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24 May 2020 : Animal Research  

Inhibition of the Peroxisome Proliferator-Activated Receptor gamma Coactivator 1-alpha (PGC-1α)/Sirtuin 3 (SIRT3) Pathway Aggravates Oxidative Stress After Experimental Subarachnoid Hemorrhage

Ke Zhang12ACE*, Hongwei Cheng2B, Lihua Song1ACDE, Wei Wei1ADF

DOI: 10.12659/MSM.923688

Med Sci Monit 2020; 26:e923688

Abstract

BACKGROUND: Emerging evidence shows that Sirtuin 3 (SIRT3) can exert an antioxidative effect in various neurodegenerative diseases, but whether and how SIRT3 modulates neuronal death after subarachnoid hemorrhage (SAH) remains to be elucidated.

MATERIAL AND METHODS: Experimental SAH was induced in adult mice by prechiasmatic cistern injection and primary neurons by OxyHb incubation. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and SIRT3 protein levels were examined at different time points after SAH induction. The PGC-1α protein gene knockdown in vivo and in vitro was achieved by transfection of lentivirus (LV) vectors expressing shPGC-1α or negative control (NC). Western blot, oxidative stress index, histopathology, neurological function, and cell viability analysis was performed.

RESULTS: Results showed that the PGC-1α/SIRT3 pathway was remarkably activated in vivo and in vitro after SAH. LV-shPGC-1α treatment significantly inhibited the activation of this pathway after SAH, accompanied by deteriorated neurologic function, aggravated oxidative stress, increased neuronal apoptosis, and enhanced cytotoxicity compared with the mice or primary neurons treated with LV-NC only.

CONCLUSIONS: The present results highlight the detrimental PGC-1α/SIRT3 pathway, involving regulation of the endogenous antioxidant activity against neuronal damage, which may provide a potential therapeutic target in SAH.

Keywords: Brain Injuries, Subarachnoid Hemorrhage, Cell Death, Mitochondria, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, Sirtuin 3, Transcription Factors

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750