In a paraquat+lectin rat 'body-first' PD model, 60 days of twice-daily levodopa/benserazide administered after established motor deficits produced no long-term changes in motor or visuospatial memory performance, nigral dopaminergic or medial septal cholinergic neuron loss, or phosphorylated…

Offers translationally relevant, if limited, preclinical evidence that chronic levodopa does not accelerate neurodegeneration or α-syn pathology in a body-first PD model, providing reassurance about levodopa safety and informing neuroprotection trial design and prioritization.

Recent studies have identified a "body-first" subtype of Parkinson's disease (PD) that is associated with more rapid progression to Parkinson's disease dementia (PDD). It is currently unknown whether chronic levodopa, the primary treatment in PD, contributes to the progression of disease in the "body-first" subtype of PD. We investigated whether chronic levodopa affects motor or cognitive function in the paraquat and lectin (P + L) rat model of PD, a model which recapitulates the "body-first" subtype of PD. Rats (n = 9) were administered 7 days of P + L (1 mg/kg P + 0.05% L in 1% sucrose solution, oral gavage) with injection of cholecystokinin (3 μg/kg CCK, ip) to induce parkinsonism. At 15 weeks post-P + L treatment, rats with bilateral forelimb motor deficit (n = 6) were administered 60 days of twice daily levodopa (4 mg/kg) + benserazide (15 mg/kg) ip injections. Motor and cognitive behavioral testing were done pre-levodopa, on levodopa, and post-levodopa washout. Rats were euthanized and brains stained for tyrosine hydroxylase (TH), choline acetyltransferase (ChAT) and phosphorylated-S129-α-synuclein (pSyn) to investigate the effects of chronic levodopa on neurodegeneration and pathology in the nigrostriatal pathways and basal forebrain nuclei. We show no long-term effects of chronic levodopa treatment on the progression of parkinsonian motor deficits, visuospatial working memory, dopaminergic nigral degeneration, or cholinergic medial septal nucleus - vertical nucleus of diagonal band of Broca complex degeneration in the P + L rat model of PD. This study provides important preclinical evidence that chronic levodopa therapy does not cause progression of neurodegeneration in this rat model which recapitulates the "body-first" subtype of PD.