Mechanisms of peripheral levodopa resistance in Parkinson’s disease

Abstract

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.

Ethnopharmacological Effects of Urtica dioica, Matricaria chamomilla, and Murraya koenigii on Rotenone-Exposed D. melanogaster: An Attenuation of Cellular, Biochemical, and Organismal Markers

“…Currently, conventional medicines or therapeutic drugs (levodopa or dopaminergic agonists) have only been used to treat motor symptoms by restoring neurotransmitters [ 7 ]. The extended use of these drugs, however, can have negative effects, such as fatigue and other motor difficulties [ 8 ].…”

Tremor in Parkinson’s Disease: From Pathophysiology to Advanced Therapies

“…Overall, it ranges widely from no objective clinical response to 80% tremor reduction [56,57]. This inconsistent response has led to the proposed classification of tremor into three subtypes: dopamine-responsive, dopamine-resistant, and a partially overlapping intermediate group [58][59][60]. The dose and duration required to consider tremor as dopamineresistant have not yet been determined.…”

“…Poor response in some patients might be attributed, in part, to pseudoresistance, a phenomenon in which levodopa sensitive symptoms falsely appear to be resistant [15,52,60]. This occurs in the context of multiple underlying mechanisms that contribute to a suboptimal response [60].…”

“…Poor response in some patients might be attributed, in part, to pseudoresistance, a phenomenon in which levodopa sensitive symptoms falsely appear to be resistant [15,52,60]. This occurs in the context of multiple underlying mechanisms that contribute to a suboptimal response [60]. Factors leading to pseudoresistance include gastrointestinal dysfunction causing poor absorption or high protein diets interfering with levodopa.…”

“…Factors leading to pseudoresistance include gastrointestinal dysfunction causing poor absorption or high protein diets interfering with levodopa. Moreover, cognitive stress is a known factor that attenuates the therapeutic effect of dopamine [24,52,60].…”