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
| Autor: | Aloke K. Dutta, Mark P. Johnson, Mrudang M. Shah, Liping Xu, Soumava Santra |
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| Rok vydání: | 2013 |
| Předmět: |
Agonist
Indoles Physiology medicine.drug_class Cognitive Neuroscience Pharmacology Biology Biochemistry Dopamine agonist Neuroprotection chemistry.chemical_compound Lycopene Dopamine Tumor Cells Cultured medicine Animals Oxidopamine Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Tyrosine hydroxylase MPTP Dopaminergic Parkinson Disease Cell Biology General Medicine Carotenoids Rats Disease Models Animal Thiazoles Neuroprotective Agents chemistry Dopamine Agonists Proto-Oncogene Proteins c-akt medicine.drug |
| Zdroj: | ACS Chemical Neuroscience. 4:1382-1392 |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/cn400106n |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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