title: Assessment of Protective Role of Multifunctional Dopamine Agonist D-512 Against Oxidative Stress Produced by Depletion of Glutathione in PC12 Cells: Implication in Neuroprotective Therapy for Parkinson's Disease.
abstract: Oxidative stress has been strongly implicated in the progression of Parkinson's disease (PD). Depletion of cytoplasmic glutathione levels is one of the indications of oxidative stress, which occur in the substantia nigra of PD patients at an early stage of the disease process. It has been shown that glutathione depletion causes the inhibition of mitochondrial complex I, thus affecting mitochondrial function leading to oxidative stress via production of reactive oxygen species. Studies were carried out to investigate the role of D-512, a potent multifunctional neuroprotective D2/D3 receptor agonist, in protecting dopaminergic PC12 cells treated with buthionine sulfoximine (BSO), an inhibitor of key enzyme in glutathione synthesis and 6-hydroxydopamine (6-OHDA), a widely used neurotoxin. D-512 was able to restore level of glutathione against BSO/6-OHDA-mediated glutathione depletion. D-512 also showed significant neuroprotection in PC12 cells against toxicity induced by combined treatment of BSO and 6-OHDA. Furthermore, D-512 was able to restore both phospho-extracellular signal-regulated kinase and phospho-Jun N-terminal kinase levels upon treatment with 6-OHDA providing an evidence on the possible mechanism of action for neuroprotection by modulating mitogen-activated protein kinases. We have further demonstrated the neuroprotective effects of D-512 against oxidative insult produced by BSO and 6-OHDA in PC12 cells.
authors.affiliation: Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, 48202, USA.
authors.forename: Chandrashekhar
authors.initials: C
authors.lastname: Voshavar
authors.affiliation: Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, 48202, USA.
authors.forename: Mrudang
authors.initials: M
authors.lastname: Shah
authors.affiliation: Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, 48202, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, 48202, USA. adutta@wayne.edu.|Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy & Health Sciences, Rm# 3128, Detroit, MI, 48202, USA. adutta@wayne.edu.
authors.forename: Aloke K
authors.initials: AK
authors.lastname: Dutta
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D018491:Dopamine Agonists / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000032:analysis / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D016627:Oxidopamine / Q000633:toxicity; D016716:PC12 Cells; D010300:Parkinson Disease / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: C000588553:D-512 compound; D018491:Dopamine Agonists; D007211:Indoles; D018696:Neuroprotective Agents; D013844:Thiazoles; D016627:Oxidopamine; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione
keywords: 6-OHDA; BSO; D2/D3 agonist; Glutathione; Oxidative stress; PC12 cells; Parkinson’s disease