Ali Tahir, Luo Yanhua, Zheng Chengyou, Rahman Shafiq Ur, Murtaza Iram, Feng Jinxing, Li Shupeng
Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen, China.
State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, PR China, 518055.
J Neuroimmune Pharmacol. 2025 Apr 3;20(1):31. doi: 10.1007/s11481-025-10193-7.
Neuroinflammation affects patients with major depressive disorder and is linked to severe, treatment-resistant symptoms, making it a promising therapeutic target for improving depressive symptoms. This study highlighted the neuroprotective role of pentoxifylline (PTX) against lipopolysaccharide (LPS)-induced neuroinflammation and associated behavioral deficits. Mice were injected with LPS (1 mg/kg, i.p) to induce neuroinflammation and treated with PTX (10 mg/kg, i.p). Behavioral and biochemical analyses were performed to evaluate depressive-like behaviors and examine hippocampal protein expression associated with neuroinflammation and synaptic plasticity. LPS administration increased proinflammatory cytokine production (IL-1, IL6, and TNF-α), microglial activation (IBA-1/GFAP), and dysregulation of key synaptic proteins, including BDNF and TrkB, in the hippocampus of mice. Concomitantly, LPS reduced Phosphatase and tensin homolog (PTEN) phosphorylation, potentially contributing to increased neuroinflammation. PTX treatment effectively attenuated LPS-induced effects by suppressing inflammatory responses, restoring BDNF/TrkB signaling, and rescuing synaptic impairments. Mechanistically, PTX treatment increased PTEN phosphorylation and was reversed by the TrkB inhibitor K252a, suggesting that PTX upregulates TrkB/BDNF signaling, leading to increased PTEN phosphorylation and subsequent inhibition of PTEN activity. These findings highlight the potential of PTX as a therapeutic agent for neuroinflammatory conditions, possibly exerting its effects by modulating the PTEN/TrkB/BDNF signaling axis and suggest a novel mechanism of action involving the modulation of the PTEN/TrkB/BDNF signaling pathway.
神经炎症影响重度抑郁症患者，并与严重的、难治性症状相关，使其成为改善抑郁症状的一个有前景的治疗靶点。本研究强调了己酮可可碱（PTX）对脂多糖（LPS）诱导的神经炎症及相关行为缺陷的神经保护作用。给小鼠注射LPS（1mg/kg，腹腔注射）以诱导神经炎症，并用PTX（10mg/kg，腹腔注射）进行治疗。进行行为和生化分析以评估抑郁样行为，并检测与神经炎症和突触可塑性相关的海马蛋白表达。给予LPS增加了小鼠海马中促炎细胞因子的产生（IL-1、IL6和TNF-α）、小胶质细胞活化（IBA-1/GFAP）以及关键突触蛋白（包括BDNF和TrkB）的失调。同时，LPS降低了磷酸酶和张力蛋白同源物（PTEN）的磷酸化，这可能导致神经炎症增加。PTX治疗通过抑制炎症反应、恢复BDNF/TrkB信号传导和挽救突触损伤，有效减轻了LPS诱导的效应。从机制上讲，PTX治疗增加了PTEN的磷酸化，而TrkB抑制剂K252a可逆转这种增加，这表明PTX上调TrkB/BDNF信号传导，导致PTEN磷酸化增加，随后抑制PTEN活性。这些发现突出了PTX作为神经炎症性疾病治疗药物的潜力，可能通过调节PTEN/TrkB/BDNF信号轴发挥其作用，并提示了一种涉及调节PTEN/TrkB/BDNF信号通路的新作用机制。
