Protein kinase C mediates peroxynitrite toxicity to oligodendrocytes

Li, Shihe; Lin, Wen Chun; Tchantchou, Flaubert; Lai, Ruby; Wen, Jie; Zhang, Yumin

doi:10.1016/j.mcn.2011.06.006

Cited by 15 publications

(9 citation statements)

References 45 publications

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“…We next examined the possible contribution of oxidative stress to AMPA‐induced [Zn 2+ ] i mobilization. Consistent with previous reports (Li et al, ; Zhang et al, ), bath application of the peroxynitrite generator SIN‐1 (500 μM) led to an increase in FluoZin‐3 fluorescence (Fig. A), further suggesting that optic nerve oligodendrocytes are sensitive to oxidant‐induced intracellular Zn 2+ release.…”

Section: Resultssupporting

confidence: 91%

“…Oligodendrocyte precursors seem to possess a high‐affinity Zn 2+ uptake mechanism (Law et al, ), and anatomical studies suggest the expression of ZIP‐1 and ZnT‐1 in white matter tracts (Belloni‐Olivi et al, ; Nitzan et al, ; Sekler et al, ). Supporting the physiopathological relevance of Zn 2+ dyshomeostasis in oligodendrocytes, these cells are vulnerable to extracellular Zn 2+ insults (Kelland et al, ) and to cytosolic Zn 2+ rises resulting from intracellular release, as the cytotoxic effects of peroxynitrite, a powerful oxidant that contributes to white matter damage in multiple sclerosis and spinal cord injury (Li et al, ; Xiong and Hall ), are initiated by Zn 2+ liberation from cytosolic pools (Li et al, ; Zhang et al, ).…”

Section: Introductionmentioning

confidence: 96%

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Cytosolic zinc accumulation contributes to excitotoxic oligodendroglial death

Mato

Sánchez‐Gómez

Bernal‐Chico

et al. 2013

Glia

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Dyshomeostasis of cytosolic Zn(2+) is a critical mediator of neuronal damage during excitotoxicity. However, the role of this cation in oligodendrocyte pathophysiology is not well understood. The current study examined the contribution of Zn(2+) deregulation to oligodendrocyte injury mediated by AMPA receptors. Oligodendrocytes loaded with the Zn(2+)-selective indicator FluoZin-3 responded to mild stimulation of AMPA receptors with fast cytosolic Zn(2+) rises that resulted from intracellular release, as they were not blocked by the extracellular Zn(2+) chelator Ca-EDTA. Pharmacological experiments suggested that AMPA-induced Zn(2+) mobilization depends on cytosolic Ca(2+) accumulation, arises from mitochondria and protein-bound pools, and is triggered by mechanisms that do not involve the generation of reactive oxygen species. Moreover, intracellular Zn(2+) rises resulting from AMPA receptor activation seem to be promoted by Ca(2+)-dependent cytosolic acidification. Addition of the cell-permeable Zn(2+) chelator TPEN significantly reduced mitochondrial membrane depolarization, reactive oxygen species production, and cell death by sub-maximal activation of AMPA receptors both in vitro and in situ, suggesting that Zn(2+) deregulation is an important mediator of oligodendrocyte excitotoxicity. These data provide evidence that strategies aimed at maintaining Zn(2+) homeostasis may be useful for the treatment of disorders in which excitotoxicity is an important trigger of oligodendroglial death.

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 96%

Cytosolic zinc accumulation contributes to excitotoxic oligodendroglial death

Mato

Sánchez‐Gómez

Bernal‐Chico

et al. 2013

Glia

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“…2005; Li et al. 2011). Alternatively, the NO donor effect enhances PKC interaction with its specific anchor protein RACK2 via nitration of tyrosine residues of PKC, resulting in its activation (Balafanova et al.…”

Section: Discussionmentioning

confidence: 99%

“…The precise mechanism by which NO causes PKCe activation is not known but several possibilities exist. NO reacts with superoxide anions to form peroxynitrite that can activate PKC (Reiter et al 2000;Chakraborti et al 2005;Li et al 2011). Alternatively, the NO donor effect enhances PKC interaction with its specific anchor protein RACK2 via nitration of tyrosine residues of PKC, resulting in its activation (Balafanova et al 2002).…”

Section: Effect Of Nos Inhibition On Propofol-and Aitc-induced Restormentioning

confidence: 99%

Propofol restores TRPV1 sensitivity via a TRPA1‐, nitric oxide synthase‐dependent activation of PKCε

