Abstract
Dopamine (DA) is a well known oxidative neurotoxin. In addition, Akt has been reported to deliver a survival signal that inhibits apoptosis. However, it has also been reported that chronic Akt activation leads to apoptosis in response to oxidative stress. The objective of the present study was to investigate the possible role of the Akt pathway in vitiligo and its possible relationship with DA‐induced cell death using Mel‐Ab cells. Cultured Mel‐Ab cells were treated with DA with and without N‐Acetyl‐L‐cysteine (NAC), which is known to have antioxidative properties. Cell viability was then assessed by a crystal violet assay and Annexin staining was performed. The changes in the expression of Akt were analyzed by western blot analysis. The cell viability was reduced by approximately 60% in response to treatment with 500 µM DA, and NAC effectively prevented this cytotoxic effect. Likewise, treatment with DA produced numerous Annexin positive cells, while treatment with NAC prevented this apoptotic cell death. Akt was slowly phosphorylated after treatment with DA, while NAC clearly inhibited the DA‐induced Akt activation. Western blot analysis also showed that treatment with DA induced the activation of Bad. Finally, LY294002 exerted a protective effect against DA‐induced apoptotic cell death. DA may induce redox‐sensitive Akt activation and increase the level of Bad, which can promote cell death by heterodimerization with survival proteins. Moreover, NAC effectively protects against DA‐induced melanocyte death via inhibition of DA‐induced Akt activation.
Highlights
Oxidative stress has been implicated in the pathophysiology of multiple human diseases.[1]
We previously reported that melanocytes were susceptible to DA, and that thiol compounds such as N-acetyl-L-cysteine (NAC) effectively protected against DA-induced melanocyte cell death.[8]
The cell viability was reduced by approximately 60% in response to treatment with 500 μM DA; this concentration was chosen for further experiments (Fig. 1A)
Summary
Oxidative stress has been implicated in the pathophysiology of multiple human diseases.[1] oxidative stress is regarded as a mediator of nerve cell death in several neurodegenerative disorders.[2]. Vitiligo is characterized by the selective destruction of melanocytes which had been derived from neuroectoderm. Dopamine (DA) is a wellknown neurotoxin that plays an etiologic role in neurodegenerative disorders such as Parkinson’s disease, and it has been reported that DA induces oxidative stress and neuronal cell death.[3,4] Neural factors have long been suspected to contribute to the development of vitiligo, and catecholamines such as norepinephrine, epinephrine, and DA and their metabolites have been found to be elevated in the urine and plasma of vitiligo patients.[5,6,7] We previously reported that melanocytes were susceptible to DA, and that thiol compounds such as N-acetyl-L-cysteine (NAC) effectively protected against DA-induced melanocyte cell death.[8] Using this model, the role of Akt in DA-induced cell death was investigated
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