Preclinical retinal neurodegeneration in a model of multiple sclerosis

Fairless, Richard; Williams, Sarah K.; Hoffmann, Dorit; Stojic, Aleksandar; Hochmeister, Sonja; Schmitz, Frank; Storch, Maria K.; Diem, Ricarda

doi:10.5214/ans.0972.7531.190307

Cited by 13 publications

(22 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One week before immunization, RGCs were retrogradely labeled following a previously described procedure (15). At the various time points after immunization, rats were perfused with 4% paraformaldehyde (PFA).…”

Section: Retrograde Labeling and Quantification Of Rgcsmentioning

confidence: 99%

“…Using this model, we have previously shown using magnetic resonance imaging (MRI) that calcium influx can be detected in the optic nerves during the acute phase of optic neuritis (14). Based on our recent findings that neurodegeneration of the RGCs has already begun before the onset of clinical EAE/optic neuritis (15,16), we wanted to investigate the role of elevated intracellular calcium during the preclinical phase of the disease before the onset of demyelination.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Calcium Influx and Calpain Activation Mediate Preclinical Retinal Neurodegeneration in Autoimmune Optic Neuritis

Hoffmann

Williams

Bojcevski

et al. 2013

J Neuropathol Exp Neurol

Self Cite

View full text Add to dashboard Cite

Optic neuritis is a common manifestation of multiple sclerosis, an inflammatory demyelinating disease of the CNS. Recently, the neurodegenerative component of multiple sclerosis has come under focus particularly because permanent disability in patients correlates well with neurodegeneration; and observations in both humans and multiple sclerosis animal models highlight neurodegeneration of retinal ganglion cells as an early event. After myelin oligodendrocyte glycoprotein immunization of Brown Norway rats, significant retinal ganglion cell loss precedes the onset of pathologically defined autoimmune optic neuritis. To study the role calcium and calpain activation may play in mediating early degeneration, manganese-enhanced magnetic resonance imaging was used to monitor preclinical calcium elevations in the retina and optic nerve of myelin oligodendrocyte glycoprotein-immunized Brown Norway rats. Calcium elevation correlated with an increase in calpain activation during the induction phase of optic neuritis, as revealed by increased calpain-specific cleavage of spectrin. The relevance of early calpain activation to neurodegeneration during disease induction was addressed by performing treatment studies with the calpain inhibitor calpeptin. Treatment not only reduced calpain activity but also protected retinal ganglion cells from preclinical degeneration. These data indicate that elevation of retinal calcium levels and calpain activation are early events in autoimmune optic neuritis, providing a potential therapeutic target for neuroprotection.

show abstract

Section: Retrograde Labeling and Quantification Of Rgcsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Calcium Influx and Calpain Activation Mediate Preclinical Retinal Neurodegeneration in Autoimmune Optic Neuritis

Hoffmann

Williams

Bojcevski

et al. 2013

J Neuropathol Exp Neurol

Self Cite

View full text Add to dashboard Cite

show abstract

“…In autoimmune inflammatory diseases of the CNS such as multiple sclerosis (MS), which is characterized by perivascular infiltrates of autoreactive, encephalitogenic T cells and subsequent demyelination and neuronal loss, BBB disruption is a hallmark of acute inflammatory lesions (3). Although the question whether BBB disruption is a primary or secondary event in lesion evolution is still a matter of debate, there is increasing evidence from studies of human MS plaques (4) and animal models of MS, such as experimental autoimmune encephalomyelitis (EAE), that the BBB integrity is disturbed as an early event preceding the influx of pathogenic T cells (5,6). BBB disruption in inflammatory conditions of the CNS may result in permission of CNS penetrance of both cells and macromolecules, signified by leakage of contrast agents and perivascular inflammatory infiltrates in acute CNS lesion in MS and EAE.…”

mentioning

confidence: 99%

Protein kinase Cβ as a therapeutic target stabilizing blood–brain barrier disruption in experimental autoimmune encephalomyelitis

