title: Calpain inhibition reduces structural and functional impairment of retinal ganglion cells in experimental optic neuritis.
abstract: Optic neuritis (ON), inflammation of the optic nerve, is strongly associated with multiple sclerosis. ON pathology is characterized by attack of autoreactive T cells against optic nerve antigens, resulting in demyelination, death of retinal ganglion cells, and cumulative visual impairment. A model of experimental autoimmune encephalomyelitis (EAE) was utilized to study the onset and progression of ON and the neuroprotective efficacy of oral treatment with the calpain inhibitor SNJ 1945. EAE was actively induced in B10.PL mice with myelin basic protein on Days 0 and 2, and mice received twice daily oral dosing of SNJ 1945 from Day 9 until sacrificing (Day 26). Visual function was determined by electroretinogram recordings and daily measurement of optokinetic responses (OKR) to a changing pattern stimulus. Optic nerve and retinal histopathology was investigated by immunohistochemical and luxol fast blue staining. EAE mice manifested losses in OKR thresholds, a measurement of visual acuity, which began early in the disease course. There was a significant bias toward unilateral OKR impairment among EAE-ON eyes. Treatment with SNJ 1945, initiated after the onset of OKR threshold decline, improved visual acuity, pattern electroretinogram amplitudes, and paralysis, with attenuation of retinal ganglion cell death. Furthermore, calpain inhibition spared oligodendrocytes, prevented degradation of axonal neurofilament protein, and attenuated reactive astrocytosis. The trend of early, unilateral visual impairment in EAE-ON parallels the clinical presentation of ON exacerbations associated with multiple sclerosis. Calpain inhibition may represent an ideal candidate therapy for the preservation of vision in clinical ON. As in multiple sclerosis (MS) patients, optic neuritis (ON) and early, primarily monocular loss in spatial acuity is observed in a rodent model (EAE, experimental autoimmune encephalomyelitis). Daily oral treatment with the calpain inhibitor SNJ 1945 preserves visual acuity and preserves retinal ganglion cells (Brn3a, brain-specific homeobox/POU domain protein 3A) and their axons (MOSP, myelin oligodendrocyte-specific protein). Calpain inhibition may represent a candidate therapy for the preservation of vision in ON.
authors: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina, USA.
authors: Amena W
authors: AW
authors: Smith
authors: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina, USA. rohrer@musc.edu.|Department of Ophthalmology, Medical University of South Carolina, Charleston, South Carolina, USA. rohrer@musc.edu.|Alexion Pharmaceuticals, Cheshire, Connecticut, USA. rohrer@musc.edu.|Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, USA. rohrer@musc.edu.
authors: Baerbel
authors: B
authors: Rohrer
authors: Medicine-Division of Biostatistics and Epidemiology, Medical University of South Carolina, Charleston, South Carolina, USA.
authors: Lee
authors: L
authors: Wheless
authors: Department of Neurology and Neurosurgery, Medical University of South Carolina, Charleston, South Carolina, USA.
authors: Supriti
authors: S
authors: Samantaray
authors: Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, USA.
authors: Swapan K
authors: SK
authors: Ray
authors: Senju Pharmaceutical Co Ltd, Kobe, Japan.
authors: Jun
authors: J
authors: Inoue
authors: Senju Pharmaceutical Co Ltd, Kobe, Japan.
authors: Mitsuyoshi
authors: M
authors: Azuma
authors: Department of Ophthalmology, Medical University of South Carolina, Charleston, South Carolina, USA. baniknl@musc.edu.|Alexion Pharmaceuticals, Cheshire, Connecticut, USA. baniknl@musc.edu.|Department of Neurology and Neurosurgery, Medical University of South Carolina, Charleston, South Carolina, USA. baniknl@musc.edu.|Research Service, Ralph H. Johnson VA Medical Center, Charleston, South Carolina, USA. baniknl@musc.edu.
authors: Naren L
authors: NL
authors: Banik
mesh_terms: D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors*; D002219:Carbamates / Q000494:pharmacology* / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D004596:Electroretinography / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D005911:Gliosis / Q000517:prevention & control; D008297:Male; D051379:Mice; D004676:Myelin Basic Protein / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D017120:Nystagmus, Optokinetic / Q000187:drug effects; D009902:Optic Neuritis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D010775:Photic Stimulation; D012165:Retinal Ganglion Cells / Q000187:drug effects*; D014792:Visual Acuity / Q000187:drug effects
chemical_list: C515164:((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester; D002219:Carbamates; D004791:Enzyme Inhibitors; D004676:Myelin Basic Protein; D018696:Neuroprotective Agents; D002154:Calpain
keywords: axonal degeneration; calpain and cell death; oligodendrocytes; optic nerve; retinal ganglion cells; visual acuity