The irreversible neurological deficits in multiple sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE), are due primarily to axonal and neuronal degeneration brought on by a pro-inflammatory assault on the central nervous system (CNS) by autoreactive T cells and other immune cells. Previous studies in our laboratory and others have indicated that the calcium (Ca2+)-activated protease, calpain, plays a role in both the immune arm and the neurodegenerative arm of EAE develop- ment. The goal of this project is to understand the precise timing and molecular mechanisms involved in axonal and neuronal damage in acute and chronic EAE as these events correlate with increased calpain expression and activity and to examine if inhibiting calpain activity will attenuate disease progression by blocking components of the immune arm and/or neurodegenerative arm. Thus, we hypothesize that changes in Ca2* influx and calpain activation will promote infiltration of autoreactive T cells and macrophages, leading to axonal and neuronal degeneration. A corollary hypothesis is that calpain inhibition will prevent migration of activated T cells and macrophages, reduce the production of antigenic myelin basic protein (MBP) peptides, and delay or prevent axonal and neuronal degener- ation; which will lead to reduced disability (paralysis, limp tail) in acute and relapsing/remitting (R/R) EAE models. Preliminary data indicate that Ca2+ influx, calpain activation, T cell activation, axonal degeneration, and apoptotic proteins are increased in EAE spinal cord at the onset of acute disease. Additionally, treatment with the calpain inhibitor SJA6017 (SJA) reduced immune cell activation and infiltration, as well as calpain activity and expression, and prevented cell death in EAE spinal cord, as compared to vehicle-treated animals. Calpain inhibition also reduced MBP degradation by MBP-specific T cells in vitro and greatly attenuated disease development in a R/R adoptive transfer EAE mouse model. To further investigate the roles of calpain in EAE, the following Specific Aims will be addressed: (1) Characterize the timing of Ca2+ influx and calpain activation as these events correlate with increased mechanisms of axonal damage and apoptosis in neurons and glial cells in spinal cord from Lewis rats with acute EAE. (2) Investigate whether treatment with the calpain inhibitor SJA will attenuate EAE development in the acute EAE Lewis rat model. (3) Examine whether calpain inhibition by SJA treatment will delay or block disease development and attenuate neurodegeneration in the R/R model of EAE in SJL/J mice. The proposed studies targeting calpain as therapeutic strategy for attenuating clinical disability in EAE/MS by blocking immune dysfunction and/or neurodegeneration will further development of novel treatments for these debilitating diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS056176-03
Application #
7386679
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2006-08-15
Project End
2011-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
3
Fiscal Year
2008
Total Cost
$354,415
Indirect Cost
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Trager, Nicole N M; Butler, Jonathan T; Harmon, Jennifer et al. (2018) A Novel Aza-MBP Altered Peptide Ligand for the Treatment of Experimental Autoimmune Encephalomyelitis. Mol Neurobiol 55:267-275
Smith, Amena W; Rohrer, Baerbel; Wheless, Lee et al. (2016) Calpain inhibition reduces structural and functional impairment of retinal ganglion cells in experimental optic neuritis. J Neurochem 139:270-284
Podbielska, Maria; Das, Arabinda; Smith, Amena W et al. (2016) Neuron-microglia interaction induced bi-directional cytotoxicity associated with calpain activation. J Neurochem 139:440-455
Samantaray, Supriti; Knaryan, Varduhi H; Shields, Donald C et al. (2015) Inhibition of Calpain Activation Protects MPTP-Induced Nigral and Spinal Cord Neurodegeneration, Reduces Inflammation, and Improves Gait Dynamics in Mice. Mol Neurobiol 52:1054-66
Knaryan, Varduhi H; Samantaray, Supriti; Park, Sookyoung et al. (2014) SNJ-1945, a calpain inhibitor, protects SH-SY5Y cells against MPP(+) and rotenone. J Neurochem 130:280-90
Park, Sookyoung; Nozaki, Kenkichi; Smith, Joshua A et al. (2014) Cross-talk between IGF-1 and estrogen receptors attenuates intracellular changes in ventral spinal cord 4.1 motoneuron cells because of interferon-gamma exposure. J Neurochem 128:904-18
Trager, Nicole; Smith, Amena; Wallace Iv, Gerald et al. (2014) Effects of a novel orally administered calpain inhibitor SNJ-1945 on immunomodulation and neurodegeneration in a murine model of multiple sclerosis. J Neurochem 130:268-79
Samantaray, Supriti; Knaryan, Varduhi H; Shields, Donald C et al. (2013) Critical role of calpain in spinal cord degeneration in Parkinson's disease. J Neurochem 127:880-90
Podbielska, Maria; Banik, Naren L; Kurowska, Ewa et al. (2013) Myelin recovery in multiple sclerosis: the challenge of remyelination. Brain Sci 3:1282-324
Trager, Nicole; Butler, Jonathan T; Haque, Azizul et al. (2013) The Involvement of Calpain in CD4(+) T Helper Cell Bias in Multple Sclerosis. J Clin Cell Immunol 4:1000153

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