Das Ankur, Mitra Ankan, Sarkar Swaimanti, Ghosh Sourav, Bandyopadhyay Debasish, Chattopadhyay Sreya
Department of Physiology, University of Calcutta, Kolkata, West Bengal, India.
Department of Physiology, Trivenidevi Bhalotia College, Kazi Nazrul University, Raniganj, West Bengal, 713347, India.
Apoptosis. 2025 Apr;30(3-4):710-733. doi: 10.1007/s10495-024-02054-0. Epub 2024 Dec 25.
Arsenic-mediated neurodegenerative disorders affect millions of individuals globally, but the specific impact of environmental arsenic on adult cerebellar degeneration and neurogenesis is incompletely understood. Of particular concern is arsenic-induced apoptosis-driven neurodegeneration. Our major objective was to investigate the molecular signaling intricacies associated with arsenic-induced death of cerebellar neurons and to propose folic acid as a possible intervention. Swiss albino mice were treated with sodium arsenite (orally: 0.05 mg/L) and folic acid (orally:10 mg/kg) for 28 days. We observed that arsenic caused noticeable cell loss with morphological alterations in cerebellum, which was remarkably restored by folic acid. Arsenic-induced morphological alterations consequently perturbed transcriptional activities of neural stem cell factors-SOX2 and KLF9, which resulted in the suppression of pro-neurogenic mediators NeuroD1, Neurogenin2, calbindin and NeuN. Interestingly, folic acid reversed the expression of these critical pro-neurogenic mediators to mitigate these degenerative changes to promote neurogenesis. Delving deep, we found that folic acid rescued arsenic-exposed cerebellum from severe oxidative and pro-inflammatory insults by increasing antioxidants like SOD, Catalase, GSH, upregulating Nrf2 and downregulating M1 macrophages, JNK, NF-κB, and STAT3 activities. For the first time, we are reporting that arsenic induced a G1/S cell cycle arrest and triggered apoptosis in mouse cerebellum by activating the p53-p21 axis, downregulating CDKs and instigated p21-mediated suppression of SOX2 transcriptional activity. Folic acid abated such alterations by modulating the p53/p21/SOX2 axis. Collectively, the anti-apoptotic and pro-neurogenic effects of folic acid present it as a promising therapeutic candidate, warranting further research into its efficacy against metal-induced neurodegenerative disorders.
砷介导的神经退行性疾病在全球影响着数百万人，但环境砷对成人小脑变性和神经发生的具体影响尚未完全明确。特别值得关注的是砷诱导的凋亡驱动的神经退行性变。我们的主要目标是研究与砷诱导的小脑神经元死亡相关的分子信号复杂性，并提出叶酸作为一种可能的干预措施。将瑞士白化小鼠用亚砷酸钠（口服：0.05mg/L）和叶酸（口服：10mg/kg）处理28天。我们观察到砷导致小脑明显的细胞丢失和形态改变，而叶酸可显著恢复这些改变。砷诱导的形态改变进而扰乱了神经干细胞因子SOX2和KLF9的转录活性，导致促神经发生介质NeuroD1、Neurogenin2、钙结合蛋白和NeuN的表达受到抑制。有趣的是，叶酸可逆转这些关键促神经发生介质的表达，减轻这些退行性变化以促进神经发生。深入研究发现，叶酸通过增加超氧化物歧化酶、过氧化氢酶、谷胱甘肽等抗氧化剂，上调核因子E2相关因子2并下调M1巨噬细胞、c-Jun氨基末端激酶、核因子κB和信号转导子和转录激活子3的活性，从而使暴露于砷的小脑免受严重的氧化和促炎损伤。我们首次报道，砷通过激活p53-p21轴、下调细胞周期蛋白依赖性激酶并引发p21介导的SOX2转录活性抑制，诱导小鼠小脑G1/S期细胞周期阻滞并触发凋亡。叶酸通过调节p53/p21/SOX2轴减轻了这些改变。总的来说，叶酸的抗凋亡和促神经发生作用使其成为一个有前景的治疗候选物，值得进一步研究其对金属诱导的神经退行性疾病的疗效。
