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Cited by 74Spinal Cord Injury ResearchNerve injury and regenerationEstrogen and related hormone effects

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

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Mosquera, Laurivette, Colón, Jennifer M., Santiago, José M., Torrado, Aranza I., Meléndez, Margarita, Segarra, Annabell C., Rodríguez-Orengo, José F., Miranda, Jorge D.·2014·Brain Research
DOI 10.1016/j.brainres.2014.03.002PMC PMC4046634
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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.

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  • Previous studies began tamoxifen treatment within 24 hours of injury, then gave low doses of tamoxifen chronically via intraperitoneal injection or intrathecal infusion.

    “Previous studies began tamoxifen treatment within 24 hours of injury, then gave low doses of tamoxifen chronically via intraperitoneal injection [39, 41] or intrathecal infusion [40, 55].”

    From Delayed short-term tamoxifen treatment does not promote remyelination or neuron sparing after spinal cord injury (2020) · cites this paper as [40]

    Experimental Procedures §§4.2–4.3 report that this study began tamoxifen treatment seven days before spinal cord injury, using subcutaneous pellets that released the drug for 30 days—not treatment begun within 24 hours after injury by intraperitoneal injection or intrathecal infusion. The Discussion (§3.3) does mention other groups starting treatment 30 minutes or two hours after injury, but does not establish the claimed administration routes for this study. Page numbers are unavailable in our copy. (LLM, conf=0.90)

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  • 21 days of tamoxifen treatment beginning immediately after SCI reduced inflammation, decreased glial reactivity, promoted cell survival, increased white matter sparing, and enhanced functional recovery in rats and cats.

    “21 days of tamoxifen treatment beginning immediately after SCI reduced inflammation, decreased glial reactivity, promoted cell survival, increased white matter sparing, and enhanced functional recovery in rats and cats [38–43].”

    From Delayed short-term tamoxifen treatment does not promote remyelination or neuron sparing after spinal cord injury (2020) · cites this paper as [40]

    Results §2.6 and Discussion §3.3 report improved locomotor recovery and white-matter sparing in rats after SCI. But Experimental Procedures §§4.2–4.3 describe tamoxifen pellets implanted seven days before SCI and designed to release the drug for 30 days, not 21 days of treatment beginning immediately afterward. Discussion §3.3 discusses reduced inflammatory markers after SCI in other rat studies, while reduced gliosis and increased viable cells concern other brain-injury models; this paper provides no evidence for cats. (LLM, conf=0.91)

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  • These results contradict other CNS trauma studies that show tamoxifen improves anatomical and motor recovery in female and male SCI rodents.

    “These results contradict other CNS trauma studies that show tamoxifen improves anatomical and motor recovery in female and male SCI rodents [39–41, 55], but this is likely attributed to differences in the timing of dosing.”

    From Delayed short-term tamoxifen treatment does not promote remyelination or neuron sparing after spinal cord injury (2020) · cites this paper as [40]

  • Studies that report a neuroprotective effect of tamoxifen have given it during the acute phase, capitalizing on tamoxifen's ability to reduce inflammation, decrease glial reactivity, and promote cell survival.

    “Studies that report a neuroprotective effect of tamoxifen have given it during this acute phase, capitalizing on tamoxifen’s ability to reduce inflammation, decrease glial reactivity, and promote cell survival [39–42, 55].”

    From Delayed short-term tamoxifen treatment does not promote remyelination or neuron sparing after spinal cord injury (2020) · cites this paper as [40]

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  1. Sribnick EA Samantaray S Das A Smith J Matzelle DD Ray SK Banik NL 2011 Post-Injury estrogen treatment of chronic spinal cord injury improves locomotor function in rats J Neurosc Res 88 1738 1750 PMC3127445 20091771

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Authors
Mosquera, L., Colón, J. M., Santiago, J. M., Torrado, A. I., Meléndez, M., Segarra, A. C., Rodríguez-Orengo, J. F., & Miranda, J. D.
Affiliations
  • University of Puerto Rico, Medical Sciences Campus (PR)
  • University of Puerto Rico at Carolina (PR)
  • Institute of Forensic Sciences (US)
ORCID
Venue
Brain Research
Publisher
Elsevier BV
Published
2014-05
Volume
1561
Pages
11-22
ISSN
0006-8993 (ISSN-L)
DOI
10.1016/j.brainres.2014.03.002
PMC
PMC4046634
OpenAlex
W2123643041
Cited by
74
References
78
Citations by year
2026: 3 · 2025: 1 · 2024: 6 · 2023: 4 · 2022: 4 · 2021: 4 · 2020: 9 · 2019: 3 · 2018: 10 · 2017: 10 · 2016: 8 · 2015: 10 · 2014: 2
FWCI
7.44
Type
journal article
Language
en
Open access
Locations
  • Brain Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5g12rr003050-25)
  • National Institute of General Medical Sciences (S06GM008224, R01GM068138, P20GM103642, R25GM061838)
  • National Center for Research Resources (G12-RR-03051, G12 RR-003050, G12RR003051)
  • National Institute on Minority Health and Health Disparities (G12MD007600)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords
spinal cord injury, tamoxifen, estradiol, estrogen receptor alpha, locomotor recovery, neuroprotection, antioxidant activity, ovariectomized rats, bruising
MeSH terms
Animals, Antioxidants, Drug Implants, Estradiol, Estrogen Antagonists, Female, Motor Activity, Nerve Fibers, Myelinated, Spinal Cord, Spinal Cord Injuries, Tamoxifen, Time Factors, Rats, Sprague-Dawley, Reactive Oxygen Species, Oxidative Stress, Neuroprotective Agents, Recovery of Function, Estrogen Receptor Modulators, Estrogen Receptor alpha

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