Symptomatic Rescue or Disease Modification? A Critical Review of Levodopa and Phytochemical Interventions in Caenorhabditis elegans Models of Parkinson's Disease.

Abstract

Parkinson's disease (PD) is characterised by progressive dopaminergic neurodegeneration and alpha-synuclein (α-syn) aggregation, with levodopa remaining the gold-standard symptomatic therapy despite its inability to halt disease progression or prevent levodopa-induced dyskinesia (LID). Caenorhabditis elegans has emerged as a highly tractable model for mechanistic PD research owing to its conserved dopaminergic pathways, optical transparency, rapid lifecycle, and suitability for high-throughput pharmacological screening. This review critically examines the pharmacological effects of levodopa in C. elegans PD models across locomotor behaviour, α-syn aggregation, lifespan, and dyskinesia-related phenotypes, while comparing these findings with phytochemicals evaluated in analogous experimental systems. Levodopa consistently restored dopamine-dependent locomotor deficits but failed to substantially reduce α-syn aggregation or extend lifespan, recapitulating the clinical dissociation between symptomatic motor rescue and persistent neurodegeneration. In contrast, phytochemicals, including Frondoside A, hydroxytyrosol/Hidrox®, Neurogrit Gold, Mucuna pruriens extract, quercetin, and quercetin nanoemulsions, demonstrated broader mechanistic profiles involving antioxidant responses, mitophagy, proteostasis, and dopaminergic neuroprotection. The available evidence suggests that phytochemicals are best regarded not as replacements for levodopa but as candidate adjuncts that, in preclinical worm models, appear to act on upstream pathological processes; whether this translates into genuine complementarity in vivo remains a hypothesis requiring direct testing. The central argument advanced here is methodological rather than pharmacological: C. elegans is currently the only PD model in which symptomatic motor rescue and α-synuclein pathology can be quantified simultaneously in the same living animal, and this dissociation provides a measurable framework for defining what an adjunctive compound would need to achieve. On this basis, levodopa is proposed as a mandatory positive control for future C. elegans phytochemical screening. Critical translational limitations-including the absence of a blood-brain barrier in C. elegans, phytochemical bioavailability constraints, and uncertainty regarding the relationship between aggregate reduction and true neuroprotection-are also discussed.