{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T07:15:55Z","timestamp":1771571755188,"version":"3.50.1"},"reference-count":33,"publisher":"Scientific Scholar","content-domain":{"domain":["surgicalneurologyint.com"],"crossmark-restriction":true},"short-container-title":[],"abstract":"\n Background:<\/jats:title>\n Spinal cord injury (SCI) remains a serious condition with limited treatment options. Methotrexate (MTX), an immunosuppressant with anti-inflammatory and neuroprotective properties, has shown promising effects in experimental SCI, but clinical observations in oncology patients raise concerns regarding neurotoxicity. The aim of this study was to systematically evaluate the effect of MTX on SCI in preclinical models and to compare these findings with available human evidence.<\/jats:p>\n <\/jats:sec>\n \n Methods:<\/jats:title>\n A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science up to the end of 2024. Animal studies investigating MTX in SCI were included. Data extraction and quality assessment were performed independently by two reviewers. A random-effects meta-analysis was conducted where appropriate. Human evidence, including large-scale retrospective data, was synthesized for interpretation.<\/jats:p>\n <\/jats:sec>\n \n Results:<\/jats:title>\n \n Six animal studies (five rats, one rabbit) met the inclusion criteria. MTX administration consistently improved functional recovery, reduced apoptosis, decreased oxidative stress, and improved preservation of myelinated axons. Meta-analysis demonstrated a significant reduction in myeloperoxidase activity (standardized mean differences = \u20133.40, 95% confidence interval [CI] \u20135.73 to \u20131.08, I\n 2<\/jats:sup>\n = 91.18%). In contrast, clinical evidence, mostly from oncology patients with intact spinal cords, consistently reported MTX-associated neurotoxicity, including encephalopathy, dorsal column myelopathy, and polyradiculopathy. The largest cohort identified a 5.2% incidence of neurotoxicity, with a higher risk in children and intrathecal (IT) administration.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion:<\/jats:title>\n Preclinical evidence supports MTX as a potential neuroprotective agent in SCI, but human data demonstrate neurotoxicity in noninjured spinal cords, especially with IT use. Differences in route of administration, dosing, host condition, and injury context likely explain this contrast. IT MTX should not be considered in traumatic SCI. Future studies should define safe systemic dosing windows in injured spinal cord models and evaluate cautious early-phase clinical trials under strict monitoring.<\/jats:p>\n <\/jats:sec>","DOI":"10.25259\/sni_953_2025","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T06:53:02Z","timestamp":1771570382000},"page":"100","update-policy":"https:\/\/doi.org\/10.25259\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neuroprotection or Neurotoxicity? Insights from preclinical and clinical studies of methotrexate in spinal cord injury"],"prefix":"10.25259","volume":"17","author":[{"given":"Amir","family":"Azimi","sequence":"first","affiliation":[{"name":"Men\u2019s Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammadhossein","family":"Vazirizadeh-Mahabadi","sequence":"additional","affiliation":[{"name":"Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mobina","family":"Yarahmadi","sequence":"additional","affiliation":[{"name":"Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arash","family":"Sarveazad","sequence":"additional","affiliation":[{"name":"Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran"},{"name":"Nursing Care Research Center, Iran University of Medical Sciences, Tehran, Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahmoud","family":"Yousefifard","sequence":"additional","affiliation":[{"name":"Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"10894","published-online":{"date-parts":[[2026,2,20]]},"reference":[{"key":"10.25259\/SNI_953_2025\/ref-1","doi-asserted-by":"crossref","first-page":"180","DOI":"10.5115\/acb.2018.51.3.180","article-title":"Stem cell transplantation and functional recovery after spinal cord injury: A systematic review and meta-analysis","volume":"51","author":"Abbaszadeh","year":"2018","journal-title":"Anat Cell Biol"},{"key":"10.25259\/SNI_953_2025\/ref-2","doi-asserted-by":"crossref","first-page":"18548","DOI":"10.1038\/s41598-024-69263-0","article-title":"Potential neurotoxicity associated with 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