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This study investigated the neurobiological and histological changes in the hippocampus as well as potential long\u2010term neurobehavioral alterations, following repeated administration of ketamine (KET) and dexmedetomidine (DEX) in neonatal rats. Postnatal Day 7 (PND7) rat pups were randomly assigned to four groups: Control (0.9% NaCl), KET (50\u00a0mg\/kg), DEX (25\u00a0\u00b5g\/kg), and DEXKET (DEX (25\u00a0\u00b5g\/kg)\u00a0+\u00a0KET (50\u00a0mg\/kg)). Intraperitoneal (i.p.) injections were performed for three consecutive days (PND8\u201010). Developmental neurotoxicity was assessed by measuring apoptotic markers (caspase\u20103, Bax, and Bcl\u20102) and pyroptosis\u2010related proteins (caspase\u20101, gasdermin D, IL\u20101\u03b2, and IL\u201018) in hippocampus via ELISA. Western blotting was used to analyze long\u2010term hippocampal caspase\u20101, brain\u2010derived neurotrophic factor (BDNF), and growth associated protein 43 (GAP43) levels. Long\u2010term cognitive effects, including learning, memory, and attention, were evaluated on PND40 using the Barnes maze and the novel object recognition (NOR) tests. Hippocampal morphology was examined by Nissl staining. Although KET or DEX alone did not alter classical apoptotic pathways, they significantly reduced caspase\u20101. However, both KET and DEX alone impaired recognition memory and attention in the long term, without altering spatial learning. Notably, the combined administration of KET and DEX enhanced sedation while maintaining caspase\u20101, BDNF, and GAP43 levels close to control values, preserving recognition memory and spatial learning. These findings indicate that co\u2010administration of KET and DEX during the neonatal period may provide a safer anesthetic strategy by reducing cognitive side effects and modulating neuroinflammatory pathways.<\/jats:p>","DOI":"10.1002\/dneu.70056","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T06:51:19Z","timestamp":1786949479000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cognitive and Pyroptotic Outcomes of Neonatal Ketamine and Dexmedetomidine: Potential Neuroprotection via Caspase\u20101 Modulation"],"prefix":"10.1002","volume":"86","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6933-926X","authenticated-orcid":false,"given":"Simay","family":"Alcan\u2010Kirtas","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Medicine Hacettepe University  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6183-1460","authenticated-orcid":false,"given":"Ozbeyen","family":"Atalay","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine Hacettepe University  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3220-465X","authenticated-orcid":false,"given":"Gokhan Burcin","family":"Kubat","sequence":"additional","affiliation":[{"name":"Institute of Transplantation and Gene Sciences Baskent University  Ankara Turkey"},{"name":"Department of Exercise and Sport Sciences, Faculty of Health Sciences Baskent University  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0341-7277","authenticated-orcid":false,"given":"Meltem","family":"Tuncer","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine Hacettepe University  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,16]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/374450a0"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10339\u2010011\u20100430\u2010z"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1213\/ANE.0000000000004529"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.205"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213\u2010020\u201005484\u20101"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1177\/0897190014525754"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2012.12.040"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2019.10438"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.672526"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003\u2010022\u201003667\u20104"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20190595"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/ACO.0b013e3282efd18b"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2008.11.004"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/5458061"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/aas.12356"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19113414"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0166\u20104328(88)90157\u2010x"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.physbeh.2021.113626"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00210\u2010018\u20101589\u2010y"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1345\/aph.1H314"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jemermed.2022.01.017"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1101\/lm.334306"},{"key":"e_1_2_11_24_1","volume-title":"Pharmacology and Physiology for Anesthesia E\u2010Book: Foundations and Clinical Application","author":"Hemmings H. 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