Novel compound FLZ alleviates rotenone-induced PD mouse model by suppressing TLR4/MyD88/NF-κB pathway through microbiota–gut–brain axis

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease, but none of the current treatments for PD can halt the progress of the disease due to the limited understanding of the pathogenesis. In PD development, the communication between the brain and the gastrointestinal system influenced by gut microbiota is known as microbiota–gut–brain axis. However, the explicit mechanisms of microbiota 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 phase I clinical trial to treat PD in China. Moreover, our previous pharmacokinetic study revealed that gut microbiota could regulate the absorption of FLZ in vivo . The aims of our study were to assess the protective effects of FLZ treatment on PD and to further explore the underlying microbiota-related mechanisms of PD by using FLZ as a tool. In the current study, chronic oral administration of rotenone was utilized to induce a mouse model to mimic the pathological process of PD. Here we revealed that FLZ treatment alleviated gastrointestinal dysfunctions, motor symptoms, and dopaminergic neuron death in rotenone-challenged mice. 16S rRNA sequencing found that PD-related microbiota alterations induced by rotenone were reversed by FLZ treatment. Remarkably, FLZ administration attenuated intestinal inflammation and gut barrier destruction, which subsequently inhibited systemic inflammation. Eventually, FLZ treatment restored blood–brain barrier structure and suppressed neuroinflammation by inhibiting the activation of astrocytes and microglia in the substantia nigra (SN). Further mechanistic research demonstrated that FLZ treatment suppressed the TLR4/MyD88/NF- κ B pathway both in the SN and colon. Collectively, FLZ treatment ameliorates microbiota dysbiosis to protect the PD model via inhibiting TLR4 pathway, which contributes to one of the underlying mechanisms beneath its neuroprotective 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.

Constitutive TDO2 expression promotes liver cancer progression by an autocrine IL-6 signaling pathway

“…The expression of IDO and TDO, the rate-limiting enzymes in the Trp/Kyn metabolism pathway, was observed in various cancer, including hepatic carcinoma [ 6 , 7 , 15 , 16 ]. To investigate the role of Trp metabolic enzymes, we examined the expression of IDO1 and TDO2 in tumor tissues from liver cancer patients.…”

“…Notably, upregulation of Trp metabolism induced by IDO/TDO enzymes represents one of the most important pathways for tumor occurrence and development [ 5 ]. IDO1 and TDO2 enzymes catalyze Trp oxidation to Kyn, which are frequently observed in tumor tissues and tightly correlated with the poor prognosis in patients [ 6 , 7 ]. Kyn synthesis has been demonstrated to promote tumorigenicity and growth by activating pro-survival signaling pathways, including PI3K/AKT and Wnt/β-catenin signals [ 8 ].…”

MANF Inhibits α-Synuclein Accumulation through Activation of Autophagic Pathways

“…In previous studies, adult male rats and mice have been widely used in the study of PD [38][39][40][41]. In this study, adult male Sprague-Dawley rats (used for detecting the expression of AAV8-MANF and RNA-seq) and male C57/BL6 mice (used for exploring the protection of AAV8…”

Trilobatin Alleviates Cognitive Deficits and Pathologies in an Alzheimer’s Disease Mouse Model

“…In line with this, studies have found that the loss of function or inhibition of TLR4 suppresses AD progression in the mouse model [35,36]. Moreover, previous studies showed that inhibiting the TLR4 pathway alleviated motor impairment and dopaminergic neuron death in the Parkinson's disease mouse model [37]. And Kwilasz et al showed that TLR4 antagonists prevented the production of proinflammatory factors and motor dysfunction in the experimental autoimmune encephalomyelitis mouse model [38].…”