Inflammation and Degeneration of Optic Nerve in EAE

Summary

Principal Investigator: Naren Banik
Affiliation: Medical University of South Carolina
Country: USA
Abstract: DESCRIPTION (provided by applicant): 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

Top Publications

  1. 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
  2. pmc KLF4 overexpression and apigenin treatment down regulated anti-apoptotic Bcl-2 proteins and matrix metalloproteinases to control growth of human malignant neuroblastoma SK-N-DZ and IMR-32 cells
    Nishant Mohan
    University of South Carolina School of Medicine, Department of Pathology, Microbiology, and Immunology, Columbia, SC 29209, USA
    Mol Oncol 7:464-74. 2013
  3. doi Sequential hTERT knockdown and apigenin treatment inhibited invasion and proliferation and induced apoptosis in human malignant neuroblastoma SK-N-DZ and SK-N-BE2 cells
    Mrinmay Chakrabarti
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA
    J Mol Neurosci 51:187-98. 2013
  4. pmc Oxidative stress, DNA damage, and the telomeric complex as therapeutic targets in acute neurodegeneration
    Joshua A Smith
    Division of Neurology, Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas St, Clinical Sciences Building Room 309, Charleston, SC 29425, USA
    Neurochem Int 62:764-75. 2013
  5. pmc miR-138 overexpression is more powerful than hTERT knockdown to potentiate apigenin for apoptosis in neuroblastoma in vitro and in vivo
    Mrinmay Chakrabarti
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA
    Exp Cell Res 319:1575-85. 2013
  6. 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
  7. pmc N-Myc knockdown and apigenin treatment controlled growth of malignant neuroblastoma cells having N-Myc amplification
    Md Motarab Hossain
    University of South Carolina School of Medicine, Department of Pathology, Microbiology, and Immunology, Columbia, SC 29209, USA
    Gene 529:27-36. 2013
  8. doi MiR-7-1 potentiated estrogen receptor agonists for functional neuroprotection in VSC4.1 motoneurons
    M Chakrabarti
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, United States
    Neuroscience 256:322-33. 2014
  9. 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
  10. 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

