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The c-Abl inhibitor, Radotinib HCl, is neuroprotective in a preclinical Parkinson's disease mouse model
Saebom Lee1,2, Sangjune Kim1,2, Yong Joo Park3
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Abstract:
Accumulating evidence suggests that the non-receptor tyrosine kinase c-Abl plays an important role in the progression of Parkinson's disease (PD) and c-Abl inhibition could be neuroprotective in PD and related α-synucleinopathies. Nilotinib, a c-Abl inhibitor, has shown improved motor and cognitive symptoms in PD patients. However, issues concerning blood-brain barrier (BBB) penetration, lack of selectivity and safety still remain. Radotinib HCl is a selective Bcr-Abl kinase inhibitor that not only effectively access the brain, but also exhibits greater pharmacokinetic properties and safety profiles compared to Nilotinib and other c-Abl inhibitors. Here, we show the neuroprotective efficacy of Radotinib HCl, a brain penetrant c-Abl inhibitor, in a pre-clinical model of PD. Importantly, in vitro studies demonstrate that the treatment of Radotinib HCl protects the α-synuclein preformed fibrils (PFF)-induced neuronal toxicity, reduces the α-synuclein PFF-induced Lewy bodies (LB)/Lewy neurites (LN)-like pathology and inhibits the α-synuclein PFF-induced c-Abl activation in primary cortical neurons. Furthermore, administration of Radotinib HCl inhibits c-Abl activation and prevents dopaminergic neuron loss, neuroinflammation and behavioral deficits following α-synuclein PFF-induced toxicity in vivo. Taken together, our findings indicate that Radotinib HCl has beneficial neuroprotective effects in PD and provides an evidence that selective and brain permeable c-Abl inhibitors can be potential therapeutic agents for the treatment of PD and related α-synucleinopathies.
Insights
Radotinib HCl, a selective c-Abl inhibitor, demonstrated neuroprotective effects in Parkinson's disease models by reducing alpha-synuclein toxicity and preventing neuron loss. This brain-penetrant drug shows promise for treating Parkinson's disease.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Non-receptor tyrosine kinase c-Abl is implicated in Parkinson's disease (PD) progression.
- c-Abl inhibition offers potential neuroprotection in PD and alpha-synucleinopathies.
- Existing inhibitors like Nilotinib face challenges with blood-brain barrier penetration, selectivity, and safety.
Purpose of the Study:
- To evaluate the neuroprotective efficacy of Radotinib HCl, a selective and brain-penetrant c-Abl inhibitor, in a pre-clinical Parkinson's disease model.
- To assess Radotinib HCl's effects on alpha-synuclein pathology and c-Abl activation in vitro and in vivo.
Main Methods:
- In vitro studies using primary cortical neurons treated with alpha-synuclein preformed fibrils (PFFs) and Radotinib HCl.
- In vivo studies in a pre-clinical PD model involving alpha-synuclein PFF administration.
- Assessment of neuronal toxicity, Lewy body-like pathology, c-Abl activation, dopaminergic neuron loss, neuroinflammation, and behavioral deficits.
Main Results:
- Radotinib HCl protected neurons from alpha-synuclein PFF-induced toxicity in vitro.
- It reduced alpha-synuclein PFF-induced Lewy body/neurite-like pathology and inhibited c-Abl activation.
- In vivo, Radotinib HCl inhibited c-Abl activation, prevented dopaminergic neuron loss, reduced neuroinflammation, and ameliorated behavioral deficits.
Conclusions:
- Radotinib HCl exhibits significant neuroprotective effects in a pre-clinical model of Parkinson's disease.
- Selective, brain-permeable c-Abl inhibitors like Radotinib HCl represent promising therapeutic candidates for PD and related alpha-synucleinopathies.