Molecular mechanisms of 6-hydroxydopamine-induced cytotoxicity in PC12 cells: Involvement of hydrogen peroxide-dependent and -independent action

Saito, Yoshiro; Nishio, Keiko; Ogawa, Yoko; Kinumi, Tomoya; Yoshida, Yasukazu; Masuo, Yoshinori; Niki, Etsuo

doi:10.1016/j.freeradbiomed.2006.12.004

Cited by 155 publications

(132 citation statements)

References 45 publications

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“…3A. It is well-established in many types of cells, including histaminestimulated ECs in the present study, that agonist-stimulated intracellular ROS serve as a signaling molecule (D' Autreaux and Toledano, 2007;Finkel, 2006;Hu et al, 2002;Saito et al, 2007;Schmidt et al, 1995;Sundaresan et al, 1995). Our experiments, as also shown in Fig.…”

Section: +supporting

confidence: 77%

Ca2+ oscillation frequency regulates agonist-stimulated gene expression in vascular endothelial cells

Zhu

Luo

Chen

et al. 2008

Journal of Cell Science

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A physiological membrane-receptor agonist typically stimulates oscillations, of varying frequencies, in cytosolic Ca2+ concentration ([Ca2+]i). Whether and how [Ca2+]i oscillation frequency regulates agonist-stimulated downstream events, such as gene expression, in non-excitable cells remain unknown. By precisely manipulating [Ca2+]i oscillation frequency in histamine-stimulated vascular endothelial cells (ECs), we demonstrate that the gene expression of vascular cell adhesion molecule 1 (VCAM1) critically depends on [Ca2+]i oscillation frequency in the presence, as well as the absence, of histamine stimulation. However, histamine stimulation enhanced the efficiency of [Ca2+]i-oscillation-frequency-regulated VCAM1 gene expression, versus [Ca2+]i oscillations alone in the absence of histamine stimulation. Furthermore, a [Ca2+]i oscillation frequency previously observed to be the mean frequency in histamine-stimulated ECs was found to optimize VCAM1 mRNA expression. All the above effects were abolished or attenuated by blocking histamine-stimulated generation of intracellular reactive oxygen species (ROS), another intracellular signaling pathway, and were restored by supplementary application of a low level of H2O2. Endogenous NF-κB activity is similarly regulated by [Ca2+]i oscillation frequency, as well as its co-operation with ROS during histamine stimulation. This study shows that [Ca2+]i oscillation frequency cooperates with ROS to efficiently regulate agonist-stimulated gene expression, and provides a novel and general strategy for studying [Ca2+]i signal kinetics in agonist-stimulated downstream events.

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Section: +supporting

confidence: 77%

Ca2+ oscillation frequency regulates agonist-stimulated gene expression in vascular endothelial cells

Zhu

Luo

Chen

et al. 2008

Journal of Cell Science

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“…Studies have demonstrated that the neurotoxic effects of 6-OHDA involve generation of hydrogen peroxide and hydroxyl radicals [15], reduction in glutathione (GSH) and SOD activity [16] and an increase in MDA levels in the striatum [17]. In addition, it has been shown that 6-OHDA is toxic to mitochondrial complex I, and leads to production of superoxide free radicals [18,19] and those molecular mechanisms of 6-OHDA-induced cytotoxicity involve hydrogen peroxidedependent and -independent action [20].…”

Section: Introductionmentioning

confidence: 99%

Effects of right-unilateral 6-hydroxydopamine infusion-induced memory impairment and oxidative stress: relevance for Parkinson’s disease

2008

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Male Wistar rats were subjected to right-unilateral 6-hydroxydopamine (6-OHDA) (2 µg/µl) lesions of the ventral tegmental area (VTA) or the substantia nigra (SN), or were sham-operated, and their ability to acquire the operant task was studied by means of Y-maze and shuttle-box tasks. Lesions of both the VTA and the SN resulted in an impairment of conditioned avoidance response and increase of crossing latency tested by means of shuttle-box task, suggesting significant effects of long-term memory. 6-OHDA significantly decreased spontaneous alternation in Y-maze task, suggesting effects on spatial memory, especially on short-term memory. In addition, 6-OHDA lesions of the VTA and the SN induced reductions in superoxide dismutase (SOD), glutathione peroxidase (GPX) activities and malondialdehyde (MDA) levels in the temporal lobe rather than in the frontal lobe homogenates. Our results provide further support for the toxic effects of 6-OHDA-induced memory impairment and oxidative stress with relevance for Parkinson's disease.

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“…Saito et al studied the dose-dependent effect of 6-OHDA on PC12 cell viability. 24 In this study, complete cell death was observed when the cells were treated with 100 M concentration of 6-OHDA for 24 h. 24 However, Jin et al reported only ϳ20% decrease in PC12 cell viability under the same condition. 25 The difference in the efficiency of the toxin in these studies can be attributed to the oxidation of 6-OHDA, which may result in its deactivation in the medium.…”

Section: Resultsmentioning

confidence: 57%

A microfluidic-based neurotoxin concentration gradient for the generation of an in vitro model of Parkinson’s disease

et al. 2011

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In this study, we developed a miniaturized microfluidic-based high-throughput cell toxicity assay to create an in vitro model of Parkinson's disease ͑PD͒. In particular, we generated concentration gradients of 6-hydroxydopamine ͑6-OHDA͒ to trigger a process of neuronal apoptosis in pheochromocytoma PC12 neuronal cell line. PC12 cells were cultured in a microfluidic channel, and a concentration gradient of 6-OHDA was generated in the channel by using a back and forth movement of the fluid flow. Cellular apoptosis was then analyzed along the channel. The results indicate that at low concentrations of 6-OHDA along the gradient ͑i.e., approximately less than 260 M͒, the neuronal death in the channel was mainly induced by apoptosis, while at higher concentrations, 6-OHDA induced neuronal death mainly through necrosis. Thus, this concentration appears to be useful for creating an in vitro model of PD by inducing the highest level of apoptosis in PC12 cells. As microfluidic systems are advantageous in a range of properties such as throughput and lower use of reagents, they may provide a useful approach for generating in vitro models of disease for drug discovery applications.

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Molecular mechanisms of 6-hydroxydopamine-induced cytotoxicity in PC12 cells: Involvement of hydrogen peroxide-dependent and -independent action

Cited by 155 publications

References 45 publications

Ca2+ oscillation frequency regulates agonist-stimulated gene expression in vascular endothelial cells

Ca2+ oscillation frequency regulates agonist-stimulated gene expression in vascular endothelial cells

Effects of right-unilateral 6-hydroxydopamine infusion-induced memory impairment and oxidative stress: relevance for Parkinson’s disease

A microfluidic-based neurotoxin concentration gradient for the generation of an in vitro model of Parkinson’s disease

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