苏州大学倪宏研究组近日取得一项新成果。经过不懈努力，他们的最新研究探明了复合素2参与NAD+对新生儿缺氧缺血后神经元存活的保护作用。2025年4月17日出版的《中国药理学报》发表了这项成果。

课题组人员最近发现，NAD⁺治疗可显著改善新生小鼠缺氧缺血（HI）后的神经行为结果，生物信息学分析显示，受损大脑皮层中复杂蛋白2 （CPLX2）的表达显著降低24但可以通过NAD⁺干预逆转。在本研究中，研究组探讨了CPLX2在新生儿缺氧缺血性皮质神经元存活和功能中的作用。通过永久性结扎小鼠左颈总动脉建立HI模型。产后第1天（P1）脑室内注射cplx2敲低慢病毒载体；CPLX2敲除小鼠也进行了主题化。NAD⁺ (5mg·kg1·d1, i.p.)在HI手术前给药，之后每天一次直到取样。

研究团队发现NAD⁺能显著改善HI小鼠的形态学损伤和神经行为缺陷，并提高癫痫发作阈值。所有NAD⁺的有益作用都被CPLX2敲除或敲除。在OGD/R的HT22神经元细胞中，用NAD⁺ (100 μM)预处理12h显著提高了细胞活力，降低了LDH水平，抑制了铁凋亡，这可以从氧化还原相关参数Fe²⁺、GSH、MDA、H₂O₂浓度以及GPX4和SLC7A11的表达变化中得到证明。HT22神经元细胞中CPLX2敲低可阻断NAD⁺的保护作用，而CPLX2过表达可增强NAD⁺对HT22神经元细胞铁凋亡的抑制作用。

据了解，烟酰胺腺嘌呤二核苷酸（Nicotinamide adenine dinucleotide， NAD）是一种参与细胞代谢的关键辅酶，与衰老、癌症、神经退行性疾病和代谢紊乱有关。

附：英文原文

Title: Complexin 2 contributes to the protective effect of NAD+ on neuronal survival following neonatal hypoxia-ischemia

Author: Xu, Xiao-wen, Zhou, Xiu-wen, Zhang, Li, Wang, Qing, Wang, Xin-xin, Jin, Yi-ming, Li, Li-li, Jin, Mei-fang, Wu, Hai-ying, Ding, Xin, Ni, Hong

Issue&Volume: 2025-04-17

Abstract: Nicotinamide adenine dinucleotide (NAD) is a key coenzyme involved in cell metabolism associated with aging, cancer, neurodegenerative diseases and metabolic disorders. We recently showed that NAD+ therapy significantly improved neurobehavioral outcomes in neonatal mice after hypoxia-ischemia (HI), and bioinformatics analysis revealed that the expression of complexin 2 (CPLX2) in the injured cerebral cortex was significantly decreased 24h after HI injury but could be reversed by NAD+ intervention. In this study we explored the role of CPLX2 in the survival and function of neonatal hypoxic-ischemic cortical neurons. HI models were established by permanent ligation of the left common carotid artery in mice. CPLX2-knockdown lentiviral vector was injected intraventricularly on postnatal day 1 (P1); CPLX2 knockout mice were also used. NAD+ (5mg·kg1·d1, i.p.) was administered before HI surgery, thereafter once a day until sampling. We showed that NAD+ administration significantly ameliorated the morphological damages and neurobehavioral defects, and elevated the seizure thresholds in HI mice. All the beneficial effects of NAD+ were abolished by CPLX2 knockdown or knockout. In HT22 neuronal cells subjected to OGD/R, pretreated with NAD+ (100μM) for 12h significantly increased the cell viability, decreased the LDH levels, and inhibited the ferroptosis evidenced by the changes in redox-related parameters including concentrations of Fe2+, GSH, MDA, H2O2 as well as the expression of GPX4 and SLC7A11. CPLX2 knockdown in HT22 neuronal cells blocked the protective effects of NAD+ as in HI mice, whereas CPLX2 overexpression enhanced the inhibitory effects of NAD+ on ferroptosis in HT22 neuronal cells.

DOI: 10.1038/s41401-025-01555-1

Source: https://www.nature.com/articles/s41401-025-01555-1