SIRT1 Activation Confers Neuroprotection in Experimental Optic Neuritis

Shindler, Kenneth S.; Ventura, Elvira; Rex, Tonia S.; Elliott, Peter J.; Rostami, Abdolmohamad

doi:10.1167/iovs.07-0131

Cited by 157 publications

(172 citation statements)

References 51 publications

(15 reference statements)

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“…In the relapsing-remitting model, we have previously found that activation of the SIRT1 deacetylase prevents RGC loss during acute optic neuritis, and these effects occur when SIRT1 activators are administered at day 11, after inflammation has begun (Shindler et al, 2007). In support of the current observations that axonal injury mediates RGC loss, SIRT1 activation was found to preserve functional axons following optic neuritis (Shindler et al, 2007).…”

Section: Discussionsupporting

confidence: 82%

“…Since optic neuritis patients do not present with symptoms until inflammation begins, the observed effects of glatiramer acetate in experimental optic neuritis may have limited clinical application, and consistent with this, immunomodulatory therapies like glatiramer acetate and interferon-β, the most widely used medications for multiple sclerosis, have only limited ability to prevent long term neurodegeneration and neurological disability (Parry et al, 2003). In the relapsing-remitting model, we have previously found that activation of the SIRT1 deacetylase prevents RGC loss during acute optic neuritis, and these effects occur when SIRT1 activators are administered at day 11, after inflammation has begun (Shindler et al, 2007). In support of the current observations that axonal injury mediates RGC loss, SIRT1 activation was found to preserve functional axons following optic neuritis (Shindler et al, 2007).…”

Section: Discussionmentioning

confidence: 90%

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Inflammatory demyelination induces axonal injury and retinal ganglion cell apoptosis in experimental optic neuritis

Shindler

Ventura

Dutt

et al. 2008

Experimental Eye Research

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139

136

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Optic neuritis is an inflammatory disease of the optic nerve that often occurs in patients with multiple sclerosis and leads to permanent visual loss mediated by retinal ganglion cell (RGC) damage. Optic neuritis occurs with high frequency in relapsing-remitting experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, with significant loss of RGCs. In the current study, mechanisms of RGC loss in this model were examined to determine whether inflammation-induced axonal injury mediates apoptotic death of RGCs. RGCs were retrogradely labeled by injection of fluorogold into superior colliculi of 6-7 week old female SJL/J mice. EAE was induced one week later by immunization with proteolipid protein peptide. Optic neuritis was detected by inflammatory cell infiltration on histological examination as early as 9 days after immunization, with peak incidence by day 12. Demyelination occurred 1-2 days after inflammation began. Loss of RGC axons was detected following demyelination, with significant axonal loss occurring by day 13 post-immunization. Axonal loss occurred prior to loss of RGC bodies at day 14. Apoptotic cells were also observed at day 14 in the ganglion cell layer of eyes with optic neuritis, but not control eyes. Together these results suggest that inflammatory cell infiltration mediates demyelination and leads to direct axonal injury in this model of experimental optic neuritis. RGCs die by an apoptotic mechanism triggered by axonal injury. Potential neuroprotective therapies to prevent permanent RGC loss from optic neuritis will likely need to be initiated prior to axonal injury to preserve neuronal function.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 90%

Inflammatory demyelination induces axonal injury and retinal ganglion cell apoptosis in experimental optic neuritis

Shindler

Ventura

Dutt

et al. 2008

Experimental Eye Research

Self Cite

139

136

View full text Add to dashboard Cite

show abstract

“…Sirtuins (SIRT), class III family members of HDAC, have been raised as one of the candidate molecules that may serve as a therapeutic target to treat axonal degeneration in MS. Intravitreal administration of SIRT1 activator, SRT647 and SRT501, was shown to ameliorate retinal ganglion cell loss in PLP [139][140][141][142][143][144][145][146][147][148][149][150][151] -induced EAE within the SJL/J mouse model [80]. The same group also administered an oral dose of resveratrol, another SIRT1 activator and demonstrated neuroprotection in the same EAE model.…”

Section: Mechanisms Of Axonal Injury and Degeneration During Ms Energmentioning

confidence: 99%

Axonal degeneration in multiple sclerosis: can we predict and prevent permanent disability?

