SIRT1 plays a neuroprotective role in traumatic brain injury in rats via inhibiting the p38 MAPK pathway  

作　　者：Hong YANG Zheng-tao GU Li LI Mac MAEGELE Bi-ying ZHOU Feng LI Ming ZHAO Ke-sen ZHAO 

机构地区：[1]Department of Intensive Care Unit, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China [2]Institute for Research in Operative Medicine (IFOM), Private University of Witten-Herdecke, Cologne Merheim Medical Center (CMMC), Ostmerheimerstr 200, D-51109 Cologne, Germany [3]Department of Pathophysiology, Guangdong Provincial Key Laboratory of Shock and Microcirculation Research, Southern Medical University, Guangzhou 510515, China

出　　处：《Acta Pharmacologica Sinica》2017年第2期168-181,共14页中国药理学报（英文版）

摘　　要：Traumatic brain injury （TBI） is a major cause of disability and death in patients who experience a traumatic injury. Mitochondrial dysfunction is one of the main factors contributing to secondary injury in TBI-associated brain damage. Evidence of compromised mitochondrial function after TBI has been, but the molecular mechanisms underlying the pathogenesis of TBI are not well understood Silent information regulator family protein 1 （SlRT1）, a member of the NAD^-dependent protein deacetylases, has been shown to exhibit neuroprotective activities in animal models of various pathologies, including ischemic brain injury, subarachnoid hemorrhage and several neurodegenerative diseases. In this study, we investigated whether SIRT1 also exert neuroprotective effect post-TBI, and further explored the possible regulatory mechanisms involved in TBI pathogenesi6. A lateral fluid-percussion （LFP） brain injury model was established in rats to mimic the insults of TBI. The expression levels of SIRT1, p-p38, cleaved caspase-9 and cleaved easpase-3 were all markedly increased and reached a maximum at 12 h post-TBI. In addition, mitochondrial function was impaired, evidenced by the presence of swollen and irregularly shaped mitochondria with disrupted and poorly defined cristae, a relative increase of the percentage of neurons with low ALPm, the opening of mPTP, and a decrease in neuronal ATP content, especially at 12 h post- TBI. Pretreatment with the SIRT1 inhibitor sirtinol （10 mg/kg, ip） induced p-p38 activation, exacerbated mitochondrial damage, and promoted the activation of the mitochondrial apoptosis pathway. In contrast, pretreatment with the p38 inhibitor SB203580 （200 pg/kg, ip） significantly attenuated post-TBI-induced expression of both cleaved caspase-9 and cleaved caspase-3 and rnitochondrial damage, whereas it had no effects on SlRT1 expression. Together, these results reveal that the 12 h after TBI may be a crucial time at which secondary damage occurs; the activation of SIRT1 expression and inTraumatic brain injury （TBI） is a major cause of disability and death in patients who experience a traumatic injury. Mitochondrial dysfunction is one of the main factors contributing to secondary injury in TBI-associated brain damage. Evidence of compromised mitochondrial function after TBI has been, but the molecular mechanisms underlying the pathogenesis of TBI are not well understood Silent information regulator family protein 1 （SlRT1）, a member of the NAD^-dependent protein deacetylases, has been shown to exhibit neuroprotective activities in animal models of various pathologies, including ischemic brain injury, subarachnoid hemorrhage and several neurodegenerative diseases. In this study, we investigated whether SIRT1 also exert neuroprotective effect post-TBI, and further explored the possible regulatory mechanisms involved in TBI pathogenesi6. A lateral fluid-percussion （LFP） brain injury model was established in rats to mimic the insults of TBI. The expression levels of SIRT1, p-p38, cleaved caspase-9 and cleaved easpase-3 were all markedly increased and reached a maximum at 12 h post-TBI. In addition, mitochondrial function was impaired, evidenced by the presence of swollen and irregularly shaped mitochondria with disrupted and poorly defined cristae, a relative increase of the percentage of neurons with low ALPm, the opening of mPTP, and a decrease in neuronal ATP content, especially at 12 h post- TBI. Pretreatment with the SIRT1 inhibitor sirtinol （10 mg/kg, ip） induced p-p38 activation, exacerbated mitochondrial damage, and promoted the activation of the mitochondrial apoptosis pathway. In contrast, pretreatment with the p38 inhibitor SB203580 （200 pg/kg, ip） significantly attenuated post-TBI-induced expression of both cleaved caspase-9 and cleaved caspase-3 and rnitochondrial damage, whereas it had no effects on SlRT1 expression. Together, these results reveal that the 12 h after TBI may be a crucial time at which secondary damage occurs; the activation of SIRT1 expression and in

关 键 词：traumatic brain injury lateral fluid-percussion SIRT1 p38 mitochondria sirtinol SB203580 NEUROPROTECTION 

分 类 号：Q257[生物学—细胞生物学] F407.7[经济管理—产业经济]