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SIRT 2 inhibition exacerbates neuroinflammation and blood–brain barrier disruption in experimental traumatic brain injury by enhancing NF ‐κB p65 acetylation and activation
Author(s) -
Yuan Fang,
Xu ZhiMing,
Lu LiYan,
Nie Hui,
Ding Jun,
Ying WeiHai,
Tian HengLi
Publication year - 2016
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13423
Subject(s) - sirtuin 1 , traumatic brain injury , neuroinflammation , sirtuin , blood–brain barrier , pharmacology , proinflammatory cytokine , medicine , neuroprotection , matrix metalloproteinase , chemistry , acetylation , downregulation and upregulation , inflammation , central nervous system , biochemistry , psychiatry , gene
Abstract Sirtuin 2 ( SIRT 2) is a member of the sirtuin family of NAD + ‐dependent protein deacetylases. In recent years, SIRT 2 inhibition has emerged as a promising treatment for neurodegenerative diseases. However, to date, there is no evidence of a specific role for SIRT 2 in traumatic brain injury ( TBI ). We investigated the effects of SIRT 2 inhibition on experimental TBI using the controlled cortical impact ( CCI ) injury model. Adult male mice underwent CCI or sham surgery. A selective brain‐permeable SIRT 2 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 SIRT 2 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, SIRT 2 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 ( AQP 4), MMP ‐9, and pro‐inflammatory cytokines. Together, these data demonstrate that SIRT 2 inhibition exacerbates TBI by increasing NF ‐κB p65 acetylation and activation. Our findings provide additional evidence of an anti‐inflammatory effect of SIRT 2.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.