Lee

Taghian

Petratos

2014

Acta Neuropathol Commun

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Axonal degeneration is a major determinant of permanent neurological impairment during multiple sclerosis (MS). Due to the variable course of clinical disease and the heterogeneity of MS lesions, the mechanisms governing axonal degeneration may differ between disease stages. While the etiology of MS remains elusive, there now exist potential prognostic biomarkers that can predict the conversion to clinically definite MS. Specialized imaging techniques identifying axonal injury and drop-out are becoming established in clinical practice as a predictive measure of MS progression, such as optical coherence tomography (OCT) or diffusion tensor imaging (DTI). However, these imaging techniques are still being debated as predictive biomarkers since controversy surrounds their lesion-specific association with expanded disability status scale (EDSS). A more promising diagnostic measure of axonal degeneration has been argued for the detection of reduced N-acetyl aspartate (NAA) and Creatine ratios via magnetic resonance spectroscopic (MRS) imaging, but again fail with its specificity for predicting actual axonal degeneration. Greater accuracy of predictive biomarkers is therefore warranted and may include CSF neurofilament light chain (NF-L) and neurofilament heavy chain (NF-H) levels, for progressive MS. Furthermore, defining the molecular mechanisms that occur during the neurodegenerative changes in the various subgroups of MS may in fact prove vital for the future development of efficacious neuroprotective therapies. The clinical translation of a combined Na + and Ca 2+ channel blocker may lead to the establishment of a bona fide neuroprotective agent for the treatment of progressive MS. However, more specific therapeutic targets to limit axonal damage in MS need investigation and may include such integral axonal proteins such as the collapsin response mediator protein-2 (CRMP-2), a molecule which upon post-translational modification may propagate axonal degeneration in MS. In this review, we discuss the current clinical determinants of axonal damage in MS and consider the cellular and molecular mechanisms that may initiate these neurodegenerative changes. In particular we highlight the therapeutic candidates that may formulate novel therapeutic strategies to limit axonal degeneration and EDSS during progressive MS.

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“…231 These mechanisms of SIRT1 activation have therefore set the foundation for potential neuroprotective interventions. Calorie restriction is one such established method of improving mitochondrial biogenesis, 232 respiration, 233 and reduction of reactive oxygen species production through upregulation of SIRT1.…”

Section: Regulation Of Mitochondrial Biogenesis As a Therapeutic Targetmentioning

confidence: 99%

Mitochondrial disorders and the eye

Bergen

Chakrabarti

O'Neill

et al. 2011

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Abstract:The clinical significance of disturbed mitochondrial function in the eye has emerged since mitochondrial DNA (mtDNA) mutation was described in Leber's hereditary optic neuropathy. The spectrum of mitochondrial dysfunction has become apparent through increased understanding of the contribution of nuclear and somatic mtDNA mutations to mitochondrial dynamics and function. Common ophthalmic manifestations of mitochondrial dysfunction include optic atrophy, pigmentary retinopathy, and ophthalmoplegia. The majority of patients with ocular manifestations of mitochondrial disease also have variable central and peripheral nervous system involvement. Mitochondrial dysfunction has recently been associated with agerelated retinal disease including macular degeneration and glaucoma. Therefore, therapeutic targets directed at promoting mitochondrial biogenesis and function offer a potential to both preserve retinal function and attenuate neurodegenerative processes.

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SIRT1 Activation Confers Neuroprotection in Experimental Optic Neuritis

Cited by 157 publications

References 51 publications

Inflammatory demyelination induces axonal injury and retinal ganglion cell apoptosis in experimental optic neuritis

Inflammatory demyelination induces axonal injury and retinal ganglion cell apoptosis in experimental optic neuritis

Axonal degeneration in multiple sclerosis: can we predict and prevent permanent disability?

Mitochondrial disorders and the eye

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