Dopamine D2 agonists, bromocriptine and quinpirole, increase MPP+-induced toxicity in PC12 cells

Abstract

Dopaminergic cell loss in the mesencephalic substantia nigra is the hallmark of Parkinson's disease and may be associated with abnormal oxidative metabolic activity. However, the delicate balance underlying dopamine decline and oxidative stress is still a matter of debate. The aim of this study was to analyze the possible modulation of D2 agonists and antagonists on MPP+ (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium ion) -induced cellular death in differentiated and undifferentiated PC12 cells. Using colorimetric assays, western blots and reverse transcriptase-PCR, we demonstrated that two D2 agonists, bromocriptine and quinpirole, consistently increased MPP+ -induced cytotoxicity in both differentiated and undifferentiated PC12 cells, whereas D2 antagonists do not modulate cell death. However, this increase in cellular death was reversed when bromocriptine or quinpirole were used in presence of D2 antagonists. On the other hand, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR 12909), a potent inhibitor of the dopamine transporter, partially reversed MPP+ -induced cellular death and completely abolished the increase of cellular death induced by bromocriptine. Dopamine agonists and antagonists also modulate the expression of the dopamine transporter in PC12 cells; in particular, bromocriptine may alter MPP+ uptake by increasing DAT expression We also show that, in our cellular paradigm, D2 receptor mRNA levels are more abundant that D3 mRNA levels and MPP+ and /or bromocriptine could not modulate D2 gene expression while D3 gene expression clearly decrease after MPP+ and /or bromocriptine treatment.

Sesamin Modulates Tyrosine Hydroxylase, Superoxide Dismutase, Catalase, Inducible No Synthase and Interleukin‐6 Expression in Dopaminergic Cells Under Mpp+‐Induced Oxidative Stress

“…In this study, we tested neuronal PC12 cells, a known, reliable and efficient paradigm for the investigation of oxidative stress and neuroprotection of DA neurons 25,42. After NGF administration, PC12 cells differentiate into the neuronal-like phenotype that secretes high DA levels and expresses TH, DAT, neurofilaments as well as ERα and ERβ 25,4346.…”

How Parkinsonian Toxins Dysregulate the Autophagy Machinery

“…While MPTP does not directly cause midbrain degeneration in vivo , the toxin efficiently crosses the blood brain barrier where it is metabolically transformed to MPP+, the destructive form of the toxin, by glia. Moreover, MPP+ is actively transported inside dopaminergic neurons via the dopamine active transporter (DAT) since treating cells with pharmacological inhibitors of DAT protects cells from MPP+-induced cell death [63–66]. Mechanistically, MPP+ blocks oxidative phosphorylation at the level of complex I and increases the steady state levels of mitochondrial superoxide.…”

Anti-Hyperprolactinemic Effect of Formula Malt Decoction, a Chinese Herbal Cocktail

“…These studies revealed D2 receptor is necessary for anti-hyperPRL activity of FMD. PC12 cells from rat pheochromocytoma abundantly express D2 receptors and DAT [15,16]. FMD significantly increased the expression of D2 receptors and DAT in PC12 cells.…”