Abstract
6-OHDA plus ascorbic acid (AA) has long been used to induce Parkinson’s disease in rodents, while only 6-OHDA is commonly used to induce cell damage in cellular PD models. AA was believed to act as an anti-oxidant to prevent the degradation of 6-OHDA; however, some studies suggested that AA dramatically enhanced the selectivity and toxicity of 6-OHDA. To understand the mechanisms by which 6-OHDA/AA induces cell death, we established a 6-OHDA/AA cell toxicity model in human dopaminergic neuroblastoma SH-SY5Y cells. We confirmed that the toxicity of 6-OHDA was dramatically increased in the presence of AA, and the toxicity can be prevented by a flavonoid, baicalein. Mechanistically, our research reveals that 6-OHDA/AA induces cell death mainly through the interruption of intracellular calcium homeostasis, which leads to calpain activation and mitochondrial damage. Baicalein prevents 6-OHDA/AA-induced intracellular calcium elevation as well as consequent mitochondria damage. Taken together, our study confirms that 6-OHDA/AA is a more sensitive model for inducing neuronal lesion in vitro and reveals the central role of intracellular calcium in 6-OHDA/AA-induced cell death. Our studies further show that baicalein prevents 6-OHDA/AA-induced cell death by inhibiting intracellular calcium elevation.
Highlights
Parkinson’s disease (PD), a progressive neurodegenerative disease strongly associated with aging, is characterized by the selective death of dopaminergic neurons in substania nigra and the accumulation of cytoplasmic inclusions called Lewy bodies1. 6-OHDA is a classic PD toxin which induces neurotoxicity through causing the production of hydrogen peroxide and hydroxyl radicals, reducing GSH content and inhibiting SOD activity[2,3,4,5]
(A) SH-SY5Y cells were treated with different concentrations of 6-OHDA alone or 6-OHDA/ascorbic acid (AA) for 15 min, and drug-containing medium was replaced with normal cell culture medium, and cells were incubated for 24 h
SH-SY5Y cells were treated with different concentrations of 6-OHDA (25 μM-100 μM) with or without 0.15% AA for 15 min and incubated with normal cell culture medium for different times (1 min-24 h)
Summary
Parkinson’s disease (PD), a progressive neurodegenerative disease strongly associated with aging, is characterized by the selective death of dopaminergic neurons in substania nigra and the accumulation of cytoplasmic inclusions called Lewy bodies1. 6-OHDA is a classic PD toxin which induces neurotoxicity through causing the production of hydrogen peroxide and hydroxyl radicals, reducing GSH content and inhibiting SOD activity[2,3,4,5]. SH-SY5Y cells were treated with 25 μM 6-OHDA/ AA in the presence or absence of 25 μM baicalein for 15 min and incubated in normal culture medium for 6 h.
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