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Adenosine is of interest in SUDEP pathophysiology due to its influence on seizures and breathing. The objective of this investigation was to examine the role of adenosine in seizure severity, seizure\u2010induced respiratory disruption, and seizure\u2010induced death using mouse models. Understanding adenosinergic contributions to seizure cessation and seizure\u2010induced death may provide insights into how SUDEP can be prevented while avoiding increased seizure severity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Our approach was to examine: (1) seizure severity and seizure\u2010induced death after 15\u2009mA electroshock seizures and during repeated pentylenetetrazol (PTZ) administration in wild\u2010type mice (\n                      <jats:italic>Adk<\/jats:italic>\n                      <jats:sup>+\/+<\/jats:sup>\n                      ) and transgenic mice with reduced adenosine metabolism (\n                      <jats:italic>Adk<\/jats:italic>\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                      ); (2) the postictal hypercapnic ventilatory response (HCVR) in wild\u2010type mice (the postictal HCVR could not be examined in\n                      <jats:italic>Adk<\/jats:italic>\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                      mice due to their high mortality rate); and (3) the effects of adenosinergic drugs on seizure severity and seizure\u2010induced death following maximal electroshock (MES).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Adk<\/jats:italic>\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                      mice were more vulnerable to seizure\u2010induced death in the 15\u2009mA electroshock and repeated PTZ models. Despite increased mortality,\n                      <jats:italic>Adk<\/jats:italic>\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                      mice had comparable seizure severity in the PTZ model and reduced seizure severity in the 15\u2009mA electroshock model. Breathing and HCVR were suppressed by 15\u2009mA electroshock seizures in wild\u2010type mice. Pharmacological inhibition of adenosine metabolism decreased MES seizure severity but did not increase mortality. A\n                      <jats:sub>1<\/jats:sub>\n                      selective and nonselective adenosine receptor antagonists increased seizure\u2010induced death following MES.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>Adenosine has opposing effects on seizure severity and seizure\u2010induced death. On the one hand, our seizure severity data highlight the importance of adenosine in seizure suppression. On the other hand, our mortality data indicate that excessive extracellular adenosine signaling can increase the risk of seizure\u2010induced respiratory arrest.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.18055","type":"journal-article","created":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T11:09:28Z","timestamp":1721214568000},"page":"2798-2811","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Disruption of adenosine metabolism increases risk of seizure\u2010induced death despite decreased seizure severity"],"prefix":"10.1111","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8750-6810","authenticated-orcid":false,"given":"Benton","family":"Purnell","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Robert Wood Johnson Medical School Rutgers University  Piscataway New Jersey 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