Inflammation and Degeneration of Optic Nerve in EAE

Summary

Principal Investigator: Naren Banik
Affiliation: Medical University of South Carolina
Country: USA
Abstract: Impaired vision due to optic nerve damage is one of the most common presenting symptoms of patients with multiple sclerosis (MS). MS-associated optic nerve damage is due to an influx of auto-reactive T cells and other immune cells. The inflammatory process is thought to contribute to demyelination, axonal degeneration, and loss of oligodendrocytes and retinal ganglion cells (RGCs). Understanding the pathophysiology of optic nerve degeneration in EAE has potential therapeutic implications to develop agents that restore visual function. Demonstration of increased activity and expression of calpain, a calcium (Ca2+)-dependent protease, in optic nerve using an animal model of MS, experimental allergic encephalomyelitis (EAE), in Lewis rats has implied a role for calpain in optic nerve damage in EAE. Since the precise timing of inflammation and mechanisms of cell and axon damage in optic nerve are not fully understood, the potential to prevent inflammation and molecular events that lead to axonal and cell damage, may improve and restore function. We hypothesize that calpain-mediated activation of auto-reactive T cells and immune cell infiltration into the CNS will result in loss of visual function due to inflammation leading to axon and oligodendrocyte damage in EAE optic nerve with subsequent loss of RGCs which may occur prior to clinical symptoms of disease. A corollary hypothesis is that inhibiting calpain at different time-points following challenge will restore visual function by preventing inflammation in the periphery and in optic nerve, and ameliorate neurodegeneration after damage to the optic nerve have begun. Data indicate that Ca2+ influx, calpain expression, axonal damage, cell death, and retinal damage are increased in EAE optic nerve with several parameters affected before disease onset. Treatment with calpain inhibitors reduced immune cell infiltration, calpain expression, cells death, and retinal damage, resulting in improved visual responses compared to untreated EAE animals. In vitro interferon (IFN?) induced calpain activation in glial cells and MBP-specific T cell supernatant degraded MBP. The following specific aims have been designed to test these hypotheses: (1) determine the timing of inflammatory responses, Ca2+ influx, Ca2+-dependent events, cell death, and axonal/myelin degeneration in EAE optic nerve and examine the status of RGCs in correlation with visual dysfunction in EAE animals following challenge; (2) investigate whether treatment with calpain inhibitors will restore visual function by altering the immune arm (T cell activation, immune cell infiltration into optic nerve) and/or the neurodegenerative arm (cell death, axonal damage) in acute EAE, as compared to vehicle treated animals; and (3) examine the effects of calpain inhibitors in preserving and protecting function of RGCs in vitro when subjected to pro-inflammatory cytokines or incubated with supernatant from activated MBP- specific T cells. Understanding the process and timing of optic nerve damage will further the development of treatment of strategies to best restore the impairment caused by optic nerve degeneration in MS. PUBLIC HEALTH RELEVANCE: Damage to the optic nerve resulting in impaired vision is one of the most common symptoms of patients with multiple sclerosis (MS). MS-associated inflammation of the optic nerve due to an influx of immune cells is thought to contribute to deficits leading to impaired vision, including demyelination, axonal degeneration, and loss of retinal ganglion cells (RGCs) and oligodendrocytes. Understanding the mechanisms by which inflammatory and neurodegenerative events contribute to optic nerve damage may have important and potentially therapeutic implications for developing agents that protect cells, preserve axons and myelin, and thus, improve vision and ultimately retard the development of MS.
Funding Period: 2009-09-30 - 2014-06-30
more information: NIH RePORT