*9-Estradiol and Tamoxifen as Neuroprotective / Neuroregenerative Agents after Spinal Cord Injury
PI: Jorge Miranda, Ph.D.
External Mentor: Anne Etgen, Ph.D.
Internal Mentor: Annabel Segarra, Ph.D.
Among the complex set of events that reduces neural plasticity after trauma are cellular responses that result in cell damage and poor survival at the lesion site. Estradiol (E2) is a strong neuroactive steroid with multiple actions, many converging on intracellular signaling pathways that promote cell rescue. Ou rhypothesis is that if E2 is infused at supraphysiological levels after spinal cord injury (SCI), apoptosis will decrease and supraspinal axonal outgrowth will be facilitated. This will lead to an improvement in locomotor behavior. Our laboratory and others have evidence that estrogen receptor (ER) α mRNA and protein are induced at the site of injury after SCI, and their enhanced expression persists for several days. Preliminary data from our laboratory show that pretreatment, followed by continuous E2 or tamoxifen (TAM, a selective ER modulator) administration promotes functional locomotor recovery after SCI in an ER dependent manner. The objective of this proposal is to improve locomotor recovery after SCI by infusion of E2 or TAM and to determine the mechanism by which this is accomplished. This study is unique, in that it uses an organismal approach to tackle the problem, combining behavioral, physiological, anatomical and molecular techniques. The specific aims of this proposal are: 1) to evaluate the effect of E2 or TAM administered at high levels to adult rats with a damaged spinal cord at the behavioral, physiological and anatomical level. These parameters will be investigated using the Basso, Beattie & Bregnaham (BBB) open field test, grid walking test, beam crossing, transcranial magnetic motor evoke potentials (tcMMEP) and histological studies to determine spared tissue and lesion volume combined with confocal microscopy to assess axonal outgrowth. 2) to determine the cellular mediator of E2 neuroprotective and/or neuroregenerative action in contused animals, ER antagonists will be used to determine any receptor dependency in apoptosis, formation of superoxides and/or neurite outgrowth. These will be analyzed by immunohistochemistry,
More information about Dr. Miranda’s research can be found at:
Dr. Anne M. Etgen, Professor Emerita, Department of Neuroscience, Albert Einstein College of Medicine, met with members of the laboratory of Dr. Jorge Miranda following her seminar “Neuroprotective Actions of Estrogens: Mechanisms and Therapeutic Implications”. Institute of Neurobiology, February 12, 2014. Left to right: Iris Salgado, Aranza Torrado, Anne Etgen, Jennifer Colón, Nilmary Grafals and Jorge Miranda. Sponsored by the NIH NIGMS COBRE Puerto Rico Center for Neuroplasticity and the Translational Neuroscience Program (TNP) of the UPR Medical Sciences Campus RCMI program.