Although the understanding of spinal cord injury (SCI) and its mechanisms have increased over the years, effective therapy to minimize tissue damage and maximize functional recovery remains a primary goal. The only treatment, methylprednisolone, has limited clinical efficacy. Emphasis is needed on early pharmacological intervention of secondary damage involving Ca2+ overload, free radicals, glutamate toxicity, and enzyme activation. Investigations into cell and fiber damage, tissue destruction, neuron protection, and maintenance of structural integrity are essential to effective treatments. After SCI, intracellular Ca2+ influx initiates secondary pathological events (cell damage, tissue destruction). Our goal is to protect CNS cells from secondary damage by using agents that preserve and restore function. Since several pathways cause cell damage and tissue destruction, multiple action drugs or a combination therapy will likely be more effective. One group of potential agents, steroid hormones, estrogen, and progesterone, are neuroprotective in cultured neurons and in CNS disorders. We hypothesize that estrogen/progesterone will control inflammatory processes, suppress intracellular Ca2+ levels, and inhibit Ca2+-dependent events. Suppression of intracellular Ca2+ will inhibit activation of lipases and proteinases (e.g., calpain) and protect cells from secondary damage. Estrogen decreases infiltration of inflammatory cells (e.g., macrophages), reduces Ca2+ levels and Ca2+-dependent events, and restores mitochondrial function in SCI lesion and penumbra (compared to vehicle-treated animals). Our preliminary data reveals that the effects seen with estrogen treatment may be superior to those seen with methylprednisolone. Cells undergoing apoptosis due to H202 and glutamate toxicity have increased intracellular Ca2+. Estrogen treatment reduced Ca2+, protected these cells from damage, and led to functional recovery. Thus, the following Specific Aims are proposed: . Examine the effects of estrogen treatment on inflammation following acute SCI . Investigate estrogen effects on intracellular Ca2+ influx and Ca2+ -dependent events in cell and tissue damage in SCI . Investigate whether estrogen treatment will preserve motor function in chronic SCI . Examine whether estrogen treatment will protect and preserve the function of neurons (cortical and motor) and glial cells subjected to oxidative stress and glutamate toxicity in culture. Novel and relevant techniques, i.e., determining Ca levels in cultured cells and SCI slices (fura-2), cell damage (TUNEL), cell function (electrophysiology), and motor recovery (""""""""BBB"""""""" scale), will be used. Understanding estrogen's mechanisms in cell protection and recovery as it relates to multidestructive pathways will establish it as a viable SCI treatment agent.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045967-04
Application #
7098036
Study Section
Brain Disorders and Clinical Neuroscience 5 (BDCN)
Program Officer
Kleitman, Naomi
Project Start
2003-09-30
Project End
2010-06-30
Budget Start
2006-07-01
Budget End
2010-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$230,784
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
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
Smith, Joshua A; Das, Arabinda; Butler, Jonathan T et al. (2011) Estrogen or estrogen receptor agonist inhibits lipopolysaccharide induced microglial activation and death. Neurochem Res 36:1587-93
McDowell, Misty L; Das, Arabinda; Smith, Joshua A et al. (2011) Neuroprotective effects of genistein in VSC4.1 motoneurons exposed to activated microglial cytokines. Neurochem Int 59:175-84
Samantaray, Supriti; Smith, Joshua A; Das, Arabinda et al. (2011) Low dose estrogen prevents neuronal degeneration and microglial reactivity in an acute model of spinal cord injury: effect of dosing, route of administration, and therapy delay. Neurochem Res 36:1809-16
Das, Arabinda; Smith, Joshua A; Gibson, Cameron et al. (2011) Estrogen receptor agonists and estrogen attenuate TNF-?-induced apoptosis in VSC4.1 motoneurons. J Endocrinol 208:171-82
Ray, Swapan K; Samantaray, Supriti; Smith, Joshua A et al. (2011) Inhibition of cysteine proteases in acute and chronic spinal cord injury. Neurotherapeutics 8:180-6
Das, Arabinda; McDowell, Misty; O'Dell, Casey M et al. (2010) Post-treatment with voltage-gated Na(+) channel blocker attenuates kainic acid-induced apoptosis in rat primary hippocampal neurons. Neurochem Res 35:2175-83

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