{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T03:07:59Z","timestamp":1789787279679,"version":"4.0.1"},"reference-count":75,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,1,1]],"date-time":"2023-01-01T00:00:00Z","timestamp":1672531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Methotrexate (MTX) is a widely used neurotoxic drug with broad antineoplastic and immunosuppressant spectra. However, the exact molecular mechanisms by which MTX inhibits hippocampal neurogenesis are yet unclear. Dexmedetomidine (Dex), an \u03b12-adrenergic receptor agonist, has recently shown neuroprotective effects; however, its full mechanism is unexplored. This study investigated the potential of Dex to mitigate MTX-induced neurotoxicity and memory impairment in rats and the possible role of the miR-15a\/ROCK-1\/ERK1\/2\/CREB\/BDNF pathway. Notably, no former studies have linked this pathway to MTX-induced neurotoxicity. Male Sprague Dawley rats were placed into four groups. Group 1 received saline i.p. daily and i.v. on days 8 and 15. Group 2 received Dex at 10 \u03bcg\/kg\/day i.p. for 30 days. Group 3 received MTX at 75 mg\/kg i.v. on days 8 and 15, followed by four i.p. doses of leucovorin at 6 mg\/kg after 18 h and 3 mg\/kg after 26, 42, and 50 h. Group 4 received MTX and leucovorin as in group 3 and Dex daily dosages as in group 2. Bioinformatic analysis identified the association of miR-15a with ROCK-1\/ERK1\/2\/CREB\/BDNF and neurogenesis. MTX lowered hippocampal doublecortin and Ki-67, two markers of neurogenesis. This was associated with the downregulation of miR-15a, upregulation of its target ROCK-1, and reduction in the downstream ERK1\/2\/CREB\/BDNF pathway, along with disturbed hippocampal redox state. Novel object recognition and Morris water maze tests demonstrated the MTX-induced memory deficiencies. Dex co-treatment reversed the MTX-induced behavioral, biochemical, and histological alterations in the rats. These neuroprotective actions could be partly mediated through modulating the miR-15a\/ROCK-1\/ERK1\/2\/CREB\/BDNF pathway, which enhances hippocampal neurogenesis.<\/jats:p>","DOI":"10.3390\/ijms24010766","type":"journal-article","created":{"date-parts":[[2023,1,2]],"date-time":"2023-01-02T04:17:38Z","timestamp":1672633058000},"page":"766","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Dexmedetomidine Attenuates Methotrexate-Induced Neurotoxicity and Memory Deficits in Rats through Improving Hippocampal Neurogenesis: The Role of miR-15a\/ROCK-1\/ERK1\/2\/CREB\/BDNF Pathway Modulation"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9806-826X","authenticated-orcid":false,"given":"Mohamed","family":"Taha","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0475-7388","authenticated-orcid":false,"given":"Omar Mohsen","family":"Eldemerdash","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, Misr International University (MIU), Cairo 44971, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismail Mohamed","family":"Elshaffei","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, Misr International University (MIU), Cairo 44971, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8935-0183","authenticated-orcid":false,"given":"Einas Mohamed","family":"Yousef","sequence":"additional","affiliation":[{"name":"Department of Histology and Cell Biology, Faculty of Medicine, Menoufia University, Shibin el Kom 3251, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3942-0275","authenticated-orcid":false,"given":"Mahmoud A.","family":"Senousy","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt"},{"name":"Department of Biochemistry, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo 11786, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1097\/NHH.0000000000000203","article-title":"Methotrexate","volume":"33","author":"Mager","year":"2015","journal-title":"Home Healthc. 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