The Role And Mechanism Of Hippocampal Neuronal Necroptosis In Paclitaxel-induced Cognitive Impairment In Mouse Model

Paclitaxel(PTX)is a commonly used chemotherapeutic drug for tumors,but its side effects such as neurotoxicity and cognitive impairment seriously restrict its clinical application.Some studies have shown that necroptosis is involved in the occurrence of cognitive impairment in a variety of neurodegenerative diseases.Therefore,it is not clear whether necroptosis is involved in PTX-induced cognitive impairment and its specific mechanism.Object: We established a mouse model of cognitive impairment induced by paclitaxel to explore the molecular mechanism of cognitive impairment induced by paclitaxel and further discussed its possible regulation,so as to provide a new idea for the clinical treatment of PTX-induced neurocognitive impairment.Method: The mouse model of cognitive impairment induced by paclitaxel was established by intraperitoneal injection of paclitaxel,the learning and cognitive ability of mice were evaluated by Morris water maze,and the role of necroptosis in the formation of cognitive impairment was determined by determination of specific protein of necroptosis and immunofluorescence staining.SIRT1 agonist resveratrol and inhibitor EX-527 were administered respectively to observe the regulation of SIRT1/PGC-1αpathway in the process of neuronal necrotic apoptosis and cognitive impairment.After that,we used microglia scavenger Gdcl3,and measured the M1/M2 type polarization morphology of microglia and the expression of inflammatory factors to determine whether microglia were involved in PTX-induced cognitive impairment.Result:1.PTX can induce cognitive impairment in C57BL/6N mice,and its effect is positively correlated with the dose and duration of treatment.2.PTX can induced necroptosis mediated by RIP3/MLKL in mouse hippocampal neurons,which mainly manifested as swelling of organelle and rupture of cell membrane,accompanied by increased oxidative stress level.Most of the necrotizing cells were hippocampal neurons.Some astrocytes and a few microglia also had necroptosis.3.By activating the SIRT1/PGC-1α pathway,resveratrol can inhibit oxidative stress and the expression of NOX2 and NOX4,up-regulate the expression of BDNF and PSD95,increase the density of dendritic spines,and reduce the necroptosis of hippocampal nerve cells,thereby alleviating cognitive injury.4.By inhibiting the expression of SIRT1,EX-527 collaborated with PTX to further inhibit the SIRT1/PGC-1α pathway,thus enhancing the oxidative stress response,reducing synaptic plasticity,increasing the number of cells that underwent necroptosis,and aggravating the cognitive impairment of mice.5.PTX can induce M1-type polarization of microglia and release inflammatory factors such as TNF-α and IL-1 β.6.After microglia were cleared by GDCL3,the number of M1-type microglia decreased significantly,and the release of TNF-α and IL-1 βdecreased,which alleviated the cognitive impairment caused by PTX.Resveratrol can promote microglia to M2-type polarization bias,release a large number of anti-inflammatory factors such as IL-4 and IL-10,and significantly improve the cognitive impairment caused by PTX.Conclusion: Necroptosis of hippocampal neurons is involved in cognitive impairment induced by PTX.PTX can inhibit SIRT1/PGC-1 αpathway and induce M1-type polarization of microglia,resulting in decreased synaptic plasticity and necroptosis of nerve cells,resulting in neurocognitive impairment.