{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T23:52:49Z","timestamp":1779321169603,"version":"3.51.4"},"reference-count":41,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T00:00:00Z","timestamp":1768348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000912","name":"March of Dimes","doi-asserted-by":"publisher","award":["#6-FY08-214"],"award-info":[{"award-number":["#6-FY08-214"]}],"id":[{"id":"10.13039\/100000912","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"NIH","doi-asserted-by":"publisher","award":["RC4 NS072966"],"award-info":[{"award-number":["RC4 NS072966"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Background\/Objectives: Infantile epileptic spasms syndrome (IESS) is a severe epilepsy of infancy. Corticotropin (ACTH) and vigabatrin are the only FDA-approved therapies. The efficacy of ACTH together with the strong convulsant effects of corticotropin-releasing hormone (CRH) suggests that excess CRH, secondary to impaired ACTH feedback, may contribute to spasms. We therefore hypothesized that CRH receptor 1 (CRHR1) antagonists would suppress spasms in a route- and drug-dependent manner. Methods: Using our validated rat model of IESS, in which prenatal priming with betamethasone was followed by postnatal triggering of spasms with N-methyl-D-aspartic acid (NMDA), we tested two CRHR1 antagonists, CP376395 and SN003, delivered intracranially (via intracerebroventricular or intraparenchymal infusion) or systemically. Results: Intracerebroventricular infusion of both antagonists suppressed spasms, with CP376395 providing more consistent effects. Intraparenchymal administration into the hypothalamic arcuate nucleus also reduced spasms, whereas misses into the mammillary bodies were ineffective, highlighting site specificity. Systemic administration yielded divergent results: SN003 robustly suppressed spasms, whereas CP376395 unexpectedly exacerbated them. No sex differences were observed. Conclusions: These findings demonstrate that CRHR1 blockade modifies experimental spasms in a route- and drug-specific manner and implicates discrete hypothalamic circuits, particularly those including the arcuate nucleus, in spasm generation. The divergent systemic responses between CP376395 and SN003 likely reflect differences in CRHR1 engagement (competitive and non-competitive antagonism, respectively) as well as differences in binding properties that may include differential network interactions beyond local CRH signaling or duration of receptor occupancy. In conclusion, SN003 may be a better option than CP376395 for further development as a CRHR1-targeted therapy pending additional pharmacokinetic\/pharmacodynamic studies. Further work should explore dosing paradigms of CP376395 to determine if a therapeutic range for CP376395 exists.<\/jats:p>","DOI":"10.3390\/children13010125","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T11:01:14Z","timestamp":1768388474000},"page":"125","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting CRHR1 Signaling in Experimental Infantile Epileptic Spasms Syndrome: Evidence for Route-Dependent Efficacy"],"prefix":"10.3390","volume":"13","author":[{"given":"Tamar","family":"Chachua","sequence":"first","affiliation":[{"name":"Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY 10595, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mi-Sun","family":"Yum","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea"},{"name":"Department of Pediatrics, Asan Medical Center Children\u2019s Hospital, Seoul 05505, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7159-7106","authenticated-orcid":false,"given":"Chian-Ru","family":"Chern","sequence":"additional","affiliation":[{"name":"Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY 10595, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0793-5558","authenticated-orcid":false,"given":"Kayla","family":"Vieira","sequence":"additional","affiliation":[{"name":"Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY 10595, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jana","family":"Vel\u00ed\u0161kov\u00e1","sequence":"additional","affiliation":[{"name":"Departments of Cell Biology & Anatomy, Obstetrics and Gynecology, and Neurology, New York Medical College, Valhalla, NY 10595, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2805-349X","authenticated-orcid":false,"given":"Libor","family":"Vel\u00ed\u0161ek","sequence":"additional","affiliation":[{"name":"Departments of Cell Biology & Anatomy, Pediatrics, and Neurology, New York Medical College, Valhalla, NY 10595, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6517","DOI":"10.1073\/pnas.78.10.6517","article-title":"Primary structure of corticotropin-releasing factor from ovine hypothalamus","volume":"78","author":"Spiess","year":"1981","journal-title":"Proc. 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