Short-chain Fatty Acids Alleviate Microglia Inflammation Induced By Paclitaxel Chemotherapy

Objective: Paclitaxel-induced cognitive dysfunction has attracted widespread attention in recent years,manifesting as a decline in memory,learning,attention,and executive ability that can last from months to years,causing great distress to chemotherapy patients.However,there is no effective treatment for this condition to date.Short-chain fatty acids affect the development of neuroglia in the brain via the brain-gut axis as well as the inflammatory response,and neuroglia play an important role in regulating learning and memory.Therefore,we investigated the role played by short-chain fatty acids in paclitaxelinduced cognitive dysfunction and the related signaling pathways.Methods: We constructed a chemotherapy model by intraperitoneal injection of paclitaxel into SD rats.We divided the SD rats into three groups: control group,paclitaxel(PTX)group and short-chain fatty acid(SCFA)+ PTX group,in which SCFA + PTX group was pre-intervened with SCFA.We observed the behavioral performance of the rats in each group using the water maze experiment,the activation of microglia and astrocytes in the hippocampus of the rats in each group using immunofluorescence staining,and analyzed the M1 microglia marker i NOS(Inducible nitric oxide synthase)and M2 microglia marker by protein immunoblotting.The expression of Arg-1(Arginase-1),TLR4(Toll-like receptor 4)-related signaling pathway protein and apoptosis factor Caspase-3 were analyzed by Western blot,and the expression of inflammatory factors IL-1β,IL-4,IL-10,TNF-α and brain-derived neurotrophic factor(BDNF)was analyzed by ELISA.Results: 1.Water maze experiments showed that pre-application of short-chain fatty acid intervention reduced the impairment of spatial learning and memory ability in paclitaxelchemotherapy rats compared with PTX group.2.Immunofluorescence staining observed that SCFA could inhibit the activation of microglia and astrocytes in the hippocampus of paclitaxel-chemotherapy rats.3.Protein immunoblotting experiments confirmed that the application of SCFA preintervention could reduce the expression of TLR4 and NF-κB p65 protein,inhibit TLR4/NF-κB signaling pathway,decrease the ratio of M1/M2 microglia,reduce the expression of apoptotic factor Caspase-3 and improve the apoptosis in hippocampus in rats compared with PTX group.4.ELISA showed that SCFA reduced the production of IL-1β and TNF-α,increased the production of IL-4 and IL-10,and increased the expression of BDNF in the hippocampus of paclitaxel-chemotherapy rats.Conclusion: This study demonstrates that short-chain fatty acids can inhibit the activation of microglia and astrocytes in the brain through the TLR4/NF-κB signaling pathway,attenuate the inflammatory response as well as neuronal apoptosis,and presumably alleviate cognitive dysfunction caused by paclitaxel chemotherapy.This suggests that short-chain fatty acids may be a potential treatment for paclitaxel-induced cognitive dysfunction.