期刊
NEUROPHARMACOLOGY
卷 123, 期 -, 页码 88-99出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2017.05.019
关键词
Multifunctional dopamine agonist; alpha-synuclein; MPTP; 6-OHDA; Neuroprotection; Parkinson's disease; Drosophila
资金
- National Institute of Neurological Disorders and Stroke/National Institute of Health [NS047198]
- Wayne State President Research Enhancement award
- NIH/NINDS [NS086778]
Here, we report the characterization of a novel hybrid D-2/D-3 agonist and iron (II) specific chelator, D-607, as a multi-target-directed ligand against Parkinson's disease (PD). In our previously published report, we showed that D-607 is a potent agonist of dopamine (DA) D-2/D-3 receptors, exhibits efficacy in a reserpinized PD animal model and preferentially chelates to iron (II). As further evidence of its potential as a neuroprotective agent in PD, the present study reveals D-607 to be protective in neuronal PC12 cells against 6-OHDA toxicity. In an in vivo Drosophila melanogaster model expressing a disease-causing variant of a-synuclein (alpha-Syn) protein in fly eyes, the compound was found to significantly suppress toxicity compared to controls, concomitant with reduced levels of aggregated a-Syn. Furthermore, D-607 was able to rescue DAergic neurons from MPTP toxicity in mice, a well-known PD neurotoxicity model, following both sub-chronic and chronic MPTP administration. Mechanistic studies indicated that possible protection of mitochondria, up-regulation of hypoxia-inducible factor, reduction in formation of a-Syn aggregates and antioxidant activity may underlie the observed neuroprotection effects. These observations strongly suggest that D-607 has potential as a promising multifunctional lead molecule for viable symptomatic and disease-modifying therapy for PD. (C) 2017 Elsevier Ltd. All rights reserved.
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