α-Crystallin Downregulates the Expression of TNF-α and iNOS by Activated Rat Retinal Microglia in vitro and in vivo

Wu, Nan; Wang, Yanhua; Zhao, Haisheng; Liu, Dongning; Xiao, Ying; Yin, Zhengqin; Wang, Yi

doi:10.1159/000219681

Cited by 28 publications

(13 citation statements)

References 59 publications

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“…Previous studies showed an important role of iNOS and COX-2 in the pathogenesis of RGC loss after crush injury [15, 17, 19, 37]. NO produced by iNOS in activated inflammatory cells, microglia or injured neurons contributes to cytotoxicity resulting in neuron death and axonal damage [38, 39].…”

Section: Discussionmentioning

confidence: 99%

“…Reactive Muller cell and astrocyte upregulating GFAP and become hypertrophic in response to injury [13, 14]. Activated glia has been showed to release multiple inflammatory mediators, such as TNF-α, IL-6, IL-1β, MCP-1, iNOS, and COX-2 [15–19]. Nitric oxide synthase inhibitors and anti-inflammatory cytokines have been used to rescue RGC from apoptosis through inhibiting microglial activation after axon injury [20–22].…”

Section: Introductionmentioning

confidence: 99%

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Oroxylin A promotes retinal ganglion cell survival in a rat optic nerve crush model

Lin¹,

Chien²,

Kapupara³

et al. 2017

PLoS ONE

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PurposeTo investigate the effect of oroxylin A on the survival of retinal ganglion cells (RGC) and the activation of microglial cells in a rat optic nerve (ON) crush model.MethodsOroxylin A (15mg/Kg in 0.2ml phosphate-buffered saline) or phosphate-buffered saline (PBS control) was immediately administered after ON crush once by subcutaneous injection. Rats were euthanized at 2 weeks after the crush injury. The density of RGC was counted by retrograde labeling with FluoroGold and immunostaining of retina flat mounts for Brn3a. Electrophysiological visual function was assessed by flash visual evoked potentials (FVEP). TUNEL assay, immunoblotting analysis of glial fibrillary acidic protein (GFAP), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the retinas, and immunohistochemistry of GFAP in the retinas and ED1 in the ON were evaluated.ResultsTwo weeks after the insult, the oroxylin A-treated group had significantly higher FG labeled cells and Brn3a+ cells suggesting preserved RGC density in the central and mid-peripheral retinas compared with those of the PBS-treated group. FVEP measurements showed a significantly better preserved latency of the P1 wave in the ON-crushed, oroxylin A-treated rats than the ON-crushed, PBS treated rats. TUNEL assays showed fewer TUNEL positive cells in the ON-crushed, oroxylin A-treated rats. The number of ED1 positive cells was reduced at the lesion site of the optic nerve in the ON-crushed, oroxylin A-treated group. Increased GFAP expression in the retina was reduced greatly in ON-crushed, oroxylin A-treated group. Furthermore, administration of oroxylin A significantly attenuated ON crush insult-induced iNOS and COX-2 expression in the retinas.ConclusionsThese results demonstrated that oroxylin A hasss neuroprotective effects on RGC survival with preserved visual function and a decrease in microglial infiltration in the ONs after ON crush injury.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Oroxylin A promotes retinal ganglion cell survival in a rat optic nerve crush model

Lin¹,

Chien²,

Kapupara³

et al. 2017

PLoS ONE

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show abstract

“…In these studies, alpha-crystallin administration prior to, or at the time of the injury, prevented retinal ganglion cell axon degeneration and decreased microglial activation, as shown by prevention of the upregulation of TNF-alpha and iNOS production (Wu et al 2009; Ying et al 2008). Interestingly, another set of publications demonstrated that fragments of alpha- or beta-crystallin could regulate crystallin functions, including their chaperone function.…”

Section: Crystallins and Therapiesmentioning

confidence: 97%

New focus on alpha-crystallins in retinal neurodegenerative diseases

Fort

Lampi

2011

Experimental Eye Research

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The crystallin proteins were initially identified as structural proteins of the ocular lens and have been recently demonstrated to be expressed in normal retina. They are dramatically upregulated by a large range of retinal diseases including diabetic retinopathy, age-related macular degeneration, uveitis, trauma and ischemia. The crystallin family of proteins is composed of alpha-, beta- and gamma-crystallin. Alpha-crystallins, which are small heat shock proteins, have received substantial attention recently. This review summarizes the current knowledge of alpha-crystallins in retinal diseases, their roles in retinal neuron cell survival and retinal inflammation, and the regulation of their expression and activity. Their potential role in the development of new treatments for neurodegenerative diseases is also discussed.

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“…In crystallin treated animals, RGC numbers in animals injured by optic nerve crush were significantly increased compared to that in saline-injected group: 124±26 cells/mm 2 , 128±31 cells/mm 2 , and 164±20 cells/mm 2 were survived in animals treated with 0.05 g/kg, 0.5 g/kg and 5 g/kg of alpha crystallin, respectively. The cell protective effect of alpha crystallin was aassociated with the inhibition of microglial activation and TNF-α/iNOS release (Wu et al, 2009; 2014). …”

Section: Crystallins Support Rgc Survival and Axon Regenerationmentioning

confidence: 99%

Heat shock proteins in the retina: Focus on HSP70 and alpha crystallins in ganglion cell survival

Piri

Kwong

et al. 2016

Progress in Retinal and Eye Research

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Heat shock proteins (HSPs) belong to a superfamily of stress proteins that are critical constituents of a complex defense mechanism that enhances cell survival under adverse environmental conditions. Cell protective roles of HSPs are related to their chaperone functions, antiapoptotic and antinecrotic effects. HSPs' antiapoptotic and cytoprotective characteristics, their ability to protect cells from a variety of stressful stimuli, and the possibility of their pharmacological induction in cells under pathological stress make these proteins an attractive therapeutic target for various neurodegenerative diseases; these include Alzheimer's, Parkinson's, Huntington's, prion disease, and others. This review discusses the possible roles of HSPs, particularly HSP70 and small HSPs (alpha A and alpha B crystallins) in enhancing the survival of retinal ganglion cells (RGCs) in optic neuropathies such as glaucoma, which is characterized by progressive loss of vision caused by degeneration of RGCs and their axons in the optic nerve. Studies in animal models of RGC degeneration induced by ocular hypertension, optic nerve crush and axotomy show that upregulation of HSP70 expression by hyperthermia, zinc, geranyl-geranyl acetone, 17-AAG (a HSP90 inhibitor), or through transfection of retinal cells with AAV2-HSP70 effectively supports the survival of injured RGCs. RGCs survival was also stimulated by overexpression of alpha A and alpha B crystallins. These findings provide support for translating the HSP70- and alpha crystallin-based cell survival strategy into therapy to protect and rescue injured RGCs from degeneration associated with glaucomatous and other optic neuropathies.

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α-Crystallin Downregulates the Expression of TNF-α and iNOS by Activated Rat Retinal Microglia in vitro and in vivo

Cited by 28 publications

References 59 publications

Oroxylin A promotes retinal ganglion cell survival in a rat optic nerve crush model

Oroxylin A promotes retinal ganglion cell survival in a rat optic nerve crush model

New focus on alpha-crystallins in retinal neurodegenerative diseases

Heat shock proteins in the retina: Focus on HSP70 and alpha crystallins in ganglion cell survival

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