Nardosinone improves levodopa-induced dyskinesia in Parkinsonian rats through the microbiota–gut–brain axis

Levodopa-induced dyskinesia (LID) is a side effect of Parkinson's disease (PD) treated with L-3,4-dihydroxyphenylalanine (L-DOPA). Nardosinone is the major active component of the dried root and rhizome of Nardostachys jatamansi DC, which is effective for treating PD. The purpose of this study was to explore the effects of nardosinone on LID and the underlying mechanism involving the microbiota-gut-brain axis. A PD rat model was established with rotenone. Behavioral and immunohistochemical staining experiments were used to investigate the synergistic effect of nardosinone on L-DOPA in PD rats. Then, the LID model was established by using high-dose L-DOPA and benserazide, and the effect of nardosinone on LID was evaluated by abnormal involuntary movement scale (AIMS) and western blotting (WB). Hematoxylin‒eosin staining (on intestinal tissues), 16 S rRNA (on gut microbiota), and ELISA (on serum and brain tissues) were used to investigate the mechanism of action of nardosinone in the treatment of LID. Behavioral tests revealed that nardosinone increased the ability of L-DOPA to treat forelimb dysfunction and autonomic activity disorders in PD, and immunohistochemical staining experiments revealed that nardosinone exerted a protective effect on dopaminergic neurons as PD-induced neuronal damage was reversed, which complements the therapeutic effect of L-DOPA. AIMS and WB analyses indicated that high-dose L-DOPA induced LID, but nardosinone exerted an effect in reducing LID by not only improving rats' abnormal involuntary movements but also downregulating ∆FosB expression. Analysis of 16 S rRNA revealed that nardosinone can regulate the intestinal flora in rats with LID. In addition, nardosinone can protect the colonic structure and reduce intestinal permeability. Moreover, nardosinone can reduce the expression of inflammatory factors in the colon and striatum of rats with LID and improve intestinal inflammation and neuroinflammation. Nardosinone can improve the effect of L-DOPA on ameliorating motor function in PD rats while alleviating LID, and its mechanism for improving LID may be related to regulating intestinal flora balance, repairing intestinal barrier integrity, and inhibiting inflammatory responses via the microbiota-gut-brain axis.