title: D-512 and D-440 as novel multifunctional dopamine agonists: characterization of neuroprotection properties and evaluation of in vivo efficacy in a Parkinson's disease animal model.
abstract: In this article, we have demonstrated the in vivo efficacy of D-512 and D-440 in a 6-OHDA-induced unilaterally lesioned rat model experiment, a Parkinson's disease animal model. D-512 is a novel highly potent D2/D3 agonist, and D-440 is a novel highly selective D3 agonist. We evaluated the neuroprotective properties of D-512 and D-440 in the dopaminergic MN9D cells. Cotreatment of these two drugs with 6-OHDA and MPP+ significantly attenuated and reversed 6-OHDA- and MPP+-induced toxicity in a dose-dependent manner in the dopaminergic MN9D cells. The inhibition of caspase 3/7 and lipid peroxidation activities along with the restoration of tyrosine hydroxylase levels by D-512 in 6-OHDA-treated cells may partially explain the mechanism of its neuroprotective property. Furthermore, studies were carried out to elucidate the time-dependent changes in the pERK1/2 and pAkt, two kinases implicated in cell survival and apoptosis, levels upon treatment with 6-OHDA in presence of D-512. The neuroprotective property exhibited by these drugs was independent of their dopamine-agonist activity, which is consistent with our multifunctional drug-development approach that is focused on the generation of disease-modifying symptomatic-treatment agents for Parkinson's disease.
authors.affiliation: Department of Pharmaceutical Sciences, Wayne State University , Detroit, Michigan 48202, United States.
authors.forename: Soumava
authors.initials: S
authors.lastname: Santra
authors.forename: Liping
authors.initials: L
authors.lastname: Xu
authors.forename: Mrudang
authors.initials: M
authors.lastname: Shah
authors.forename: Mark
authors.initials: M
authors.lastname: Johnson
authors.forename: Aloke
authors.initials: A
authors.lastname: Dutta
mesh_terms: D000818:Animals; D002338:Carotenoids / Q000037:antagonists & inhibitors / Q000633:toxicity; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use*; D000077276:Lycopene; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D016627:Oxidopamine / Q000037:antagonists & inhibitors / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D013844:Thiazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: C000588554:D-440 compound; C000588553:D-512 compound; D018491:Dopamine Agonists; D007211:Indoles; D018696:Neuroprotective Agents; D013844:Thiazoles; D002338:Carotenoids; D016627:Oxidopamine; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000077276:Lycopene
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