Shen Ya, Xu Tianli, Sun Yezi, Zhang Kelun, Cao Xiaojun, Shen Limin, Tang Mengjie
Department of Endocrinology, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, 215123, Jiangsu, China.
Department of Orthopedics, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, 215123, Jiangsu, China.
J Neurovirol. 2025 Jun 4. doi: 10.1007/s13365-025-01263-w.
Metformin, a first-line drug used to treat type 2 diabetes mellitus (T2DM), also reduces neuroinflammation and improves motor and cognitive outcomes. Metformin binds to presenilin enhancer 2 (PEN2) and further enhances its therapeutic benefits. The mechanisms of HIV-associated neurocognitive disorders (HANDs) remain unclear. HIV-1 trans-activator of transcription (Tat) contributes to neurotoxicity in HAND. We revealed that PEN2 expression decreased markedly in HAND patients and Tat-infected microglia. Metformin (200 µM) treatment significantly reduced Tat-induced decreases in cell viability, oxidative stress, the proinflammatory response and excessive glutamate and iNOS release and had neuroprotective effects. Tat subsequently increased NF-κB activity, which was prominently suppressed during treatment. In addition, PEN2 knockdown in microglia dramatically reversed the neuroprotective effect of metformin against Tat. Our findings indicate that metformin binds PEN2 and modulates microglia-mediated HIV-1 Tat neurotoxicity in HAND.
二甲双胍是用于治疗2型糖尿病（T2DM）的一线药物，它还能减轻神经炎症并改善运动和认知结果。二甲双胍与早老素增强子2（PEN2）结合，并进一步增强其治疗效果。HIV相关神经认知障碍（HANDs）的机制尚不清楚。HIV-1转录反式激活因子（Tat）在HAND中导致神经毒性。我们发现，HAND患者和Tat感染的小胶质细胞中PEN2表达显著降低。二甲双胍（200 μM）处理显著减少了Tat诱导的细胞活力下降、氧化应激、促炎反应以及过量谷氨酸和诱导型一氧化氮合酶（iNOS）释放，并具有神经保护作用。Tat随后增加了核因子κB（NF-κB）活性，而在处理过程中该活性受到显著抑制。此外，小胶质细胞中PEN2基因敲低显著逆转了二甲双胍对Tat的神经保护作用。我们的研究结果表明，二甲双胍与PEN2结合并调节小胶质细胞介导的HAND中HIV-1 Tat神经毒性。
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