Mechanisms of peripheral levodopa resistance in Parkinson’s disease

Parkinson’s disease (PD) is an increasingly common neurodegenerative condition. The disease has a significant negative impact on quality of life, but a personalized management approach can help reduce disability. Pharmacotherapy with levodopa remains the cornerstone of treatment, and a gratifying and sustained response to this treatment is a supportive criterion that argues in favor of an underlying diagnosis of PD. Yet, in daily practice, it is not uncommon to encounter patients who appear to have true PD, but who nevertheless seem to lose the responsiveness to levodopa (secondary non-responders). Some patients may even fail to respond altogether (primary non-responders). Here, we address how two mechanisms of “peripheral resistance” may underlie this failing response to levodopa in persons with PD. The first explanation relates to impaired bowel motility leading to secondary bacterial overgrowth, and more specifically, to the excessive bacterial production of the enzyme tyrosine decarboxylase (TDC). This enzyme may convert levodopa to dopamine in the gut, thereby hampering entry into the circulation and, subsequently, into the brain. The second explanation relates to the systemic induction of the enzyme aromatic l-amino acid decarboxylase (AADC), leading to premature conversion of levodopa into dopamine, again limiting the bioavailability within the brain. We discuss these two mechanisms and focus on the clinical implications, potential treatments and directions for future research.