Erfani Sohaila, Khaksari Mehdi, Oryan Shahrbanoo, Shamsaei Nabi, Aboutaleb Nahid, Nikbakht Farnaz
Department of Animal Physiology, Faculty of Biology, Kharazmi University, Tehran, Iran.
J Mol Neurosci. 2015 May;56(1):237-43. doi: 10.1007/s12031-014-0486-1. Epub 2015 Jan 22.
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.
烟酰胺磷酸核糖转移酶/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。Nampt/PBEF/内脂素通过合成烟酰胺腺嘌呤二核苷酸（NAD(+)）来维持能量供应，这对细胞存活起着关键作用。脑缺血会导致能量耗竭，并最终通过特定脑区尤其是海马体中的细胞凋亡导致神经元死亡。然而，Nampt/PBEF/内脂素在大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，研究了向海马CA3区注射Nampt/PBEF/内脂素的作用。双侧颈总动脉闭塞20分钟后再灌注。在脑再灌注时，分别经脑室内（ICV）注射作为载体的生理盐水和剂量为100 ng的Nampt/PBEF/内脂素。为了研究Nampt/PBEF/内脂素神经保护作用的潜在机制，通过免疫组化染色测定缺血96小时后凋亡相关蛋白（半胱天冬酶-3激活、Bax蛋白水平和Bcl-2蛋白水平）的表达水平。与假手术组相比，缺血组CA3区活性半胱天冬酶-3阳性神经元数量显著增加（P < 0.001），与缺血组相比，Nampt/PBEF/内脂素治疗显著降低了缺血/再灌注诱导的半胱天冬酶-3激活（P < 0.05）。此外，结果表明，与假手术组相比，缺血组Bax/Bcl-2比值显著升高（P < 0.01）。然而，与缺血组相比，Nampt/PBEF/内脂素治疗显著减弱了缺血/再灌注诱导的Bax/Bcl-2比值升高（P < 0.05）。本研究表明，在脑再灌注时使用Nampt/PBEF/内脂素对缺血性损伤具有神经保护作用。Nampt/PBEF/内脂素的这些神经保护机制是通过降低促凋亡蛋白（裂解的半胱天冬酶-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/内脂素是脑缺血的一个新的治疗靶点。
