Timing of Corticosteroid Therapy Is Critical to Prevent Retinal Ganglion Cell Loss in Experimental Optic Neuritis

Dutt, Mahasweta; Tabuena, Philomela; Ventura, Elvira; Rostami, Abdolmohamad; Shindler, Kenneth S.

doi:10.1167/iovs.09-4009

Cited by 39 publications

(30 citation statements)

References 22 publications

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“…A meta-analysis of use of methylprednisolone and other steroids in the recovery from multiple sclerosis exacerbations showed the superiority of methylprednisolone [14]. A study of a mouse model of optic neuropathy used dexamethasone and methylprednisolone, and found slightly better outcome with methylprednisolone [15]. These findings suggest that methylprednisolone is the first choice for steroid therapy.…”

Section: Discussionmentioning

confidence: 99%

Outcomes of surgically treated rhinogenic optic neuropathy

Nakaya

Oshima

Ikeda

et al. 2011

Acta Oto-Laryngologica

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Section: Discussionmentioning

confidence: 99%

Outcomes of surgically treated rhinogenic optic neuropathy

Nakaya

Oshima

Ikeda

et al. 2011

Acta Oto-Laryngologica

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“…Their role in brain and retina has multiple facets, as different neuronal phenotypes respond in opposite fashion. [35][36][37][38] The diverse roles of GRa on cell death and survival depend on differential modulation of pro-and antiapoptotic Bcl-2 family members. 39 As previously stated, the prosurvival effect of glucocorticoids is associated with increased expression of Bcl-X L , 17 the antiapoptotic molecule preferentially expressed by adult central and retinal neurons.…”

Section: Figure 5 (A)mentioning

confidence: 99%

Mifepristone, a Blocker of Glucocorticoid Receptors, Promotes Photoreceptor Death

Cubilla¹,

Bermúdez²,

Marquioni-Ramella³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Glucocorticoids are best known by their protective effect on retinal photoreceptor damage. However, they could also be involved in photoreceptor homeostasis under basal, nonstressful conditions. Therefore, we aimed to study glucocorticoid-induced changes of survival-related molecules in male mice retinas under standard illumination conditions (12 hours light, 60 lux/12 h dark).METHODS. Male Balb-c mice were injected with dexamethasone (DEX), a selective glucocorticoid receptor a (GRa) agonist, its antagonist mifepristone (MFP), or both drugs (DþM) at noon. A group of mice was subjected to surgical adrenalectomy (AdrX). Retinas were studied by histology, immunohistochemistry, TUNEL procedure, and Western blotting at different periods after pharmacological or surgical intervention (6 hours, 48 hours, or 7 days). RESULTS.The antiapoptotic molecule Bcl-X L significantly increased 6 hours after DEX injection. By contrast, this molecule could no longer be found after MFP injection. At the same time, high levels of cleaved caspase-3 (CC-3) and Bax appeared in retinal extracts, and TUNEL þ nuclei selectively showed in the outer nuclear layer (ONL). After MFP, retinal extracts also contained phosphorylated histone H2AX (p-H2AX), a marker of DNA breakage and repair. Loss of ONL nuclear rows and decrease of rhodopsin levels were evident 7 days after MFP administration. These changes were minimized when DEX was given together with MFP (DþM). In the absence of MFP, DEX increased Bcl-X L in every retinal layer, with a marked intensification in photoreceptor inner segments. Numerous TUNEL þ nuclei rapidly appeared in the ONL after AdrX. CONCLUSIONS.A single dose of MFP induced selective photoreceptor damage in the absence of other environmental stressors. Because damage was prevented by DEX, and was reproduced by AdrX, our findings suggest that glucocorticoids play a critical role in photoreceptor survival. (Invest Ophthalmol Vis Sci. 2013;54:313-322)

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“…EAE optic neuritis models have provided important insight into mechanisms of retinal ganglion cell (RGC) loss induced by inflammation, and have provided a means of examining potential therapies designed to preserve RGCs damaged during optic neuritis (Guy et al, 1998; Hobom et al, 2004; Shindler et al, 2007, 2008; Dutt et al, 2010). However, the development of optic neuritis is variable, with bilateral optic neuritis occurring in some animals, and unilateral or no optic neuritis in others (Shindler et al, 2006, 2008).…”

Section: Introductionmentioning

confidence: 99%

In vivo detection of experimental optic neuritis by pupillometry

Shindler

Revere

Dutt

et al. 2012

Experimental Eye Research

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Optic neuritis is an inflammatory demyelination of optic nerve often occurring in multiple sclerosis (MS) patients. Mice with experimental autoimmune encephalomyelitis (EAE), an MS model, develop optic neuritis, but it is detected histologically after sacrifice, limiting the ability to monitor progression or treatment in vivo. We examined whether pupillary light responses measured by pupillometry can identify eyes with optic neuritis in EAE mice. C57BL/6 mice were exposed to unilateral light flashes of increasing intensity at 10 second intervals (4.7, 37, and 300 μW/cm2). Pupillary responses were recorded with a commercially available pupillometer. EAE was then induced by immunization with myelin oligodendrocyte glycoprotein. Pupillometry was repeated up to 17 days post-immunization, and responses were correlated with optic nerve inflammation. By day 17 post-immunization, 90% of EAE eyes had optic nerve inflammation. EAE eyes had significantly reduced pupillary constriction compared to control eyes. Mice exhibited more than a 25% decrease in pupillary constriction in at least one eye by days 13-15 post-immunization. In some eyes, pupil responses decreased prior to onset of detectable inflammation. Results show that pupillometry detects decreased optic nerve function in experimental optic neuritis, even in the absence of histological detection. Measuring pupillary constriction allows in vivo identification and functional assessment of eyes with optic neuritis that will be useful in evaluating potential therapies over time. Furthermore, results demonstrate that decreased visual function occurs early in optic neuritis, before optic nerve inflammation reaches its peak level.

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Timing of Corticosteroid Therapy Is Critical to Prevent Retinal Ganglion Cell Loss in Experimental Optic Neuritis

Abstract: Corticosteroids can suppress optic neuritis and prevent RGC loss if treatment is initiated before optic nerve inflammation onset. Treatment is less effective after inflammation begins. Results suggest that chronic immunomodulation may prevent recurrent optic neuritis and RGC damage.

Cited by 39 publications

References 22 publications

Outcomes of surgically treated rhinogenic optic neuropathy

Outcomes of surgically treated rhinogenic optic neuropathy

Mifepristone, a Blocker of Glucocorticoid Receptors, Promotes Photoreceptor Death

In vivo detection of experimental optic neuritis by pupillometry

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