Journal
JOURNAL OF MOLECULAR NEUROSCIENCE
Volume 50, Issue 3, Pages 453-461Publisher
SPRINGERNATURE
DOI: 10.1007/s12031-013-9955-1
Keywords
Apoptosis; Antioxidant; Hydrogen peroxide; Mitochondria; Neuroprotection; Reactive oxygen species
Categories
Funding
- Ministry of Science and Technology of China [2011CB510004]
- National Natural Science Foundation of China [81173034, 81072646]
- National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China [2012ZX09301001-001, 2012ZX09301001-004]
- SKLDR/SIMM Projects [SIMM1105KF-04, SIMM1203KF-02]
- Shanghai Science and Technology Development Funds, SA-SIBS Scholarship Program [10QA1408100]
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Oxidative stress has been implicated in pathophysiology of many neurodegenerative diseases (ND) and increased oxidative stress is closely associated with mitochondrial dysfunction. As a result, looking for potent antioxidants, especially those targeting mitochondria, has become an attractive strategy in ND therapy. In this study, we explored protective effects and potential mechanism of Ac-cel, a novel compound, against hydrogen peroxide (H2O2)-induced injury in PC12 cells. Pretreatment of PC12 cells with Ac-cel prior to 24 h of H2O2 exposure markedly attenuated cytotoxicity induced by H2O2 as evidenced by morphological changes and 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Ac-cel also exhibited potent antiapoptotic effect demonstrated by results of annexin V and PI staining. The above beneficial effects of Ac-cel were accompanied by improved mitochondrial function, reduced caspase-3 cleavage as well as upregulated ratio of Bcl-2/Bax protein expression. Moreover, Ac-cel pretreatment markedly reversed intracellular reactive oxygen species (ROS) accumulation following 30 min of H2O2 exposure in PC12 cells. Further, subcellular investigation indicated that Ac-cel significantly reduced production of mitochondrial ROS in isolated rat cortical mitochondria. Taken together, the present study, for the first time, reports that Ac-cel pretreatment inhibits H2O2-stimulated early accumulation of intracellular ROS possibly via reducing mitochondrial ROS production directly and leads to subsequent preservation of mitochondrial function. These results indicate that Ac-cel is a potential drug candidate for treatment of oxidative stress-associated ND.
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