NEUROPHARMACOLOGY | 卷:123 |
A novel iron (II) preferring dopamine agonist chelator D-607 significantly suppresses α-syn- and MPTP-induced toxicities in vivo | |
Article | |
Das, Banibrata1  Rajagopalan, Subramanian3  Joshi, Gnanada S.2  Xu, Liping1  Luo, Dan1  Andersen, Julie K.3  Todi, Sokol V.2  Dutta, Aloke K.1  | |
[1] Wayne State Univ, Dept Pharmaceut Sci, Detroit, MI 48202 USA | |
[2] Wayne State Univ, Dept Pharmacol, Detroit, MI 48201 USA | |
[3] Buck Inst Res Aging, 8001 Redwood Blvd, Novato, CA 94945 USA | |
关键词: Multifunctional dopamine agonist; alpha-synuclein; MPTP; 6-OHDA; Neuroprotection; Parkinson's disease; Drosophila; | |
DOI : 10.1016/j.neuropharm.2017.05.019 | |
来源: Elsevier | |
【 摘 要 】
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.
【 授权许可】
Free
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
10_1016_j_neuropharm_2017_05_019.pdf | 6110KB | download |