Nampt/PBEF/Visfatin Exerts Neuroprotective Effects Against Ischemia/Reperfusion Injury via Modulation of Bax/Bcl-2 Ratio and Prevention of Caspase-3 Activation
Nampt/PBEF/Visfatin Exerts Neuroprotective Effects Against Ischemia/Reperfusion Injury via Modulation of Bax/Bcl-2 Ratio and Prevention of Caspase-3 Activation
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DOI：
10.1007/s12031-014-0486-1
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发表时间：
2015-05-01
影响因子：
3.1
通讯作者：
Nikbakht, Farnaz
中科院分区：
文献类型：
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作者：
Erfani, Sohaila;Khaksari, Mehdi;Nikbakht, Farnaz
烟酰胺磷酸核糖基转移酶/前 B 细胞集落增强因子/内脂素 (Nampt/PBEF/内脂素) 是一种脂肪细胞因子。通过合成烟酰胺腺嘌呤二核苷酸 (NAD(+))，Nampt/PBEF/内脂素可维持能量供应，这对细胞生存至关重要。脑缺血导致能量耗尽，最终导致特定脑区（特别是海马体）细胞凋亡导致神经元死亡。然而，Nampt/PBEF/visfatin 在脑和脑缺血中的作用仍有待研究。本研究使用短暂性全脑缺血模型研究了 Nampt/PBEF/visfatin 在海马 CA3 区的作用。将两条颈总动脉闭塞20分钟，然后再灌注。在脑再灌注时，将盐水作为载体和剂量为 100 ng 的 Nampt/PBEF/内脂素注射到脑室内 (ICV)。为了研究Nampt/PBEF/visfatin神经保护的潜在机制，通过免疫组织化学染色测定缺血后96小时凋亡相关蛋白的表达水平（caspase-3激活、Bax蛋白水平和Bcl-2蛋白水平）。与假手术组相比，缺血组CA3中活跃的caspase-3阳性神经元数量显着增加（P < 0.001），并且与缺血组相比，Nampt/PBEF/visfatin治疗显着减少了缺血/再灌注诱导的caspase-3激活（P < 0.05）。此外，结果表明，与假手术组相比，缺血组的 Bax/Bcl-2 比率显着增加（P < 0.01）。然而，与缺血组相比，Nampt/PBEF/visfatin 治疗显着减弱了缺血/再灌注引起的 Bax/Bcl-2 比率的增加（P < 0.05）。这项研究表明，Nampt/PBEF/visfatin 在脑再灌注时使用时具有针对缺血损伤的神经保护作用。 Nampt/PBEF/visfatin 的这些神经保护机制是通过降低促凋亡蛋白（裂解的 caspase-3 和 Bax）的表达，另一方面增加抗凋亡蛋白（Bcl-2）的表达来实现的。因此，我们的研究结果表明Nampt/PBEF/visfatin是脑缺血的新治疗靶点。
Nicotinamide phosphoribosyl transferase/pre-B cell colony-enhancing factor/visfatin (Nampt/PBEF/visfatin) is an adipocytokine. By synthesizing nicotinamide adenine dinucleotide (NAD(+)), Nampt/PBEF/visfatin functions to maintain an energy supply that has critical roles in cell survival. Cerebral ischemia leads to energy depletion and eventually neuronal death by apoptosis in specific brain regions specially the hippocampus. However, the role of Nampt/PBEF/visfatin in brain and cerebral ischemia remains to be investigated. This study investigated the role of administration Nampt/PBEF/visfatin in hippocampal CA3 area using a transient global cerebral ischemia model. Both common carotid arteries were occluded for 20 min followed by reperfusion. Saline as a vehicle and Nampt/PBEF/visfatin at a dose of 100 ng were injected intracerebroventricularly (ICV) at the time of cerebral reperfusion. To investigate the underlying mechanisms of Nampt/PBEF/visfatin neuroprotection, levels of expression of apoptosis-related proteins (caspase-3 activation, Bax protein levels, and Bcl-2 protein levels) 96 h after ischemia were determined by immunohistochemical staining. The number of active caspase-3-positive neurons in CA3 was significantly increased in the ischemia group, compared with the sham group (P < 0.001), and treatment with Nampt/PBEF/visfatin significantly reduced the ischemia/reperfusion-induced caspase-3 activation, compared to the ischemia group (P < 0.05). Also, results indicated a significant increase in Bax/Bcl-2 ratio in the ischemia group, compared with the sham group (P < 0.01). However, treatment with Nampt/PBEF/visfatin significantly attenuated the ischemia/reperfusion-induced increase in Bax/Bcl-2 ratio, compared with the ischemia group (P < 0.05). This study has indicated that Nampt/PBEF/visfatin entails neuroprotective effects against ischemia injury when used at the time of cerebral reperfusion. These neuroprotective mechanisms of Nampt/PBEF/visfatin occur through decrease the expression ofproapoptotic proteins (cleaved caspase-3 and Bax) and, on the other hand, increase the expression ofantiapoptotic proteins (Bcl-2). Thus, our findings indicate that Nampt/PBEF/visfatin is a new therapeutic target for cerebral ischemia.