Administration of low dose estrogen attenuates gliosis and protects neurons in acute spinal cord injury in rats

• Type of Material: Article
• Authors: Supriti Samantaray, Medical University of South Carolina; Arabinda Das, Medical University of South Carolina; Denise C. Matzelle, Medical University of South Carolina; Shan Yu, Emory University; Ling Wei, Emory University; Abhay Varma, Medical University of South Carolina; Swapan K. Ray, University of South Carolina; Naren L. Banik, Medical University of South Carolina
• Language: English
• Date: 2016-03-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 International Society for Neurochemistry.
• Final Published Version (URL): http://dx.doi.org/10.1111/jnc.13464
• Title of Journal or Parent Work: Journal of Neurochemistry
• ISSN: 0022-3042
• Volume: 136
• Issue: 5
• Start Page: 1064
• End Page: 1073
• Grant/Funding Information: This work was supported in part by funding from NIH (R01-NS3166); Veterans Administration (1IOBX00126; 1IOBX002349); South Carolina State Spinal Cord Research Fund (SCIRF-2015P-01, SCIRF-2015P-04); Department of Neurosurgery, MUSC; and MUSC-CTSA program.
• Keywords: calpain; Biochemistry & Molecular Biology; SIGNAL-TRANSDUCTION; Science & Technology; Life Sciences & Biomedicine; Neurosciences & Neurology; CORTICAL-NEURONS; CALPAIN INHIBITORS; FUNCTIONAL RECOVERY; CEREBRAL BLOOD-VESSELS; NEUROPROTECTIVE AGENT; APOPTOTIC CELL-DEATH; estrogen receptors; neuroprotection; TRAUMATIC BRAIN-INJURY; Neurosciences; estrogen; gliosis; acute spinal cord injury; RECEPTOR-ALPHA; UP-REGULATION
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pathology; Biology, Neuroscience

Abstract

Spinal cord injury (SCI) is a debilitating condition with neurological deficits and loss of motor function that, depending on the severity, may lead to paralysis. The only treatment currently available is methylprednisolone, which is widely used and renders limited efficacy in SCI. Therefore, other therapeutic agents must be developed. The neuroprotective efficacy of estrogen in SCI was studied with a pre-clinical and pro-translational perspective. Acute SCI was induced in rats that were treated with low doses of estrogen (1, 5, 10, or 100 μg/kg) and compared with vehicle-treated injured rats or laminectomy control (sham) rats at 48 h post-SCI. Changes in gliosis and other pro-inflammatory responses, expression and activity of proteolytic enzymes (e.g., calpain, caspase-3), apoptosis of neurons in SCI, and cell death were monitored via Western blotting and immunohistochemistry. Negligible pro-inflammatory responses or proteolytic events and very low levels of neuronal death were found in sham rats. In contrast, vehicle-treated SCI rats showed profound pro-inflammatory responses with reactive gliosis, elevated expression and activity of calpain and caspase-3, elevated Bax:Bcl-2 ratio, and high levels of neuronal death in lesion and caudal regions of the injured spinal cord. Estrogen treatment at each dose reduced pro-inflammatory and proteolytic activities and protected neurons in the caudal penumbra in acute SCI. Estrogen treatment at 10 μg was found to be as effective as 100 μg in ameliorating the above parameters in injured animals. Results from this investigation indicated that estrogen at a low dose could be a promising therapeutic agent for treating acute SCI. Experimental studies with low dose estrogen therapy in acute spinal cord injury (SCI) demonstrated the potential for multi-active beneficial outcomes. Estrogen has been found to ameliorate several degenerative pathways following SCI. Thus, such early protective effects may even lead to functional recovery in long term injury. Studies are underway in chronic SCI in a follow up manuscript. Experimental studies with low dose estrogen therapy in acute spinal cord injury (SCI) demonstrated the potential for multi-active beneficial outcomes. Estrogen has been found to ameliorate several degenerative pathways following SCI. Thus, such early protective effects may even lead to functional recovery in long term injury. Studies are underway in chronic SCI in a follow up manuscript.