Universität zu Köln

Yang, Hong, Gu, Zheng-tao, Li, Li, Maegele, Mac, Zhou, Bi-ying, Li, Feng, Zhao, Ming and Zhao, Ke-sen (2017). SIRT1 plays a neuroprotective role in traumatic brain injury in rats via inhibiting the p38 MAPK pathway. Acta Pharmacol. Sin., 38 (2). S. 168 - 182. SHANGHAI: ACTA PHARMACOLOGICA SINICA. ISSN 1745-7254

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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 Delta psi m, 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 mu g/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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Yang, Hong UNSPECIFIED UNSPECIFIED UNSPECIFIED Gu, Zheng-tao UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Li UNSPECIFIED UNSPECIFIED UNSPECIFIED Maegele, Mac UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhou, Bi-ying UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Feng UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhao, Ming UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhao, Ke-sen UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-241343
DOI:	10.1038/aps.2016.130
Journal or Publication Title:	Acta Pharmacol. Sin.
Volume:	38
Number:	2
Page Range:	S. 168 - 182
Date:	2017
Publisher:	ACTA PHARMACOLOGICA SINICA
Place of Publication:	SHANGHAI
ISSN:	1745-7254
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ACTIVATED PROTEIN-KINASES; REDUCE OXIDATIVE STRESS; MITOCHONDRIAL DYSFUNCTION; HEMORRHAGIC-SHOCK; CEREBRAL ISCHEMIA/REPERFUSION; GLUCOSE DEPRIVATION; ALZHEIMERS-DISEASE; FOREBRAIN ISCHEMIA; SLICE CULTURES; CELL-DEATH Multiple languages Chemistry, Multidisciplinary; Pharmacology & Pharmacy Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/24134