School of Graduate, North China University of Science and Technology, Tangshan 063210, Hebei, China.
Institute of Mental Health, North China University of Science and Technology, Tangshan 063210, Hebei, China.
Brain Res. 2019 Dec 1;1724:146430. doi: 10.1016/j.brainres.2019.146430. Epub 2019 Aug 31.
Vitamin D (VD) has important neuroprotective functions in the central nervous system. However, further exploration is still needed in the neuroprotective effects of VD monomer therapy on global cerebral ischemia (GCI) and its potential molecular mechanism.
To investigate whether calcitriol, a biologically active metabolite of VD, could alleviate cognitive impairment induced by GCI via reducing cell apoptosis and activating the extracellular signal-regulated kinase (ERK) signaling pathway.
A total of 145 adult male Sprague Dawley rats were randomly divided into five groups: Sham group (n = 45), GCI group (n = 45), calcitriol treatment group (GCI + calcitriol, n = 45), PD98059 treatment group (n = 5) and vehicle group (n = 5). Morris water maze test was used for evaluating spatial learning and memory functions. Neurological Severity Score and wet-dry weight method were applied to detect neurological deficits and brain water content, respectively. Hematoxylin and eosin staining, transmission electron microscopy, and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end-labeling staining were performed for evaluating the changes of hippocampal CA1 neurons. Immunocytochemistry, immunofluorescence chemistry, and western blot analysis were performed for evaluating the changes of related proteins.
Calcitriol significantly ameliorated the spatial learning and memory impairments, improved neurological function, attenuated brain edema, and improved the morphological defects in the CA1 area of the hippocampus. Besides, calcitriol reduced GCI-induced cell apoptosis and reversed the up-regulation of pro-apoptotic proteins (Caspase-3 and Bax) and the down-regulation of anti-apoptotic protein (Bcl-2). Furthermore, calcitriol also increased the expression of VD receptors (VDR) and activated the ERK signaling pathway. Moreover, the p-ERK1/2 inhibitor PD98059 reversed the effect of calcitriol on the expression of apoptosis-related proteins.
Calcitriol may have a protective effect against GCI-induced cognitive impairments via inhibition of apoptotic cascade by activating the VDR/ERK signaling pathway.
维生素 D（VD）在中枢神经系统中具有重要的神经保护功能。然而，VD 单体治疗对全脑缺血（GCI）的神经保护作用及其潜在的分子机制仍需进一步探索。
探讨 1,25-二羟维生素 D3[活性代谢产物]是否通过减少细胞凋亡和激活细胞外信号调节激酶（ERK）信号通路来减轻 GCI 引起的认知障碍。
将 145 只成年雄性 Sprague Dawley 大鼠随机分为 5 组：假手术组（n=45）、GCI 组（n=45）、1,25-二羟维生素 D3 治疗组（GCI+1,25-二羟维生素 D3，n=45）、PD98059 治疗组（n=5）和载体组（n=5）。Morris 水迷宫实验用于评估空间学习和记忆功能。神经功能缺损评分和干湿重法用于检测神经功能缺损和脑水含量。苏木精-伊红染色、透射电镜和末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记染色用于评估海马 CA1 神经元的变化。免疫细胞化学、免疫荧光化学和 Western blot 分析用于评估相关蛋白的变化。
1,25-二羟维生素 D3 显著改善了空间学习和记忆障碍，改善了神经功能，减轻了脑水肿，并改善了海马 CA1 区的形态学缺陷。此外，1,25-二羟维生素 D3 减少了 GCI 诱导的细胞凋亡，并逆转了促凋亡蛋白（Caspase-3 和 Bax）的上调和抗凋亡蛋白（Bcl-2）的下调。此外，1,25-二羟维生素 D3 还增加了维生素 D 受体（VDR）的表达并激活了 ERK 信号通路。此外，p-ERK1/2 抑制剂 PD98059 逆转了 1,25-二羟维生素 D3 对凋亡相关蛋白表达的影响。
1,25-二羟维生素 D3 通过激活 VDR/ERK 信号通路抑制细胞凋亡级联反应，对 GCI 诱导的认知障碍可能具有保护作用。
