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

• Published in: Journal of neuropathology and experimental neurology 2013-08, Vol.72 (8), p.745-757
• Main Authors: Hoffmann, Dorit B, Williams, Sarah K, Bojcevski, Jovana, Müller, Andreas, Stadelmann, Christine, Naidoo, Vinogran, Bahr, Ben A, Diem, Ricarda, Fairless, Richard
• Format: Article
• Language: English
• Subjects: Acquisitions & mergers; Amyloid beta-Protein Precursor - metabolism; Animal models; Animals; Aqueous solutions; Calcium - metabolism; Calpain - metabolism; Cell adhesion & migration; Chlorides - pharmacology; Dipeptides - pharmacology; Disease Models, Animal; Ectodysplasins - metabolism; Encephalomyelitis, Autoimmune, Experimental - chemically induced; Encephalomyelitis, Autoimmune, Experimental - complications; Encephalomyelitis, Autoimmune, Experimental - immunology; Female; Magnetic Resonance Imaging; Manganese Compounds - pharmacology; Medicin och hälsovetenskap; Multiple sclerosis; Myelin-Oligodendrocyte Glycoprotein - toxicity; Nerve Degeneration - etiology; Nerve Degeneration - prevention & control; Neurodegeneration; Neuroprostanes - pharmacology; Neuroprostanes - therapeutic use; NMR; Nuclear magnetic resonance; Optic nerve; Optic Nerve - drug effects; Optic Nerve - pathology; Optic Neuritis - complications; Optic Neuritis - drug therapy; Optic Neuritis - etiology; Optic Neuritis - pathology; Rats; Retina - pathology; Retinal Ganglion Cells - pathology; Rodents; Studies; Time Factors
• ISSN: 0022-3069; 1554-6578; 1554-6578
• DOI: 10.1097/NEN.0b013e31829c7370

ABSTRACTOptic 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.