{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T12:40:01Z","timestamp":1756298401545,"version":"3.44.0"},"reference-count":26,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"15","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,8,5]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">The 3\u2010ethoxycarbonyl\u20102\u2010methyl\u20104\u2010(2\u2010nitrophenyl)\u20104,11\u2010dihydro\u20101H\u2010pyrido[2,3\u2010b][1,5]benzodiazepine (JM\u201020) molecule is a novel multifunctional molecule with potent neuroprotective effects in rat focal cerebral ischemia. To confirm previous results obtained in single laboratories with small sample sizes, and to provide a robust preclinical evidence base for potential clinical development in stroke, we performed a 2\u2010center preclinical trial with sufficiently large group sizes to detect relevant effects, minimizing biases in experimental design as much as possible (randomization, blinding, predefined in\u2010 and exclusion criteria) and increasing external and construct validities.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods<\/jats:title>\n            <jats:p xml:lang=\"en\">Experimental focal cerebral ischemia was induced by different surgeons in 2 different laboratories on 2 continents, including 2 species (480 mice and 55 rats), different suppliers, mature adult and middle\u2010aged male animals (age range, 2\u201316\u2009months) as well as comorbid animals (streptozotocin\u2010induced diabetes).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Results<\/jats:title>\n            <jats:p xml:lang=\"en\">Although JM\u201020 improved functional outcomes after middle cerebral artery occlusion in young adult mice at day 7 and appeared to reduce mortality (not statistically significant), it had no effect on mature adult or comorbid mice. Effect sizes, where statistically significant, were modest, and much lower than those reported in the previous studies. Meta\u2010analysis of all individual mouse data did not reveal statistically significant different functional outcomes or mortalities between vehicle\u2010 and JM\u201020\u2010treated animals, although neuroscores and survival were slightly better in JM\u201020\u2010treated animals. In the less\u2010severe model of permanent cortical focal cerebral ischemia in rats, JM\u201020 significantly reduced brain infarction.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">We were able to confirm the neuroprotective potential of JM\u201020. However, effect sizes were substantially lower than previously described in small monocentric trials. Further study is needed to determine whether JM\u201020 could be effective in less\u2010severe cases of focal cerebral ischemia or when used in combination with thrombolysis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Registration<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              URL: Unique identifier: DOI:\n              <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/doi.org\/10.17590\/asr.0000181\">10.17590\/asr.0000181<\/jats:ext-link>\n              .\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.124.040621","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T12:07:15Z","timestamp":1752754035000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Randomized Controlled Preclinical Trial of a Benzodiazepine\u2013Dihydropyridine Hybrid Molecule in Rodent Stroke"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2345-1923","authenticated-orcid":false,"given":"Jeney","family":"Ram\u00edrez\u2010S\u00e1nchez","sequence":"first","affiliation":[{"name":"Center for Pharmaceutical Research and Development","place":["La Habana, Cuba"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3924-956X","authenticated-orcid":false,"given":"Andr\u00e9","family":"Rex","sequence":"additional","affiliation":[{"name":"Charit\u00e9 Universit\u00e4tsmedizin Berlin","place":["Berlin, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4737-2349","authenticated-orcid":false,"given":"Sarah K.","family":"McCann","sequence":"additional","affiliation":[{"name":"Berlin Institute of Health","place":["Berlin, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9415-2555","authenticated-orcid":false,"given":"Daniel","family":"Schulze","sequence":"additional","affiliation":[{"name":"Charit\u00e9 Universit\u00e4tsmedizin Berlin","place":["Berlin, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8916-4620","authenticated-orcid":false,"given":"Maylin","family":"Wong\u2010Guerra","sequence":"additional","affiliation":[{"name":"Center for Pharmaceutical Research and Development","place":["La Habana, Cuba"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6904-5854","authenticated-orcid":false,"given":"Luis A.","family":"Fonseca\u2010Fonseca","sequence":"additional","affiliation":[{"name":"Center for Pharmaceutical Research and Development","place":["La Habana, Cuba"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7789-6528","authenticated-orcid":false,"given":"Enrique","family":"Garc\u00eda\u2010Alfonso","sequence":"additional","affiliation":[{"name":"Center for Pharmaceutical Research and Development","place":["La Habana, Cuba"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9920-7930","authenticated-orcid":false,"given":"Ail\u00edn","family":"Ram\u00edrez\u2010Abreu","sequence":"additional","affiliation":[{"name":"Center for Pharmaceutical Research and Development","place":["La Habana, Cuba"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2216-9622","authenticated-orcid":false,"given":"Ricardo","family":"Limonta","sequence":"additional","affiliation":[{"name":"Center for Pharmaceutical Research and Development","place":["La Habana, 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