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We investigated this relationship by using MK-801, a non-competitive NMDA receptor antagonist and by determining infarct size and blood\u2013brain barrier (BBB) disruption under the condition of markedly reduced mTORC1 activity. Rats received rapamycin (20\u00a0mg\/kg, i.p.) for two days before transient middle cerebral artery occlusion (MCAO). At 15\u00a0min after MCAO, half of the rats received MK-801 (5\u00a0mg\/kg i.v.). At two hours\u2019 reperfusion after 90\u00a0min MCAO, BBB permeability, plasma volume and infarct size were determined. In rats without MCAO, one hour after MK-801, protein levels of pS6 (Ser240\/244), pAkt (Ser473), mBDNF, proBDNF and MMP-2 were analyzed by Western blot. MK-801 reduced the percentage of cortical infarct in the Control (8.4%\u2009\u00b1\u20092.1 vs 4.7%\u2009\u00b1\u20091.5) and in the Rapamycin Group (12.2%\u2009\u00b1\u20092.3 vs 6.7%\u2009\u00b1\u20092.0). The BBB permeability were not changed. The average plasma volume of the MK-801 Group was largest of all Groups. In the non-ischemic brain, MK-801 increased pS6 levels, which were markedly reduced by rapamycin pretreatment. MK-801 also increased proBDNF levels without affecting mBDNF levels, and neither response was altered by rapamycin pretreatment. In conclusion, our data indicate that high-dose MK-801 reduced TTC-defined cortical injury even under conditions of suppressed pS6 signaling and elevated proBDNF levels. The larger plasma volume observed in the MK-801-treated rats may have contributed to the reduced cortical injury. Therefore, mechanisms other than mTORC1 signaling should be considered in the neuroprotective effects of MK-801 during the early stage of cerebral ischemia\u2013reperfusion.<\/jats:p>","DOI":"10.1007\/s00210-026-05877-7","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T04:24:41Z","timestamp":1788150281000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["High-Dose MK-801 Attenuated Early TTC-Defined Cortical Injury Even under the Conditions of Suppressed Rapamycin-Sensitive pS6 Signaling during Early Cerebral Ischemia\u2013Reperfusion"],"prefix":"10.1007","author":[{"given":"Oak Z.","family":"Chi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harvey R.","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoon-Seong","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woom-Yee","family":"Bae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"5877_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2025.111338","volume":"226","author":"H Alnoaman","year":"2025","unstructured":"Alnoaman H, Al-Kuraishy HM, Al-Gareeb AI, Turkistani A, Allam A, Alexiou A, Papadakis M, Batiha GE-S (2025) Dysregulation of proBDNF\/p75NTR and BDNF\/TrkB signaling in acute ischemic stroke: different sides of the same coins. 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