Lanz

Becker

Osswald³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Disruption of the blood-brain barrier (BBB) is a hallmark of acute inflammatory lesions in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis. This disruption may precede and facilitate the infiltration of encephalitogenic T cells. The signaling events that lead to this BBB disruption are incompletely understood but appear to involve dysregulation of tight-junction proteins such as claudins. Pharmacological interventions aiming at stabilizing the BBB in MS might have therapeutic potential. Here, we show that the orally available small molecule LY-317615, a synthetic bisindolylmaleimide and inhibitor of protein kinase Cβ, which is clinically under investigation for the treatment of cancer, suppresses the transmigration of activated T cells through an inflamed endothelial cell barrier, where it leads to the induction of the tight-junction molecules zona occludens-1, claudin 3, and claudin 5 and other pathways critically involved in transendothelial leukocyte migration. Treatment of mice with ongoing experimental autoimmune encephalomyelitis with LY-317615 ameliorates inflammation, demyelination, axonal damage, and clinical symptoms. Although LY-317615 dose-dependently suppresses T-cell proliferation and cytokine production independent of antigen specificity, its therapeutic effect is abrogated in a mouse model requiring pertussis toxin. This abrogation indicates that the anti-inflammatory and clinical efficacy is mainly mediated by stabilization of the BBB, thus suppressing the transmigration of encephalitogenic T cells. Collectively, our data suggest the involvement of endothelial protein kinase Cβ in stabilizing the BBB in autoimmune neuroinflammation and imply a therapeutic potential of BBB-targeting agents such as LY-317615 as therapeutic approaches for MS.

show abstract

“…Fairless et al reported that before manifestation of ON, degeneration of retinal ganglion cell bodies had already begun and ultrastructural signs of axon degeneration could be detected in a rat model. 11 Reis et al have found evidence for independent damage of retinocortical parallel pathways in patients with MS without previous ON, in distinction to the post-ON group in their study. 12 Gelfand et al performed spectral-domain optical coherence tomography (OCT) in eyes without ON and demonstrated that retinal axonal thinning begins early in the course of MS and independently of the occurrence of symptomatic ON.…”

Section: Discussionmentioning

confidence: 62%

Comparison of Visual Field Parameters in Early and Advanced Stages of Multiple Sclerosis Patients Without a History of Optic Neuritis

Güler

Türkçüoğlu²,

Yılmaz

et al. 2013

Neuro-Ophthalmology

View full text Add to dashboard Cite

This study compared the visual field parameters of multiple sclerosis patients without optic neuritis in early versus advanced stage of the disease. Patients were divided into two groups: group 1 (early stage, n = 14) constituted of patients with Expanded Disability Status Scale scores 53 and group 2 (advanced stage, n = 13) constituted of patients with Expanded Disability Status Scale scores !3. Mean visual acuities in both groups were similar (p = 0.674). Mean sensitivity, mean defect, loss of variance, reliability factor parameters (Octopus 101 perimeter) of groups 1 and 2 were 24.17 AE 3.62, 21.81 AE 3.04; 4.14 AE 3.05, 6.49 AE 2.58; 21.61 AE 22.17, 33.31 AE 18.67; and 1.57 AE 2.79, 2.59 AE 3.09, respectively. Compared with group 1, mean sensitivity was significantly lower in group 2 (p = 0.013). Mean defect (p = 0.004) and loss of variance (p = 0.042) parameters in group 2 were significantly higher than in group 1. Mean reliability factor was similar between two groups (p = 0.211). Multiple scleorisis may alter visual field parameters without severe loss of visual acuity by possibly involving optic pathways other than optic nerve.

show abstract

Preclinical retinal neurodegeneration in a model of multiple sclerosis

Cited by 13 publications

References 5 publications

Calcium Influx and Calpain Activation Mediate Preclinical Retinal Neurodegeneration in Autoimmune Optic Neuritis

Calcium Influx and Calpain Activation Mediate Preclinical Retinal Neurodegeneration in Autoimmune Optic Neuritis

Protein kinase Cβ as a therapeutic target stabilizing blood–brain barrier disruption in experimental autoimmune encephalomyelitis

Comparison of Visual Field Parameters in Early and Advanced Stages of Multiple Sclerosis Patients Without a History of Optic Neuritis

Contact Info

Product

Resources

About