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.
Highlights
Parkinson’s disease (PD) is the second most common, late onset, progressive neurodegenerative disorder and is characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), which causes motor dysfunction such as bradykinesia, rest tremor, and rigidity
To firstly examine whether c-Abl contributes to the pathology of a-synuclein preformed fibrils (PFF) mouse model of sporadic PD, primary cortical neurons were treated with a-synuclein PFF (1 lg/ml) or PBS and c-Abl activation was assessed using phospho-Tyr245 cAbl antibody
We observed that c-Abl activation induced by asynuclein PFF was significantly decreased in the neurons with treatment of Radotinib HCl (1 lM) (Fig. 1C and D). c-Abl inhibition by Radotinib HCl was further assessed on the level of phosphotyrosine 39-a-synuclein, which shows increased propensity for aggregation and neuronal toxicity
Summary
Parkinson’s disease (PD) is the second most common, late onset, progressive neurodegenerative disorder and is characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), which causes motor dysfunction such as bradykinesia, rest tremor, and rigidity. Dopamine replacement alleviates the symptomatic motor dysfunction, its effectiveness is reduced as the disease progresses, leading to side effects such as severe motor fluctuations and dyskinesia. This palliative therapeutic approach does not address the underlying mechanisms of the disease [2,3]. Accumulating evidence suggests that the non-receptor tyrosine kinase, c-Abl is activated by oxidative stress and its activation plays a role in neurologic disorders including PD [7–9]. Stress-induced activation of the non-receptor tyrosine kinase, c-Abl could contribute to the pathogenesis of sporadic PD and its inhibition could have neuroprotective effect in PD
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