A novel iron (II) preferring dopamine agonist chelator D-607 significantly suppresses alpha-syn- and MPTP-induced toxicities in vivo

作者：Das Banibrata; Rajagopalan Subramanian; Joshi Gnanada S; Xu Liping; Luo Dan; Andersen Julie K; Todi Sokol V; Dutta Aloke K

来源：Neuropharmacology, 2017, 123: 88-99.

DOI：10.1016/j.neuropharm.2017.05.019

• Multifunctional dopamine agonist
• alpha-synuclein
• MPTP
• 6-OHDA
• Neuroprotection
• Parkinson's disease
• Drosophila

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.

• 出版日期2017-9-1