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Role of apoptosis signal-regulating kinase 1 in stress-induced neural cell apoptosis in vivo.

Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu, Tokyo 183-8526, Japan.
American Journal Of Pathology (Impact Factor: 4.6). 02/2006; 168(1):261-9. DOI: 10.2353/ajpath.2006.050765
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ABSTRACT Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays an important role in oxidative stress-induced apoptosis. In the present study, we used ASK1 knockout (KO) mice to examine the possibility that ASK1 is involved in the neural cell apoptosis that occurs during retinal development and ischemic injury. ASK1 was expressed in retinal neurons, including retinal ganglion cells (RGCs), but retinal structure and extent of cell death during development were normal in ASK1 KO mice. On the other hand, the strain was less susceptible to ischemic injury, and the number of surviving retinal neurons was significantly increased compared with that in wild-type mice. Interestingly, ischemia-induced phosphorylation of p38 mitogen-activated protein kinase (p38), which mediates RGC apoptosis, was almost completely suppressed in ASK1 KO mice. In such retinas, the numbers of cleaved caspase-3- and TUNEL-positive neurons were apparently decreased compared with those in wild-type mice. Furthermore, cultured RGCs from ASK1 KO mice were resistant to H(2)O(2)-induced apoptosis. Our findings suggest that ASK1 is involved in the neural cell apoptosis after various kinds of oxidative stress. Thus, inhibition of the ASK1-p38 pathway could be useful for the treatment of neurodegenerative diseases including glaucoma.

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    • "A microscopic image of each section within 0.5–1 mm from the optic disc was scanned. The RGC number and the extent of retinal degeneration were quantified in two ways [5] [7]. First, the number of neurons in the ganglion cell layer (GCL) was counted from one ora serrata through the optic nerve to the other ora serrata. "
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    ABSTRACT: The dedicator of cytokinesis 3 (Dock3) is an atypical guanine nucleotide exchange factor that is predominantly expressed in the CNS. Dock3 exerts neuroprotective effects and stimulates optic nerve regeneration. The p38 mitogen-activated protein kinase acts downstream of apoptosis signal-regulating kinase 1 (ASK1) signaling and plays an important role in neural cell death. We assessed a therapeutic efficacy of Dock3 stimulation and p38 inhibition in retinal degeneration induced by optic nerve injury (ONI). In vivo retinal imaging using optical coherence tomography revealed that ONI-induced retinal degeneration was ameliorated in SB203580 (a p38 inhibitor)-treated WT mice and PBS-treated Dock3 overexpressing (Dock3 Tg) mice, and SB203580 further stimulated retinal protection in Dock3 Tg mice. In addition, SB203580 increased the number of regenerating axons after ONI in both WT and Dock3 Tg mice. ONI-induced phosphorylation of ASK1, p38 and the N-methyl-d-aspartate receptor 2B subunit were suppressed in the retina of Dock3 Tg mice. Inhibition of the ASK1 pathway in Dock3 Tg mice suggests that Dock3 may have an antioxidant-like property. These results indicate that overexpression of Dock3 and pharmacological interruption of p38 have synergistic effects for both neuroprotection and axon regeneration, thus combined application may be beneficial for the treatment of ONI.
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    • "Combined, these studies suggest that an upstream activator common to the stress pathways, like ASK1 (apoptosis signal-regulating kinase 1), could be a primary step in RGC degeneration in glaucoma. If so, it is possible that an early insult stems from mitochondrial dysfunction induced by oxidative stress (Nguyen et al., 2011; Osborne, 2010), which is sufficient to activate the ASK1- p38 MAPK pathway in the retina (Harada et al., 2006). Interestingly, ASK1 is predominantly expressed in RGCs and has been linked to optic nerve degeneration (Harada et al., 2010). "
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    • "However, when 6-OHDA-induced ROS generation was blocked by NAC, three MAPKs activities and apoptosis were decreased markedly (Fig. 6), while Asx inhibited only p38 MAPK activation (Fig. 4a). An increasing body of the evidence indicated that apoptosis signal-regulating kinase 1, a member of MAPK family, acts upstream of p38 MAPK and JNK1/2 in neuronal cell death induced by ROS (Harada et al. 2006; Ouyang and Shen 2006; Pan et al. 2007). These findings along with the present results raise intriguing possibility that Asx directly suppress not apoptosis signalregulating kinase 1 but p38 MAPK activation. "
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    ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta. Although understanding of the pathogenesis of PD remains incomplete, increasing evidence from human and animal studies has suggested that oxidative stress is an important mediator in its pathogenesis. Astaxanthin (Asx), a potent antioxidant, has been thought to provide health benefits by decreasing the risk of oxidative stress-related diseases. This study examined the protective effects of Asx on 6-hydroxydopamine (6-OHDA)-induced apoptosis in the human neuroblastoma cell line SH-SY5Y. Pre-treatment of SH-SY5Y cells with Asx suppressed 6-OHDA-induced apoptosis in a dose-dependent manner. In addition, Asx strikingly inhibited 6-OHDA-induced mitochondrial dysfunctions, including lowered membrane potential and the cleavage of caspase 9, caspase 3, and poly(ADP-ribose) polymerase. In western blot analysis, 6-OHDA activated p38 MAPK, c-jun NH(2)-terminal kinase 1/2, and extracellular signal-regulated kinase 1/2, while Asx blocked the phosphorylation of p38 MAPK but not c-jun NH(2)-terminal kinase 1/2 and extracellular signal-regulated kinase 1/2. Pharmacological approaches showed that the activation of p38 MAPK has a critical role in 6-OHDA-induced mitochondrial dysfunctions and apoptosis. Furthermore, Asx markedly abolished 6-OHDA-induced reactive oxygen species generation, which resulted in the blockade of p38 MAPK activation and apoptosis induced by 6-OHDA treatment. Taken together, the present results indicated that the protective effects of Asx on apoptosis in SH-SY5Y cells may be, at least in part, attributable to the its potent antioxidative ability.
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