Novel compound FLZ alleviates rotenone-induced Parkinson disease model by sup⁃pressing TLR4/MyD88/NF-κB pathway through microbiota-gut-brain axis

ZHAO Zhe; LI Fang-yuan; NING Jing-wen; BAO Xiu-qi; ZHANG Dan

摘要

OBJECTIVES Parkinson disease(PD)is the second most common neurodegener⁃ative disease,but none of the current treatments for PD could halt the progress of the disease due to the limited understanding of the pathogenesis.Increasing evidence proves that the close com⁃munication between the brain and the gastroin⁃testinal system is influenced by gut microbiota in PD pathogenesis,known as microbiota-gut-brain axis.However,the explicit mechanisms of micro⁃biota dysbiosis in PD development have not been well elucidated yet.FLZ,a novel squamosamide derivative,has been proved to be effective in many PD models and is undergoing the phaseⅠclinical trial to treat PD in China.The aims of our study are to assess the neuroprotective effects of FLZ treatment on PD and to further explore the underlying microbiota-related mechanisms of PD by using FLZ as a tool.METHODS Chronic administration of rotenone(30 mg·kg-1 per day)was utilized to induce a mouse model to mimic the pathological process of PD.Behavioral tests and gastrointestinal function tests were conduct⁃ed to evaluate the PD symptoms.Gut microbiota alterations were analyzed by 16s rRNA sequenc⁃ing.The intestinal permeability and blood-brain barrier structures were assessed by various methods.The pro-inflammatory cytokines and LPS levels in the colon,serum,and brain were detected by ELISA.Furthermore,the levels of in⁃flammation and TLR4/MyD88/NF-κB pathway in the substantia nigra(SN)and colon were mea⁃sured.RESULTS Behavioral tests and gastroin⁃testinal function tests found that rotenone-in⁃duced mice showed gastrointestinal dysfunctions(week 3)prior to the motor deficits(week 4).However,FLZ treatment significantly alleviated these PD symptoms.16S rRNA sequencing illus⁃trated that PD-related microbiota alterations in⁃duced by rotenone were reversed by FLZ treatment at various taxa levels.Especially,we identified an increased genus Akkermansia in the Rotenone group(P=0.0006),which could be reversed by FLZ administration(P=0.0070).By reducing microbiota dysbiosis,qPCR results showed that FLZ treatment suppressed intestinal inflammation of rotenone-challenged mice.After⁃wards,transmission electron microscopy(TEM),in vivo FITC permeability assay,bacterial translocation assay,and Western blotting togeth⁃er suggested that FLZ treatment attenuated the intestinal barrier destruction induced by rote⁃none.Subsequently,ELISA results showed that FLZ administration inhibited the leakage of pro-inflammatory cytokines(TNF-α,IL-1β,and IL-6)and LPS into the serum,suggesting the atten⁃uation of systemic inflammation.Then,several experiments including TEM analysis found that FLZ treatment restored blood-brain barrier struc⁃ture.Consequently,the immunofluorescence staining demonstrated that neuroinflammation(increased Iba-1+and GFAP+cells)and dopami⁃nergic neuronal death(reduced TH+cells)in the SN caused by rotenone were remarkably attenu⁃ated.Further mechanistic research proved that the anti-inflammatory effects of FLZ administra⁃tion were mediated through the TLR4/MyD88/NF-κB pathway both in the SN and colon.CONCLU⁃SION FLZ treatment ameliorates microbiota dys⁃biosis to protect the PD model via inhibiting TLR4 pathway,which contributes to one of the underlying mechanisms beneath its neuroprotec⁃tive effects.Our research also supports the importance of microbiota-gut-brain axis in PD pathogenesis,suggesting its potential role as a novel therapeutic target for PD treatment.

Novel compound FLZ alleviates rotenone-induced Parkinson disease model by sup⁃pressing TLR4/MyD88/NF-κB pathway through microbiota-gut-brain axis

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