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The high‐affinity D2/D3 agonist D512 protects PC 12 cells from 6‐ OHDA ‐induced apoptotic cell death and rescues dopaminergic neurons in the MPTP mouse model of Parkinson's disease
Author(s) -
Shah Mrudang,
Rajagopalan Subramanian,
Xu Liping,
Voshavar Chandrashekhar,
Shurubor Yevgeniya,
Beal Flint,
Andersen Julie K.,
Dutta Aloke K.
Publication year - 2014
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12767
Subject(s) - mptp , neuroprotection , substantia nigra , pharmacology , agonist , lipid peroxidation , dopaminergic , dopamine , in vivo , reactive oxygen species , chemistry , biology , microbiology and biotechnology , oxidative stress , biochemistry , neuroscience , receptor
Abstract 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 PC 12 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 DA ergic 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.Neuroprotective properties of dopamine D2/D3 agonist D‐512 was evaluated both in vitro and in vivo models of Parkinson's disease (PD). D‐512 rescued PC12 cells from toxicity induced by 6‐hydroxydopamine (6‐OHDA). D‐512 reduced intracellular reactive oxygen species and lipid peroxidation as well as protection of DNA damage from toxicity of 6‐OHDA. D‐512 was protective against neurodegenerative phenotypes induced by MPTP in mouse. Our studies strongly suggest that D‐512 with its multifunctional property may constitute a novel viable therapy for Parkinson's disease.