Sinharoy

Zhang

Sinha

et al. 2015

Pharmacology Res & Perspec

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We previously demonstrated that the intravenous anesthetic, propofol, restores the sensitivity of transient receptor potential vanilloid channel subtype-1 (TRPV1) receptors via a protein kinase C epsilon (PKCε)-dependent and transient receptor potential ankyrin channel subtype-1 (TRPA1)-dependent pathway in sensory neurons. The extent to which the two pathways are directly linked or operating in parallel has not been determined. Using a molecular approach, our objectives of the current study were to confirm that TRPA1 activation directly results in PKCε activation and to elucidate the cellular mechanism by which this occurs. F-11 cells were transfected with complimentary DNA (cDNA) for TRPV1 only or both TRPV1 and TRPA1. Intracellular Ca2+ concentration was measured in individual cells via fluorescence microscopy. An immunoblot analysis of the total and phosphorylated forms of PKCε, nitric oxide synthase (nNOS), and TRPV1 was also performed. In F-11 cells containing both channels, PKCε inhibition prevented the propofol- and allyl isothiocyanate (AITC)-induced restoration of TRPV1 sensitivity to agonist stimulation as well as increased phosphorylation of PKCε and TRPV1. In cells containing TRPV1 only, neither agonist induced PKCε or TRPV1 phosphorylation. Moreover, NOS inhibition blocked propofol-and AITC-induced restoration of TRPV1 sensitivity and PKCε phosphorylation, and PKCε inhibition prevented the nitric oxide donor, SNAP, from restoring TRPV1 sensitivity. Also, propofol-and AITC-induced phosphorylation of nNOS and nitric oxide (NO) production were blocked with the TRPA1-antagonist, HC-030031. These data indicate that the AITC- and propofol-induced restoration of TRPV1 sensitivity is mediated by a TRPA1-dependent, nitric oxide synthase-dependent activation of PKCε.

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“…For culturing mature oligodendrocytes, cells at day 7 were changed to BDM plus T3 (15 nM) and ciliary neurotrophic factor (CNTF) (10 ng/ml) for another 2 weeks. This results in a culture where the purity of oligodendrocytes is more than 95%, and only 1-2% of cells are identified to be either microglia or astrocytes as described previously (Li et al, 2012).…”

Section: Oligodendrocyte Cell Culturementioning

confidence: 95%

Therapeutic potential of a novel cannabinoid agent CB52 in the mouse model of experimental autoimmune encephalomyelitis

Ribeiro

Wen

et al. 2013

Neuroscience

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Abstract-Multiple Sclerosis (MS) is a demyelinating disease which causes inflammation, demyelination, and axonal injury. Currently, there is no cure for the disease. The endocannabinoid system has recently emerged as a promising therapeutic target for MS. The protective mechanisms of cannabinoids are thought to be mediated by the activation of the cannabinoid type 1 (CB1) and type 2 (CB2) receptors expressed primarily in neurons and immune cells, respectively. However, the molecular mechanisms and the contribution of each receptor in ameliorating disease progression are still debatable. Although CB1 and CB2 receptors are expressed in oligodendrocytes, the myelin producing cells in the central nervous system, the role of cannabinoids in oligodendrocyte survival has not been well investigated. Using primary cultures of mature oligodendrocytes, we tested the effect of a novel synthetic cannabinoid CB52 on oligodendrocyte toxicity induced by peroxynitrite, the primary toxic species released by microglia. Interestingly, we found that CB52 is more potent than a number of broad and selective CB1 and CB2 agonists in protecting oligodendrocytes against peroxynitrite-induced toxicity. The protection provided by CB52 is likely due to its reduction of ERK1/2 phosphorylation and reactive oxygen species (ROS) generation in these cells. Using experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we found that CB52 reduces microglia activation, nitrotyrosine formation, T cell infiltration, oligodendrocyte toxicity, myelin loss and axonal damage in the mouse spinal cord white matter and alleviates the clinical scores when given either before or after disease onset. These effects are reversed by the CB1 receptor antagonist, but not by the CB2 receptor antagonist, suggesting that the activation of CB1 receptors contributes significantly to the anti-inflammatory and neuroprotective effects of cannabinoids on MS. Published by Elsevier Ltd. on behalf of IBRO.

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Protein kinase C mediates peroxynitrite toxicity to oligodendrocytes

Cited by 15 publications

References 45 publications

Cytosolic zinc accumulation contributes to excitotoxic oligodendroglial death

Cytosolic zinc accumulation contributes to excitotoxic oligodendroglial death

Propofol restores TRPV1 sensitivity via a TRPA1‐, nitric oxide synthase‐dependent activation of PKCε

Therapeutic potential of a novel cannabinoid agent CB52 in the mouse model of experimental autoimmune encephalomyelitis

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