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SIRT1 plays a neuroprotective role in traumatic brain injury in rats via inhibiting the p38 MAPK pathway.
Yang, Hong; Gu, Zheng-Tao; Li, Li; Maegele, Mac; Zhou, Bi-Ying; Li, Feng; Zhao, Ming; Zhao, Ke-Sen.
Afiliação
  • Yang H; Department of Intensive Care Unit, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China.
  • Gu ZT; Department of Pathophysiology, Guangdong Provincial Key Laboratory of Shock and Microcirculation Research, Southern Medical University, Guangzhou 510515, China.
  • Li L; Department of Intensive Care Unit, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China.
  • Maegele M; Department of Pathophysiology, Guangdong Provincial Key Laboratory of Shock and Microcirculation Research, Southern Medical University, Guangzhou 510515, China.
  • Zhou BY; Department of Intensive Care Unit, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China.
  • Li F; Department of Pathophysiology, Guangdong Provincial Key Laboratory of Shock and Microcirculation Research, Southern Medical University, Guangzhou 510515, China.
  • Zhao M; Institute for Research in Operative Medicine (IFOM), Private University of Witten-Herdecke, Cologne Merheim Medical Center (CMMC), Ostmerheimerstr 200, D-51109 Cologne, Germany.
  • Zhao KS; Department of Pathophysiology, Guangdong Provincial Key Laboratory of Shock and Microcirculation Research, Southern Medical University, Guangzhou 510515, China.
Acta Pharmacol Sin ; 38(2): 168-181, 2017 Feb.
Article em En | MEDLINE | ID: mdl-28017962
ABSTRACT
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 (SIRT1), 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 pathogenesis. 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 caspase-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 ΔΨm, 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 µg/kg, ip) significantly attenuated post-TBI-induced expression of both cleaved caspase-9 and cleaved caspase-3 and mitochondrial damage, whereas it had no effects on SIRT1 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 inhibition of the p38 MAPK pathway may play a neuroprotective role in preventing secondary damage post-TBI. For this reason, both SIRT1 and p38 are likely to be important targets to prevent secondary damage post-TBI.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fármacos Neuroprotetores / Sistema de Sinalização das MAP Quinases / Proteínas Quinases p38 Ativadas por Mitógeno / Sirtuína 1 / Lesões Encefálicas Traumáticas Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Acta Pharmacol Sin Assunto da revista: FARMACOLOGIA Ano de publicação: 2017 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fármacos Neuroprotetores / Sistema de Sinalização das MAP Quinases / Proteínas Quinases p38 Ativadas por Mitógeno / Sirtuína 1 / Lesões Encefálicas Traumáticas Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Acta Pharmacol Sin Assunto da revista: FARMACOLOGIA Ano de publicação: 2017 Tipo de documento: Article País de afiliação: China