 inhibition. AK-7 treatment increased TBI-induced microglial activation both in vivo and in vitro, accompanied by a large increase in the expression and release of inflammatory cytokines. Mechanistically, SIRT2 inhibition increased both K310 acetylation and nuclear translocation of NF-κB p65, leading to enhanced NF-κB activation and up-regulation of its target genes, including aquaporin 4 (AQP4), MMP-9, and pro-inflammatory cytokines. Together, these data demonstrate that SIRT2 inhibition exacerbates TBI by increasing NF-κB p65 acetylation and activation. Our findings provide additional evidence of an anti-inflammatory effect of SIRT2. SIRT2 is a member of the sirtuin family of NAD+-dependent protein deacetylases. Our study suggests that the SIRT2 inhibitor AK-7 exacerbates traumatic brain injury (TBI) via a potential mechanism involving increased acetylation and nuclear translocation of NF-κB p65, resulting in up-regulation of NF-κB target genes, including aquaporin 4 (AQP4), matrix metalloproteinase 9 (MMP-9), and pro-inflammatory cytokines. Our findings provide additional evidence of an anti-inflammatory effect of SIRT2.

Keywords: SIRT2; blood-brain barrier; cerebral edema; inflammation; traumatic brain injury.