Abstract
Parkinson’s disease (PD) is one common neurodegenerative disease caused by a significant loss of midbrain dopaminergic neurons. Previous reports showed that 7, 8- dihydroxyflavone (7, 8-DHF) as a potent TrkB agonist can mimic BDNF and play neuroprotective roles for mouse dopaminergic neurons. Nonetheless, the safety and neuroprotective effects are unclear in monkey models of PD. Here, we find that 7, 8-DHF could be absorbed and metabolized into 7-hydroxy-8-methoxyflavone through oral administration in monkeys. The half-life time of 7, 8-DHF in monkey plasma is about 4–8 hrs. Furthermore, these monkeys maintain health state throughout the course of seven-month treatments of 7, 8-DHF (30 mg/kg/day). Importantly, 7, 8-DHF treatments can prevent the progressive degeneration of midbrain dopaminergic neurons by attenuating neurotoxic effects of MPP+ and display strong neuroprotective effects in monkeys. Our study demonstrates that this promising small molecule may be transited into a clinical useful pharmacological agent.
Highlights
Parkinson’s disease (PD) is one common neurodegenerative disease with typical motor symptoms including bradykinesia, postural instability, rigidity and tremor, and characteristic pathological change, resulting from dopaminergic neuron death in the substantia nigra pars compacta (SNc) of midbrain[1]
Non-human primate models of PD induced by MPTP are important for evaluating potential protective efficiency of 7, 8-DHF on dopaminergic neurons in primates before moving into clinical trials to test its efficacy in patients with PD
Our study is the first time to demonstrate that 7, 8-DHF treatments can attenuate dopamingeric neuron loss in higher non-human primates (NHPs), implying that this promising small molecule may be transited into a clinical useful pharmacological agent
Summary
Parkinson’s disease (PD) is one common neurodegenerative disease with typical motor symptoms including bradykinesia, postural instability, rigidity and tremor, and characteristic pathological change, resulting from dopaminergic neuron death in the substantia nigra pars compacta (SNc) of midbrain[1]. Over the past few decades, there were major advances on neurological treatments of PD including pharmacological treatments, physical or behavioral therapy, deep brain stimulation (DBS) and noninvasive stimulation approaches[2,3]. These treatments are temporary symptomatic relief; so far, no treatment has delayed the onset and/or slowed the progression of this disease[4]. A new approach was used to develop Parkinsonian monkeys with intracerebroventricular injections of MPP+11 This new method avoids the damage of gastrointestinal dopamine neurons induced by MPTP and targets brain dopamine neurons[11]
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