Detail Information

Publications23

  1. 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...
  2. pmc KLF4 overexpression and apigenin treatment down regulated anti-apoptotic Bcl-2 proteins and matrix metalloproteinases to control growth of human malignant neuroblastoma SK-N-DZ and IMR-32 cells
    Nishant Mohan
    University of South Carolina School of Medicine, Department of Pathology, Microbiology, and Immunology, Columbia, SC 29209, USA
    Mol Oncol 7:464-74. 2013
    ..Collectively, our results from this investigation strongly suggest that KLF4 functions as a tumor suppressor and potentiates the anti-cancer activities of APG in two different human malignant neuroblastoma cell lines...
  3. doi Sequential hTERT knockdown and apigenin treatment inhibited invasion and proliferation and induced apoptosis in human malignant neuroblastoma SK-N-DZ and SK-N-BE2 cells
    Mrinmay Chakrabarti
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA
    J Mol Neurosci 51:187-98. 2013
    ....
  4. pmc Oxidative stress, DNA damage, and the telomeric complex as therapeutic targets in acute neurodegeneration
    Joshua A Smith
    Division of Neurology, Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas St, Clinical Sciences Building Room 309, Charleston, SC 29425, USA
    Neurochem Int 62:764-75. 2013
    ..g. telomerase) as novel therapeutic targets in the treatment of neurodegeneration due to their ability to modulate the neuronal response to both oxidative stress and DNA damage...
  5. pmc miR-138 overexpression is more powerful than hTERT knockdown to potentiate apigenin for apoptosis in neuroblastoma in vitro and in vivo
    Mrinmay Chakrabarti
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA
    Exp Cell Res 319:1575-85. 2013
    ....
  6. 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. ..
  7. pmc N-Myc knockdown and apigenin treatment controlled growth of malignant neuroblastoma cells having N-Myc amplification
    Md Motarab Hossain
    University of South Carolina School of Medicine, Department of Pathology, Microbiology, and Immunology, Columbia, SC 29209, USA
    Gene 529:27-36. 2013
    ..Collectively, N-Myc knockdown and APG treatment is a promising strategy for controlling the growth of human malignant neuroblastoma cell lines that harbor N-Myc amplification. ..
  8. doi MiR-7-1 potentiated estrogen receptor agonists for functional neuroprotection in VSC4.1 motoneurons
    M Chakrabarti
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, United States
    Neuroscience 256:322-33. 2014
    ..In conclusion, our data indicated that miR-7-1 most significantly potentiated efficacy of EST for functional neuroprotection and this therapeutic strategy could be used in the future to attenuate apoptosis of motoneurons in SCI...
  9. 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...
  10. 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. ..
  11. doi Overexpression of miR-7-1 increases efficacy of green tea polyphenols for induction of apoptosis in human malignant neuroblastoma SH-SY5Y and SK-N-DZ cells
    Mrinmay Chakrabarti
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA
    Neurochem Res 38:420-32. 2013
    ..In conclusion, our current investigation clearly indicates that overexpression of miR-7-1 can highly potentiate efficacy of EGCG for induction of apoptosis in human malignant neuroblastoma cells...
  12. pmc Calpain inhibitor attenuated optic nerve damage in acute optic neuritis in rats
    Arabinda Das
    Division of Neurology, Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
    J Neurochem 124:133-46. 2013
    ..Thus, these data suggest that calpain is involved in inflammatory as well as in neurodegenerative aspects of the disease and may be a promising target for treating ON in EAE and MS...
  13. pmc Synergistic anti-cancer mechanisms of curcumin and paclitaxel for growth inhibition of human brain tumor stem cells and LN18 and U138MG cells
    Motarab Hossain
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA
    Neurochem Int 61:1102-13. 2012
    ..Collectively, the combination of CCM and PTX worked as a promising therapy for controlling the growth of HBTSC and other glioblastoma cells...
  14. pmc Neuroprotective efficacy of estrogen in experimental spinal cord injury in rats
    Supriti Samantaray
    Division of Neurology, Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    Ann N Y Acad Sci 1199:90-4. 2010
    ..Taken together, these studies confirm that estrogen is a potential therapeutic agent for treating SCI...
  15. pmc Post-treatment with voltage-gated Na(+) channel blocker attenuates kainic acid-induced apoptosis in rat primary hippocampal neurons
    Arabinda Das
    Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucus Street, Charleston, SC 29425, USA
    Neurochem Res 35:2175-83. 2010
    ....
  16. 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
    ....
  17. pmc Calpain inhibition attenuates apoptosis of retinal ganglion cells in acute optic neuritis
    Amena W Smith
    Departments of Neurosciences, Division of Neurology, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    Invest Ophthalmol Vis Sci 52:4935-41. 2011
    ....
  18. 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...
  19. pmc Calpain inhibition protected spinal cord motoneurons against 1-methyl-4-phenylpyridinium ion and rotenone
    S Samantaray
    Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 309 CSB, PO Box 250606, Charleston, SC 29425, USA
    Neuroscience 192:263-74. 2011
    ..Cytoprotection rendered by calpeptin further validated the involvement of calpain in apoptosis and suggested calpain inhibition as a potential neuroprotective strategy...
  20. pmc Inhibition of cysteine proteases in acute and chronic spinal cord injury
    Swapan K Ray
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina 29209, USA
    Neurotherapeutics 8:180-6. 2011
    ..Recent studies suggest that physiological hormones, such as estrogen and melatonin, can be successfully used for prevention of neurodegeneration and preservation of motor function in acute SCI as well as in chronic SCI in rats...
  21. pmc Combination of N-(4-hydroxyphenyl) retinamide and apigenin suppressed starvation-induced autophagy and promoted apoptosis in malignant neuroblastoma cells
    Nishant Mohan
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA
    Neurosci Lett 502:24-9. 2011
    ..Collectively, combination of 4-HPR and APG worked synergistically to suppress autophagy and promote apoptosis in human malignant neuroblastoma cells...
  22. 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...
  23. doi SU5416 and EGCG work synergistically and inhibit angiogenic and survival factors and induce cell cycle arrest to promote apoptosis in human malignant neuroblastoma SH-SY5Y and SK-N-BE2 cells
    Nishant Mohan
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC, 29209, USA
    Neurochem Res 36:1383-96. 2011
    ..Taken together, this combination of drugs can be a promising therapeutic strategy for controlling the growth of human malignant neuroblastoma cells...