{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T07:55:28Z","timestamp":1793692528209,"version":"4.5.1"},"reference-count":170,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Drug\u2010resistant epilepsy (DRE) affects nearly one\u2010third of patients and remains a major unmet clinical need, despite advances in anti\u2010seizure medications (ASMs). Carbogen, a low\u2010concentration carbon dioxide (CO\n                      <jats:sub>2<\/jats:sub>\n                      ) and oxygen (O\n                      <jats:sub>2<\/jats:sub>\n                      ) gas mixture, has reemerged as a physiology\u2010based therapy owing to renewed insights into pH\u2010sensitive seizure mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This review summarizes preclinical and clinical evidence on carbogen inhalation for seizure control. Mechanistic data on pH\u2010dependent ion channels, GABAergic inhibition, and adenosine signaling were condensed, and clinical outcomes across seizure types and inhalation protocols were compared for safety and efficacy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Carbogen induces short\u2010term respiratory acidosis, lowering brain extracellular pH to activate acid\u2010sensitive ion channels (e.g., ASIC1a and NaV1.2), enhance GABAergic inhibition, and boost adenosine signaling. These effects are rapid, reversible, and distinct from conventional ASMs. Preclinical studies show strong seizure suppression, especially under hyperventilation\u2010induced alkalosis. Clinically, brief low\u2010dose inhalation (5%\u2009CO\n                      <jats:sub>2<\/jats:sub>\n                      \u2009for \u2264\u20093\u2009min) is effective and well tolerated in focal and absence seizures, whereas earlier high\u2010concentration protocols caused adverse effects. Efficacy varies by seizure type: benefits in nonconvulsive status epilepticus (NCSE) are limited, and the CARDIF trial found no advantage for pediatric febrile seizures. Ongoing work, such as the CRESCENT trial, is exploring carbogen as an adjunct therapy for pediatric convulsive status epilepticus (CSE).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Evidence supports carbogen's therapeutic promise and highlights the need for precise patient selection, controlled delivery, and comprehensive safety testing. Future research should develop biomarker\u2010guided, closed\u2010loop systems and test synergy with established ASMs to advance carbogen as a mechanism\u2010based therapy within precision epilepsy care.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.70686","type":"journal-article","created":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T10:22:04Z","timestamp":1764843724000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Carbogen Inhalation Therapy for Epileptic Seizures: Mechanisms, Evidence, and Future Directions"],"prefix":"10.1002","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1427-3803","authenticated-orcid":false,"given":"Li","family":"Wang","sequence":"first","affiliation":[{"name":"School of Medicine Jingchu University of Technology  Jingmen 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