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

Abstract 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.