The high-affinity D2/D3 agonist D512 protects PC12 cells from 6-OHDA-induced apoptotic cell death and rescues dopaminergic neurons in the MPTP mouse model of Parkinson's disease.
In this study, in vitro and in vivo experiments were carried out with the high-affinity multifunctional D2/D3 agonist D-512 to explore its potential neuroprotective effects in models of Parkinson's disease and the potential mechanism(s) underlying such properties. Pre-treatment with D-512 in vitro was found to rescue rat adrenal Pheochromocytoma PC12 cells from toxicity induced by 6-hydroxydopamine administration in a dose-dependent manner. Neuroprotection was found to coincide with reductions in intracellular reactive oxygen species, lipid peroxidation, and DNA damage. In vivo, pre-treatment with 0.5 mg/kg D-512 was protective against neurodegenerative phenotypes associated with systemic administration of MPTP, including losses in striatal dopamine, reductions in numbers of DAergic neurons in the substantia nigra (SN), and locomotor dysfunction. These observations strongly suggest that the multifunctional drug D-512 may constitute a novel viable therapy for Parkinson's disease.
Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan, USA.
Mrudang
M
Shah
Subramanian
S
Rajagopalan
Liping
L
Xu
Chandrashekhar
C
Voshavar
Yevgeniya
Y
Shurubor
Flint
F
Beal
Julie K
JK
Andersen
Aloke K
AK
Dutta
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016627:Oxidopamine / Q000633:toxicity; D016716:PC12 Cells; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050637:Receptors, Dopamine D3 / Q000819:agonists*; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*
C000588553:D-512 compound; D007211:Indoles; D017382:Reactive Oxygen Species; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013844:Thiazoles; D016627:Oxidopamine
6-hydroxydopamine; MPTP; Parkinson's disease; multifunctional dopamine agonist; neuroprotection; oxidative stress