A Novel, Selective c‑Abl Inhibitor, Compound 5, Prevents Neurodegeneration in Parkinson’s Disease

Parkinson’s
disease (PD) is a progressive neurodegenerative
disorder that affects movement. The nonreceptor tyrosine kinase c-Abl
has shown a potential role in the progression of PD. As such, c-Abl
inhibition is a promising candidate for neuroprotection in PD and
α-synucleinopathies. Compound 5 is a newly synthesized blood–brain
barrier penetrant c-Abl inhibitor with higher efficacy than existing
inhibitors. The objective of the current study was to demonstrate
the neuroprotective effects of compound 5 on the α-synuclein
preformed fibril (α-syn PFF) mouse model of PD. Compound 5 significantly
reduced neurotoxicity, activation of c-Abl, and Lewy body pathology
caused by α-syn PFF in cortical neurons. Additionally, compound
5 markedly ameliorated the loss of dopaminergic neurons, c-Abl activation,
Lewy body pathology, neuroinflammatory responses, and behavioral deficits
induced by α-syn PFF injection in vivo. Taken
together, these results suggest that compound 5 could be a pharmaceutical
agent to prevent the progression of PD and α-synucleinopathies.