Spinal cord injury (SCI), a major health-care problem, warrants pathophysiological and therapeutic study to minimize damage for functional recovery. Increased calpain activity and expression concomitant with structural protein loss in SCI lesions indicate a pivotal role for this protease in the irreversible cell damage. Partially damaged cells in the area surrounding a necrotic lesion (traumatic penumbral) and areas adjacent to the traumatic penumbra may be rescued or protected by calpain inhibitors, facilitated by additional drugs, synergistic for tissue protection. Since many pathways participate in secondary tissue destruction in SCI, calpain inhibitor inclusion with other agents that block degradative reactions could offer more potent neuroprotection.
Their specific aims are to: (1) Define calpain's expression in both the SCI necrotic lesion and the surrounding traumatic penumbra and its adjacent areas which have a potentially reversible apoptotic component; (2) Examine strategies to improve neuroprotection in SCI that emphasize exploration and delineation of synergistic agents affecting reactions in the secondary injury cascade; (3) Study calpain's role in the induction of apoptosis in vitro and how this is related to events and their constraint by specific calpain inhibitors in the traumatic penumbra. To support these aims, they will: (1) Determine activity and expression (mRNA and protein levels) of u and mcalpain and their inhibitor, calpastatin; ascertain their cellular localization by double-label immunofluorescence; define the extent and nature of cell death in defined areas of the cord following injury; (2) Study the therapeutic effects and synergy of calpain-specific cell permeable inhibitors (calpeptin, E64-d, MDL-28170) with methylprednisolone, indomethacin and brain-derived neutrotrophic factors in acute and chronic SCI, examining parameters indicated previously; correlate changes with behavioral outcome; (3) Determine the effect of cytokines on calpain activation in neural cell culture, examining apoptotic characteristics (biochemical and morphological) effected by calpain inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS031622-07
Application #
6126252
Study Section
Neurology A Study Section (NEUA)
Program Officer
Michel, Mary E
Project Start
1993-12-13
Project End
2001-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
7
Fiscal Year
2000
Total Cost
$260,549
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
Samantaray, Supriti; Das, Arabinda; Matzelle, Denise C et al. (2016) Administration of low dose estrogen attenuates persistent inflammation, promotes angiogenesis, and improves locomotor function following chronic spinal cord injury in rats. J Neurochem 137:604-17
Samantaray, Supriti; Das, Arabinda; Matzelle, Denise C et al. (2016) Administration of low dose estrogen attenuates gliosis and protects neurons in acute spinal cord injury in rats. J Neurochem 136:1064-73
Thakore, Nakul P; Samantaray, Supriti; Park, Sookyoung et al. (2016) Molecular Changes in Sub-lesional Muscle Following Acute Phase of Spinal Cord Injury. Neurochem Res 41:44-52
Cox, April; Varma, Abhay; Banik, Naren (2015) Recent advances in the pharmacologic treatment of spinal cord injury. Metab Brain Dis 30:473-82
Cox, April; Varma, Abhay; Barry, John et al. (2015) Nanoparticle Estrogen in Rat Spinal Cord Injury Elicits Rapid Anti-Inflammatory Effects in Plasma, Cerebrospinal Fluid, and Tissue. J Neurotrauma 32:1413-21
Das, Arabinda; Guyton, M Kelly; Smith, Amena et al. (2013) Calpain inhibitor attenuated optic nerve damage in acute optic neuritis in rats. J Neurochem 124:133-46
Wallace 4th, Gerald C; Dixon-Mah, Yaenette N; Vandergrift 3rd, W Alex et al. (2013) Targeting oncogenic ALK and MET: a promising therapeutic strategy for glioblastoma. Metab Brain Dis 28:355-66
Varma, Abhay K; Das, Arabinda; Wallace 4th, Gerald et al. (2013) Spinal cord injury: a review of current therapy, future treatments, and basic science frontiers. Neurochem Res 38:895-905
Das, Arabinda; Wallace 4th, Gerald; Reiter, Russel J et al. (2013) Overexpression of melatonin membrane receptors increases calcium-binding proteins and protects VSC4.1 motoneurons from glutamate toxicity through multiple mechanisms. J Pineal Res 54:58-68
Smith, Joshua A; Park, Sookyoung; Krause, James S et al. (2013) Oxidative stress, DNA damage, and the telomeric complex as therapeutic targets in acute neurodegeneration. Neurochem Int 62:764-75

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