Levodopa

Levodopa is the gold-standard treatment for the motor symptoms of Parkinson's disease (PD) as it is the only therapy that effectively and reliably restores brain dopamine levels. Levodopa crosses into the brain using the LAT1 transporter, is then converted to dopamine using remaining AADC in the remaining nigrostriatal terminals and the co-administered peripheral AADC and COMT inhibitors extend its half-life to allow for pulsatile or continuous dopaminergic stimulation. The newly generated dopamine is taken up by D1-like receptors that mediate the direct striatonigral pathway and D2-like receptors that mediate the indirect striatopallidal pathway, effectively restoring the imbalanced abnormally up-regulated indirect and down-regulated direct signaling due to denervation, while also temporarily correcting the postsynaptic normalization of D1/D2 expression and presynaptic D2 loss.
Functionally, levodopa increases putamen–anterior cerebellum–brainstem connectivity, decreases pathological STN–thalamo-cortical coupling and increases prefrontal–supplementary-motor and ventral striato-prefrontal interactions, which correlate with improvements in bradykinesia and working memory, respectively.

Fig. 1 Molecular mechanism of Levodopa. (Muthuraman M.; et al. 2018)

van Vliet E F et al. provided experimental evidence of nanoparticle-based approaches for targeted delivery of levodopa for the treatment of Parkinson's disease (PD). The poor oral bioavailability of L-DOPA, gastrointestinal degradation, first-pass hepatic metabolism, and limited transport across the blood-brain barrier (BBB), result in a bioavailability of < 1%, large doses, and consequently long-term adverse effects like dyskinesia. Polymeric, lipid, and hybrid nanoparticles were optimized for size, surface charge, and ligand modification to improve stability, circulation time, and BBB transport mechanisms for better protection of L-DOPA. Intravenous, transdermal, and intranasal administration routes were compared, with the intranasal route being the most feasible and non-invasive.
Their developed chitosan- or lactoferrin-modified PLGA nanoparticles, exhibited rapid brain uptake in 10–30 minutes, sustained 6-hour release, significantly increased striatal dopamine, decreased systemic exposure, and improved motor performance in rodents.

Fig. 2 Levodopa-loaded nanoparticles for Parkinson's disease therapy. (van Vliet E F.; et al. 2023)