title: Tamoxifen and estradiol improved locomotor function and increased spared tissue in rats after spinal cord injury: their antioxidant effect and role of estrogen receptor alpha.
abstract: 17β-Estradiol is a multi-active steroid that imparts neuroprotection via diverse mechanisms of action. However, its role as a neuroprotective agent after spinal cord injury (SCI), or the involvement of the estrogen receptor-alpha (ER-α) in locomotor recovery, is still a subject of much debate. In this study, we evaluated the effects of estradiol and of Tamoxifen (an estrogen receptor mixed agonist/antagonist) on locomotor recovery following SCI. To control estradiol cyclical variability, ovariectomized female rats received empty or estradiol filled implants, prior to a moderate contusion to the spinal cord. Estradiol improved locomotor function at 7, 14, 21, and 28 days post injury (DPI), when compared to control groups (measured with the BBB open field test). This effect was ER-α mediated, because functional recovery was blocked with an ER-α antagonist. We also observed that ER-α was up-regulated after SCI. Long-term treatment (28 DPI) with estradiol and Tamoxifen reduced the extent of the lesion cavity, an effect also mediated by ER-α. The antioxidant effects of estradiol were seen acutely at 2 DPI but not at 28 DPI, and this acute effect was not receptor mediated. Rats treated with Tamoxifen recovered some locomotor activity at 21 and 28 DPI, which could be related to the antioxidant protection seen at these time points. These results show that estradiol improves functional outcome, and these protective effects are mediated by the ER-α dependent and independent-mechanisms. Tamoxifen׳s effects during late stages of SCI support the use of this drug as a long-term alternative treatment for this condition.
authors.affiliation: Department of Physiology, University of Puerto Rico-School of Medicine, San Juan, PR 00936, USA.
authors.forename: Laurivette
authors.initials: L
authors.lastname: Mosquera
authors.affiliation: Department of Physiology, University of Puerto Rico-School of Medicine, San Juan, PR 00936, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Colón
authors.affiliation: University of Puerto Rico Carolina Campus, Department of Natural Sciences, Carolina, PR 00984, USA.
authors.forename: José M
authors.initials: JM
authors.lastname: Santiago
authors.affiliation: Department of Physiology, University of Puerto Rico-School of Medicine, San Juan, PR 00936, USA.
authors.forename: Aranza I
authors.initials: AI
authors.lastname: Torrado
authors.affiliation: Institute of Forensic Science, San Juan, PR, USA.
authors.forename: Margarita
authors.initials: M
authors.lastname: Meléndez
authors.affiliation: Department of Physiology, University of Puerto Rico-School of Medicine, San Juan, PR 00936, USA.
authors.forename: Annabell C
authors.initials: AC
authors.lastname: Segarra
authors.affiliation: Department of Biochemistry, University of Puerto Rico-School of Medicine, San Juan, PR 00936, USA.
authors.forename: José F
authors.initials: JF
authors.lastname: Rodríguez-Orengo
authors.affiliation: Department of Physiology, University of Puerto Rico-School of Medicine, San Juan, PR 00936, USA. Electronic address: jorge.miranda3@upr.edu.
authors.forename: Jorge D
authors.initials: JD
authors.lastname: Miranda
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D004343:Drug Implants; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000097:blood / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013629:Tamoxifen / Q000097:blood / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000975:Antioxidants; D004343:Drug Implants; D004965:Estrogen Antagonists; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D013629:Tamoxifen; D004958:Estradiol
keywords: 17β-estradiol; Estrogen receptor expression; Locomotor recovery; Neuroprotection; Selective estrogen receptor modulators; Trauma