Necroptosis of hippocampal neurons in paclitaxel chemotherapy-induced cognitive impairment mediates microglial activation via TLR4/MyD88 signaling pathway.

BACKGROUND: Paclitaxel (PTX) chemotherapy frequently induces cognitive impairment, which is closely associated with two key pathological processes: necroptosis of hippocampal neurons and microglial polarization. Necroptotic neurons release damage-associated molecular patterns, triggering inflammatory responses. As the primary immune cells in the central nervous system, microglia can exhibit either pro-inflammatory or anti-inflammatory activity depending on their polarization state. However, the relationship between PTX-induced neuronal necroptosis and microglial activation remains unclear. METHODS: In this study, both in vivo and in vitro experiments were conducted. In vivo, an adult male C57BL/6N mouse model of PTX-induced cognitive impairment was established and divided into three groups: Veh (vehicle control), PTX (paclitaxel only), and P + N (paclitaxel with Nec-1 treatment). Necrostatin-1 (Nec-1), a specific inhibitor of RIPK1, was used to inhibit necroptosis. In vitro, HT22 cells were used to prepare necroptosis-conditioned medium, and BV-2 cells were treated with this medium. TAK-242, a TLR4 inhibitor, was used to explore the role of the TLR4/MyD88 signaling pathway. Immunofluorescence staining, western blot, and ELISA were employed to detect relevant markers and cytokines. RESULTS: The results demonstrated that PTX-induced necroptosis of hippocampal neurons activated microglia. Nec-1 effectively suppressed neuronal necroptosis and reduced M1 polarization of microglia. The TLR4/MyD88 signaling pathway was involved in microglial polarization induced by the necroptotic-conditioned medium of PTX-treated HT22 cells. TAK-242 significantly blocked the regulatory effect of PTX-induced neuronal necroptosis on BV-2 microglial polarization. CONCLUSION: This study reveals that hippocampal neuron necroptosis activates microglia through the TLR4/MyD88 signaling pathway in PTX-induced cognitive impairment, promoting M1 polarization and neuroinflammation. Inhibiting necroptosis promotes M2 polarization and neuroprotection. These findings uncover a novel mechanism of PTX-induced cognitive impairment and suggest potential therapeutic targets.