title: Calcium influx and calpain activation mediate preclinical retinal neurodegeneration in autoimmune optic neuritis.
abstract: 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.
authors.affiliation: Department of Neurology, University of the Saarland, Homburg/Saar, Germany.
authors.forename: Dorit B
authors.initials: DB
authors.lastname: Hoffmann
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Williams
authors.forename: Jovana
authors.initials: J
authors.lastname: Bojcevski
authors.forename: Andreas
authors.initials: A
authors.lastname: Müller
authors.forename: Christine
authors.initials: C
authors.lastname: Stadelmann
authors.forename: Vinogran
authors.initials: V
authors.lastname: Naidoo
authors.forename: Ben A
authors.initials: BA
authors.lastname: Bahr
authors.forename: Ricarda
authors.initials: R
authors.lastname: Diem
authors.forename: Richard
authors.initials: R
authors.lastname: Fairless
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D002712:Chlorides / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D053331:Ectodysplasins / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000150:complications / Q000276:immunology; D005260:Female; D008279:Magnetic Resonance Imaging; D017895:Manganese Compounds / Q000494:pharmacology; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D009410:Nerve Degeneration / Q000209:etiology* / Q000517:prevention & control; D058632:Neuroprostanes / Q000494:pharmacology / Q000627:therapeutic use; D009900:Optic Nerve / Q000187:drug effects / Q000473:pathology; D009902:Optic Neuritis / Q000150:complications* / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D051381:Rats; D012160:Retina / Q000473:pathology*; D012165:Retinal Ganglion Cells / Q000473:pathology*; D013997:Time Factors
chemical_list: D016564:Amyloid beta-Protein Precursor; D002712:Chlorides; D004151:Dipeptides; D053331:Ectodysplasins; D017895:Manganese Compounds; D063308:Myelin-Oligodendrocyte Glycoprotein; D058632:Neuroprostanes; C071482:calpeptin; D002154:Calpain; C025340:manganese chloride; D002118:Calcium