Pre-B-cell colony-enhancing factor protects against apoptotic neuronal death and mitochondrial damage in ischemia

被引:27
作者
Wang, Xiaowan [1 ]
Li, Hailong [1 ,2 ]
Ding, Shinghua [1 ,2 ]
机构
[1] Univ Missouri, Dept Bioengn, Columbia, MO 65211 USA
[2] Univ Missouri, Dalton Cardiovasc Res Ctr, Columbia, MO 65211 USA
关键词
NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE; CEREBRAL-ISCHEMIA; NAD(+) DEPLETION; OXIDATIVE STRESS; AMYLOID-BETA; BRAIN-INJURY; MOUSE MODEL; BIOGENESIS; NEUROPROTECTION; DYNAMICS;
D O I
10.1038/srep32416
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
We previously demonstrated that Pre-B-cell colony-enhancing factor (PBEF), also known as nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD+ biosynthesis pathway, plays a brain and neuronal protective role in ischemic stroke. In this study, we further investigated the mechanism of its neuroprotective effect after ischemia in the primary cultured mouse cortical neurons. Using apoptotic cell death assay, fluorescent imaging, molecular biology, mitochondrial biogenesis measurements and Western blotting analysis, our results show that the overexpression of PBEF in neurons can significantly promote neuronal survival, reduce the translocation of apoptosis inducing factor (AIF) from mitochondria to nuclei and inhibit the activation of capase-3 after glutamate-induced excitotoxicity. We further found that the overexpression of PBEF can suppress glutamate-induced mitochondrial fragmentation, the loss of mitochondrial DNA (mtDNA) content and the reduction of PGC-1 and NRF-1 expressions. Furthermore, these beneficial effects by PBEF are dependent on its enzymatic activity of NAD+ synthesis. In summary, our study demonstrated that PBEF ameliorates ischemia-induced neuronal death through inhibiting caspase-dependent and independent apoptotic signaling pathways and suppressing mitochondrial damage and dysfunction. Our study provides novel insights into the mechanisms underlying the neuroprotective effect of PBEF, and helps to identify potential targets for ischemic stroke therapy.
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页数:13
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