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A. W. Smith, J. T. Butler, B. Rohrer, M. Azuma, J. Inoue, N. L. Banik; Calpain Inhibition Confers Histological and Functional Neuroprotection to Retinal Ganglion Cells in Experimental Optic Neuritis. Invest. Ophthalmol. Vis. Sci. 2010;51(13):821.
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© ARVO (1962-2015); The Authors (2016-present)
Optic neuritis (ON), inflammation of the optic nerve, is primarily due to influx of auto-reactive T cells and is manifested by visual dysfunction. Decreased amplitude of visual evoked potential (VEP) and pattern electroretinogram (PERG) responses in patients indicates degeneration of the optic nerve with subsequent retinal damage, respectively. We previously detected increased activity of calpain, a Ca2+-activated protease, in optic nerves and retinas of experimental autoimmune encephalomyelitis (EAE) animals. The roles of calpain in T cell chemotaxis, demyelination, and axonal degeneration are well established. Thus, we hypothesized that retrograde retinal ganglion cell (RGC) death will occur during EAE-induced ON, accompanied by loss of visual function, and early calpain inhibition will confer functional rescue.
B10.PL mice were immunized subcutaneously with an emulsion of complete Freund's adjuvant and myelin basic protein. Treated ON mice received twice daily oral dosing of 25mg/kg SNJ-1945 from day 9 post-induction until day 35. PERG analysis and enucleation of eyes for immunohistochemistry was executed on day 35.
PERG P1 amplitudes in response to a sinusoidal grating of low spatial (0.1c/d) and temporal (1Hz) frequency were compared. While amplitudes were markedly reduced in EAE mice treated with vehicle (2.1µV) when compared to control animals (4.7µV; P<0.05), EAE animals treated with SNJ-1945 were significantly protected (3.8µV; P<0.05). The number of TUNEL+ cells in the RGC layer was increased in ON-vehicle versus control and ON-treated retinas. IHC revealed milder astrogliosis (GFAP), increased numbers of oligodendrocytes (MOSP), and a decreased deNFP/NFP ratio in SNJ-1945-treated nerves compared to vehicle-treated nerves.
Daily oral dosing of calpain inhibitor protects RGCs in EAE-induced ON. Current inhibitor studies are assessing daily visual function of control and treated mice. We are also examining the mechanisms by which calpain inhibition is modifying the immune cell response in this model.
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