Targeting protein kinases in Parkinson's disease: the emerging role of phytoconstituents

Parkinson's disease (PD) is a progressive, age-associated neurodegenerative disorder characterized by loss of nigrostriatal dopaminergic neurons, leading to motor and non-motor dysfunctions. Central to PD pathogenesis are dysregulated protein kinases, such as LRRK2, PINK1, GSK-3β, and CDK5, that govern neuroinflammation, autophagy impairment, oxidative stress, mitochondrial dysfunction, and α-synuclein aggregation.

To critically assess the potential of phytoconstituents as modulators of key protein kinases in PD.

A comprehensive literature review was carried out with PubMed, SCOPUS, SciDirect, Google Scholar, Hindawi, clinicaltrials.gov, and Wiley Online Library, integrating data from in silico, in vitro, and in vivo studies focused on the potential role of phytoconstituents in kinase modulation.

Preclinical studies consistently demonstrate that flavonoids, polyphenols, and alkaloids mitigate oxidative stress, restore mitochondrial function, inhibit apoptotic signaling, and reduce α-synuclein aggregation via modulation of LRRK2, GSK-3β, CDK5, and related protein kinases. In silico analyses reveal favorable binding affinities to kinase domains, while network pharmacology suggests synergistic multi-kinase effects. These insights align with challenges observed in translational trials of small-molecule kinase inhibitors, particularly regarding bioavailability and target selectivity.

While current PD therapies focus on symptomatic relief, targeting protein kinases with phytoconstituents presents a promising disease-modifying approach. Future research should prioritize clinical validation and mechanistic studies to establish their therapeutic potential, paving the way for novel kinase-targeted interventions in PD management.Trial registration: ClinicalTrials.gov identifier: NCT02281474.Trial registration: ClinicalTrials.gov identifier: NCT02954978.Trial registration: ClinicalTrials.gov identifier: NCT02970019.Trial registration: ClinicalTrials.gov identifier: NCT03445338.Trial registration: ClinicalTrials.gov identifier: NCT03655236.Trial registration: ClinicalTrials.gov identifier: NCT04691661.Trial registration: ClinicalTrials.gov identifier: NCT04551534.Trial registration: ClinicalTrials.gov identifier: NCT03710707.Trial registration: ClinicalTrials.gov identifier: NCT04557800.Trial registration: ClinicalTrials.gov identifier: NCT04056689.Trial registration: ClinicalTrials.gov identifier: NCT03205488.Trial registration: ClinicalTrials.gov identifier: NCT05348785.