Potential Neuroprotective Role of L-Citrulline in Parkinson’s Disease: Mechanisms, Experimental Evidence and Future Perspectives

Abstract

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterised by the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta and the pathological accumulation of α-synuclein in the form of Lewy bodies. Despite decades of pharmacological research, current therapeutic strategies remain symptomatic, failing to halt or reverse the underlying neurodegeneration. Emerging evidence has implicated mitochondrial dysfunction, oxidative stress, and neuroinflammation. In this context, naturally occurring bioactive compounds with neuroprotective properties have attracted considerable interest. L-citrulline, a non-proteinogenic amino acid abundant in watermelon and a key intermediate in the urea cycle, has garnered attention for its capacity to enhance nitric oxide (NO) bioavailability, modulate antioxidant enzyme activity, attenuate neuroinflammation, and support mitochondrial homeostasis. This narrative review critically integrates existing preclinical and experimental findings on the neuroprotective properties of L-citrulline, with emphasis on its potential relevance to the molecular and cellular mechanisms underlying Parkinson’s disease (PD). It examines major aspects of PD, including its epidemiological burden and multifactorial pathogenesis, the utility of the rotenone-induced animal model in translational PD research, and the contributions of oxidative stress and SNCA/PINK1-associated molecular pathways to dopaminergic neurodegeneration. Furthermore, the review evaluates current mechanistic and functional evidence supporting the therapeutic potential of L-citrulline. It identifies significant knowledge gaps, particularly the limited availability of studies assessing L-citrulline in PD-specific experimental models with integrated gene expression analyses, and underscores the need for robust preclinical investigations and well-designed translational clinical studies to validate L-citrulline as a potential adjunctive therapy for Parkinson’s disease.