Attenuation of Axonal Damage and Neuronal Death in EAE

Summary

Principal Investigator: Naren Banik
Abstract: 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.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Increased calpain correlates with Th1 cytokine profile in PBMCs from MS patients
    Sarah A Imam
    Department of Neurosciences, Division of Neurology, Medical University of South Carolina, Charleston, SC 29425, USA
    J Neuroimmunol 190:139-45. 2007
  2. pmc Time-dependent increases in protease activities for neuronal apoptosis in spinal cords of Lewis rats during development of acute experimental autoimmune encephalomyelitis
    Arabinda Das
    Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    J Neurosci Res 86:2992-3001. 2008
  3. ncbi Activation of calpain and caspase pathways in demyelination and neurodegeneration in animal model of multiple sclerosis
    Arabinda Das
    Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
    CNS Neurol Disord Drug Targets 7:313-20. 2008
  4. doi Calpain inhibition attenuated morphological and molecular changes in skeletal muscle of experimental allergic encephalomyelitis rats
    Sookyoung Park
    Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    J Neurosci Res 90:2134-45. 2012
  5. pmc Critical role of calpain in spinal cord degeneration in Parkinson's disease
    Supriti Samantaray
    Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina, USA
    J Neurochem 127:880-90. 2013
  6. pmc Cross-talk between IGF-1 and estrogen receptors attenuates intracellular changes in ventral spinal cord 4.1 motoneuron cells because of interferon-gamma exposure
    Sookyoung Park
    Department of Neurosciences, Division of Neurology, College of Health Professions, Medical University of South Carolina, Charleston, South Carolina, USA
    J Neurochem 128:904-18. 2014
  7. pmc SNJ-1945, a calpain inhibitor, protects SH-SY5Y cells against MPP(+) and rotenone
    Varduhi H Knaryan
    Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina, USA
    J Neurochem 130:280-90. 2014
  8. pmc Effects of a novel orally administered calpain inhibitor SNJ-1945 on immunomodulation and neurodegeneration in a murine model of multiple sclerosis
    Nicole Trager
    Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina, USA Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
    J Neurochem 130:268-79. 2014
  9. pmc Involvement of calpain in the process of Jurkat T cell chemotaxis
    Jonathan T Butler
    Department of Molecular and Cellular Biology and Pathobiology, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    J Neurosci Res 87:626-35. 2009
  10. pmc Calpeptin attenuated inflammation, cell death, and axonal damage in animal model of multiple sclerosis
    M Kelly Guyton
    Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    J Neurosci Res 88:2398-408. 2010

Detail Information

Publications11

  1. pmc Increased calpain correlates with Th1 cytokine profile in PBMCs from MS patients
    Sarah A Imam
    Department of Neurosciences, Division of Neurology, Medical University of South Carolina, Charleston, SC 29425, USA
    J Neuroimmunol 190:139-45. 2007
    ..Calpain inhibitor also reduced degradation of myelin basic protein (MBP) by inhibiting the calpain secreted from MBP-specific T cells. Taken together, these results suggested calpain involvement in Th1/Th2 dysregulation in MS patients...
  2. pmc Time-dependent increases in protease activities for neuronal apoptosis in spinal cords of Lewis rats during development of acute experimental autoimmune encephalomyelitis
    Arabinda Das
    Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    J Neurosci Res 86:2992-3001. 2008
    ..From these findings, we conclude that increases in calpain and caspase activities play crucial roles in neuronal apoptosis during the development of acute EAE...
  3. ncbi Activation of calpain and caspase pathways in demyelination and neurodegeneration in animal model of multiple sclerosis
    Arabinda Das
    Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
    CNS Neurol Disord Drug Targets 7:313-20. 2008
    ..This review discusses the major involvement of calpain and caspase pathways in causing demyelination and neurodegeneration in EAE animals...
  4. doi Calpain inhibition attenuated morphological and molecular changes in skeletal muscle of experimental allergic encephalomyelitis rats
    Sookyoung Park
    Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    J Neurosci Res 90:2134-45. 2012
    ..These results indicate that morphological and molecular changes including apoptotic cell death and protein breakdown develop in skeletal muscle of EAE animals and that these changes can be reversed by calpain inhibition...
  5. pmc Critical role of calpain in spinal cord degeneration in Parkinson's disease
    Supriti Samantaray
    Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina, USA
    J Neurochem 127:880-90. 2013
    ..This may be one of the crucial mechanisms in the degenerative process. ..
  6. pmc Cross-talk between IGF-1 and estrogen receptors attenuates intracellular changes in ventral spinal cord 4.1 motoneuron cells because of interferon-gamma exposure
    Sookyoung Park
    Department of Neurosciences, Division of Neurology, College of Health Professions, Medical University of South Carolina, Charleston, South Carolina, USA
    J Neurochem 128:904-18. 2014
    ..1 motoneurons following IFN-γ and IGF-1 exposure. These results suggest that IGF-1 protects motoneurons from inflammatory insult by a mechanism involving pivotal interactions with ERα and ERβ...
  7. pmc SNJ-1945, a calpain inhibitor, protects SH-SY5Y cells against MPP(+) and rotenone
    Varduhi H Knaryan
    Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina, USA
    J Neurochem 130:280-90. 2014
    ..MPP+ and rotenone induced up-regulation of calpain, expression, and activity as a common mechanism of neurodegeneration. SNJ-1945, a novel calpain inhibitor, protected both the cell phenotypes against MPP+ and rotenone. ..
  8. pmc Effects of a novel orally administered calpain inhibitor SNJ-1945 on immunomodulation and neurodegeneration in a murine model of multiple sclerosis
    Nicole Trager
    Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina, USA Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
    J Neurochem 130:268-79. 2014
    ....
  9. pmc Involvement of calpain in the process of Jurkat T cell chemotaxis
    Jonathan T Butler
    Department of Molecular and Cellular Biology and Pathobiology, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    J Neurosci Res 87:626-35. 2009
    ..These studies provide evidence for the involvement of calpain in the mechanisms of chemotaxis and warrants further exploration in MS patient and EAE animal samples...
  10. pmc Calpeptin attenuated inflammation, cell death, and axonal damage in animal model of multiple sclerosis
    M Kelly Guyton
    Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    J Neurosci Res 88:2398-408. 2010
    ..These results indicate that calpain inhibition may offer a novel therapeutic avenue for treating EAE and MS...
  11. pmc Regulation of Th1/Th17 cytokines and IDO gene expression by inhibition of calpain in PBMCs from MS patients
    Amena W Smith
    Department of Neurosciences, Division of Neurology, Medical University of South Carolina, 96 Jonathan Lucas St, Charleston, SC 29425, USA
    J Neuroimmunol 232:179-85. 2011
    ..These results suggest that calpain inhibition may attenuate MS pathology and augment the efficacy of standard immunomodulatory agents used to treat this disease...