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

🥈 Top 2% JournalSep 30, 2021Acta pharmaceutica Sinica. B

New compound FLZ reduces Parkinson’s symptoms in mice by targeting immune signals through the gut-brain connection

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Abstract

FLZ treatment alleviated gastrointestinal dysfunctions, motor symptoms, and dopaminergic neuron death in a mouse model of Parkinson's disease.

Chronic oral administration of rotenone induced a mouse model that mimics the pathological process of Parkinson's disease.
FLZ treatment reversed PD-related microbiota alterations caused by rotenone.
FLZ administration reduced intestinal inflammation and gut barrier destruction, which inhibited systemic inflammation.
FLZ treatment restored the structure of the blood-brain barrier and suppressed neuroinflammation by inhibiting astrocyte and microglia activation in the substantia nigra.
FLZ treatment suppressed the TLR4/MyD88/NF-κB pathway in both the substantia nigra and colon.

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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. 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-B pathway both in the SN and colon. Collectively, FLZ treatment ameliorates microbiota dysbiosis to protect the PD modelinhibiting 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. in vivo κ via

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