Mitigating gut microbial degradation of levodopa and enhancing brain dopamine: Implications in Parkinson's disease.

Publisher: Nature Publishing Group UK Country of Publication: England NLM ID: 101719179 Publication Model: Electronic Cited Medium: Internet ISSN: 2399-3642 (Electronic) Linking ISSN: 23993642 NLM ISO Abbreviation: Commun Biol Subsets: MEDLINE

Original Publication: London, United Kingdom : Nature Publishing Group UK, [2018]-

Levodopa*/metabolism ; Levodopa*/administration & dosage ; Gastrointestinal Microbiome*/drug effects ; Dopamine*/metabolism ; Parkinson Disease*/drug therapy ; Parkinson Disease*/metabolism ; Parkinson Disease*/microbiology ; Brain*/metabolism ; Brain*/drug effects ; Enterococcus faecalis*/metabolism ; Enterococcus faecalis*/drug effects; Animals ; Male ; Antiparkinson Agents/metabolism ; Antiparkinson Agents/administration & dosage ; Antiparkinson Agents/pharmacology ; Carbidopa ; Humans ; Biphenyl Compounds/metabolism ; Mice ; Organophosphorus Compounds/metabolism ; Mice, Inbred C57BL

Parkinson's disease is managed using levodopa; however, as Parkinson's disease progresses, patients require increased doses of levodopa, which can cause undesirable side effects. Additionally, the oral bioavailability of levodopa decreases in Parkinson's disease patients due to the increased metabolism of levodopa to dopamine by gut bacteria, Enterococcus faecalis, resulting in decreased neuronal uptake and dopamine formation. Parkinson's disease patients have varying levels of these bacteria. Thus, decreasing bacterial metabolism is a promising therapeutic approach to enhance the bioavailability of levodopa in the brain. In this work, we show that Mito-ortho-HNK, formed by modification of a naturally occurring molecule, honokiol, conjugated to a triphenylphosphonium moiety, mitigates the metabolism of levodopa-alone or combined with carbidopa-to dopamine. Mito-ortho-HNK suppresses the growth of E. faecalis, decreases dopamine levels in the gut, and increases dopamine levels in the brain. Mitigating the gut bacterial metabolism of levodopa as shown here could enhance its efficacy.
(© 2024. The Author(s).)

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R01 CA208648 United States CA NCI NIH HHS; R01CA208648 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI); International Research Project SuperO2 Centre National de la Recherche Scientifique (National Center for Scientific Research)

46627O600J (Levodopa)
VTD58H1Z2X (Dopamine)
0 (Antiparkinson Agents)
MNX7R8C5VO (Carbidopa)
0 (Biphenyl Compounds)
0 (Organophosphorus Compounds)

Date Created: 20240530 Date Completed: 20240530 Latest Revision: 20240603

20240603

PMC11139878

10.1038/s42003-024-06330-2

38816577