Objective: To develop a Parkinson’s disease (PD) model replicating levodopa (LD) resistance by incorporating degeneration of both the substantia nigra (SN) and locus coeruleus (LC), providing a platform for studying treatment challenges in PD.

Background: LD remains the cornerstone of PD management; however, up to 20% of patients develop a suboptimal response over time. Emerging evidence suggests that LC degeneration disrupts noradrenergic modulation of dopaminergic pathways, potentially contributing to LD resistance. Despite this, preclinical models incorporating this mechanism remain scarce.

Method: PD was induced in male Swiss albino mice using rotenone (2.5 mg/kg, s.c.) for 28 days to target SN dopaminergic neurons. To model LC involvement and LD resistance, DSP-4 (50 mg/kg, i.p.), a selective noradrenergic neurotoxin, was administered. Motor function was evaluated using open-field, rotarod, catalepsy, and hang tests. Neurochemical analysis (HPLC) quantified midbrain dopamine (DA) and norepinephrine (NE) levels. LD therapy (100 mg/kg + 10 mg/kg carbidopa, i.p.) was assessed for efficacy.

Results: Rotenone-treated mice exhibited hallmark PD-like motor impairments, including a 62% reduction in locomotor activity (p<0.0001) and a 48% decline in rotarod performance (p<0.0001). LD administration significantly improved mobility, increasing locomotor activity by 55% (p<0.0001) and reducing catalepsy time. However, DSP-4-induced LC degeneration led to a 39% reduction in NE (p<0.0001) and 27% decline in DA (p<0.01), correlating with a diminished therapeutic response to LD. These findings align with clinical observations, where LC dysfunction is associated with disease progression and treatment resistance.

Conclusion: This clinically relevant PD model successfully replicates LD resistance by integrating LC degeneration, reinforcing the role of noradrenergic and dopaminergic pathways in PD pathophysiology. It provides a valuable preclinical toolfor testing adjunct therapies aimed at optimizing LD response in PD patients.

Figure 1

References: 1. Zhou, C., Guo, T., Wu, J., Wang, L., Bai, X., Gao, T., et al. (2022). Locus Coeruleus Degeneration Correlated with Levodopa Resistance in Parkinson’s Disease: A Retrospective Analysis. Journal of Parkinson’s Disease, 11(4), 1631–1640. https://doi.org/10.3233/JPD-212720

2. Beckers, M., Bloem, B. R., & Verbeek, M. M. (2022). Mechanisms of peripheral levodopa resistance in Parkinson’s disease. NPJ Parkinson’s Disease, 8(1), 56. https://doi.org/10.1038/s41531-022-00321-y

3. Mavridis, M., Degryse, A. D., Lategan, A. J., Marien, M. R., & Colpaert, F. C. (1991). Effects of locus coeruleus lesions on parkinsonian signs, striatal dopamine, and substantia nigra cell loss after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in monkeys: A possible role for the locus coeruleus in the progression of Parkinson’s disease. Neuroscience, 41(2-3), 507–523. https://doi.org/10.1016/0306-4522(91)90345-o

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MDS Abstracts - https://www.mdsabstracts.org/abstract/modeling-levodopa-resistance-in-parkinsons-disease-a-novel-approach-targeting-locus-coeruleus-degeneration/