尽管血脑屏障 (BBB) 和脑保护组织具有保护性质，但某些类型的中枢神经系统损伤或应激可导致脑细胞因子的产生和脑功能的深刻改变。神经炎症还伴随着脑细胞因子产生的增加，对许多神经系统疾病的发病机制有显着影响，包括血脑屏障完整性丧失和缺血性中风，但目前这些疾病缺乏有效的治疗选择。尽管人们对二甲双胍（MF）（一种常用的一线抗糖尿病药物）对大脑的影响知之甚少，但先前的研究表明，它可能有助于预防血脑屏障恶化和吸烟（TS）引起的中风风险增加。因此，通过增加抗炎细胞因子的产生和减少促炎细胞因子的产生来减少神经炎症可能被证明是治疗缺血性中风的有效策略。因此，当前的研究计划探索 MF 对中风和 TS 诱导的神经炎症和活性氧 (ROS) 产生的潜在作用。我们的研究表明，MF 通过针对原代神经元中的核因子 kappa B (NF-κB) 信号通路，抑制肿瘤坏死因子-α (TNF-α) 和白介素-1β (IL-1β) 等促炎介质的释放，星形胶质细胞。 MF 还通过上调 Nrf2-ARE 信号通路来上调抗炎介质，如白细胞介素 10 (IL-10) 和白细胞介素 4 (IL-4)。与未接受 MF 治疗的小鼠相比，接受 MF 和 TS 暴露的青春期小鼠的 NF-κB 表达也显着降低，并且 TNF-α、IL-1β、MCP-1 和 MIP-2 水平显着降低，并且 TNF-α、IL-1β、MCP-1 和 MIP-2 水平显着降低。通过激活 Nrf2-ARE 信号通路来调节 IL-10 和 IL-4 的水平。这些结果表明 MF 通过激活 Nrf2-ARE 抑制 NF-κB 信号传导而具有抗神经炎症作用。这些研究表明 MF 可能是治疗和/或预防 TS 引起的神经炎症和缺血性中风的有力候选药物。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Despite the protective nature of the blood-brain barrier (BBB) and brain-protecting tissues, some types of CNS injury or stress can cause cerebral cytokine production and profound alterations in brain function. Neuroinflammation, which can also be accompanied by increased cerebral cytokine production, has a remarkable impact on the pathogenesis of many neurological illnesses, including loss of BBB integrity and ischemic stroke, yet effective treatment choices for these diseases are currently lacking. Although little is known about the brain effects of Metformin (MF), a commonly prescribed first-line antidiabetic drug, prior research suggested that it may be useful in preventing BBB deterioration and the increased risk of stroke caused by tobacco smoking (TS). Therefore, reducing neuroinflammation by escalating anti-inflammatory cytokine production and declining pro-inflammatory cytokine production could prove an effective therapeutic strategy for ischemic stroke. Hence, the current investigation was planned to explore the potential role of MF against stroke and TS-induced neuroinflammation and reactive oxygen species (ROS) production. Our studies revealed that MF suppressed releasing pro-inflammatory mediators like tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) by aiming at the nuclear factor kappa B (NF-κB) signaling pathway in primary neurons and astrocytes. MF also upregulated anti-inflammatory mediators, like interleukin-10 (IL-10), and interleukin-4 (IL-4), by upregulating the Nrf2-ARE signaling pathway. Adolescent mice receiving MF along with TS exposure also showed a notable decrease in NF-κB expression compared to the mice not treated with MF and significantly decreased the level of TNF-α, IL-1β, MCP-1, and MIP-2 and increased the levels of IL-10 and IL-4 through the activation of Nrf2-ARE signaling pathway. These results suggest that MF has anti-neuroinflammatory effects via inhibiting NF-κB signaling by activating Nrf2-ARE. These studies support that MF could be a strong candidate drug for treating and or preventing TS-induced neuroinflammation and ischemic stroke.Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.