{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T21:48:16Z","timestamp":1774993696872,"version":"3.50.1"},"reference-count":49,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,7,1]],"date-time":"2020-07-01T00:00:00Z","timestamp":1593561600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia Open"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Sudden unexpected death in epilepsy (SUDEP) is the cause of premature death of 50% patients with chronic refractory epilepsy. Respiratory failure during seizures is regarded as an important mechanism of SUDEP. Previous studies have shown that abnormal serotonergic neurotransmission is involved in the pathogenesis of seizure\u2010induced respiratory failure, while enhancing serotonergic neurotransmission in the brainstem suppresses it. Because peripheral inflammation is known to enhance serotonergic neuron activation and 5\u2010HT synthesis and release, we investigated the effect of intraperitoneal lipopolysaccharide (LPS)\u2010induced inflammation on the S\u2010IRA susceptibility during audiogenic seizures in DBA\/1 mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>After DBA\/1 mice were primed by exposing to sound stimulation for three consecutive days, they were tested for seizure severity and seizure\u2010induced respiratory arrest (S\u2010IRA) induced by sound stimulation under different conditions. We determined the dose and time course of the effects of intraperitoneal administration of LPS on audiogenic seizures and S\u2010IRA. The effects of blocking TLR4 or RAGE receptors and blocking 5\u2010HT receptors on the LPS\u2010induced effect on S\u2010IRA were investigated. Statistical significance was evaluated using the Kruskal\u2010Wallis test.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Intraperitoneal injection of LPS significantly had dose\u2010dependent effects in reducing the incidence of S\u2010IRA as well as seizure severity in DBA\/1 mice. The protective effect of LPS on S\u2010IRA peaked at 8\u201012\u00a0hours after LPS injection and was related to both reducing seizure severity and enhancing autoresuscitation. Blocking TLR4 or RAGE receptor with TAK\u2010242 or FPS\u2010ZM1, respectively, prior to LPS injection attenuated its effects on S\u2010IRA and seizure severity. Injection of a nonselective 5\u2010HT receptor antagonist, cyproheptadine, or a 5\u2010HT<jats:sub>3<\/jats:sub> receptor antagonist, ondansetron, was effective in blocking LPS\u2010induced effect on S\u2010IRA. Immunostaining results showed a significant increase in c\u2010Fos\u2010positive serotonergic neurons in the dorsal raphe.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>This is the first study that demonstrates the effect of intraperitoneal LPS injection\u2010induced inflammation on reducing S\u2010IRA susceptibility and provides additional evidence supporting the serotonin hypothesis on SUDEP. Our study suggests that inflammation may enhance brainstem 5\u2010HT neurotransmission to promote autoresuscitation during seizure and prevent SUDEP.<\/jats:p><\/jats:sec>","DOI":"10.1002\/epi4.12410","type":"journal-article","created":{"date-parts":[[2020,5,31]],"date-time":"2020-05-31T10:54:46Z","timestamp":1590922486000},"page":"386-396","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Intraperitoneal injection of lipopolysaccharide prevents seizure\u2010induced respiratory arrest in a DBA\/1 mouse model of SUDEP"],"prefix":"10.1002","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7136-2282","authenticated-orcid":false,"given":"Yadav","family":"Adhikari","sequence":"first","affiliation":[{"name":"Spinal Cord and Brain Injury Research Group Stark Neurosciences Research Institute. Indiana University School of Medicine Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8671-8640","authenticated-orcid":false,"given":"Xiaoming","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Cell Biology and Physiology Stark Neurosciences Research Institute Indiana University School of Medicine Indianapolis Indiana USA"},{"name":"Department of Neurological Surgery Stark Neurosciences Research Institute Indiana University School of Medicine Indianapolis Indiana USA"},{"name":"Spinal Cord and Brain Injury Research Group Stark Neurosciences Research Institute. 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