{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T03:25:24Z","timestamp":1790220324163,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2018,8,31]],"date-time":"2018-08-31T00:00:00Z","timestamp":1535673600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R01HD090884 (SDK)"],"award-info":[{"award-number":["R01HD090884 (SDK)"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Developmental Neurobiology"],"published-print":{"date-parts":[[2018,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Neonatal seizures are harmful to the developing brain and are associated with mortality and long\u2010term neurological comorbidities. Hypoxic\u2010ischemic encephalopathy (HIE) seizures represent a significant proportion of such seizures. Phenobarbital (PB) remains the first line anti\u2010seizure drug (ASD) treatment but fails ~50% of the time. Translational models of neonatal seizures are crucial to investigating mechanisms underlying PB\u2010resistance. A model of PB\u2010resistant ischemic seizures in postnatal day 7 (P7) CD\u20101 mice reported K\u2010Cl cotransporter 2 (KCC2) degradation that has been shown to be due to activation of the TrkB pathway. We investigated PB\u2010efficacy in a pentylenetetrazole (PTZ) model of neonatal seizures in the same strain and age using identical treatment protocols to gain insights into mechanisms underlying PB\u2010resistance. A single dose of PTZ (80\u00a0mg\/kg; IP) consistently induced repetitive seizures that did not progress to status epilepticus (SE). PB (25 mg\/kg; IP, single dose) significantly suppressed the PTZ\u2010induced seizures. This was associated with significant KCC2 upregulation and stable Na\u2010K\u2010Cl cotransporter 1 (NKCC1) expression at 24h. The TrkB pathway was not activated. PTZ seizure burdens were significantly higher than those reported for ischemic seizures, indicating seizure severity did not dictate the differences in PB\u2010efficacy. Bumetanide (BTN) (0.1\u20130.2 mg\/kg; IP) did not work as an anti\u2010seizure agent, similar to the ischemic model. When investigating mechanisms underlying the emergence of PB\u2010resistance in translational models, the method by which seizures are induced may dictate mechanisms underlying emergence of PB\u2010resistance.<\/jats:p>","DOI":"10.1002\/dneu.22634","type":"journal-article","created":{"date-parts":[[2018,8,23]],"date-time":"2018-08-23T08:03:52Z","timestamp":1535011432000},"page":"1117-1130","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Pharmaco\u2010resistant Neonatal Seizures: Critical Mechanistic Insights from a Chemoconvulsant Model"],"prefix":"10.1002","volume":"78","author":[{"given":"Shivani C.","family":"Kharod","sequence":"first","affiliation":[{"name":"Neuroscience Laboratory Hugo Moser Research Institute at Kennedy Krieger Baltimore Maryland 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon M.","family":"Carter","sequence":"additional","affiliation":[{"name":"Neuroscience Laboratory Hugo Moser Research Institute at Kennedy Krieger Baltimore Maryland 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shilpa D.","family":"Kadam","sequence":"additional","affiliation":[{"name":"Neuroscience Laboratory Hugo Moser Research Institute at Kennedy Krieger Baltimore Maryland 21205"},{"name":"Department of Neurology Johns Hopkins University School of Medicine Baltimore Maryland 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,8,31]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2010.10.019"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2016.00090"},{"key":"e_1_2_9_4_1","doi-asserted-by":"crossref","unstructured":"Carter B.M. Sullivan B.J. Landers J.R. andKadam S.D.(2018)Dose\u2010dependent reversal of KCC2 hypofunction and phenobarbital\u2010resistant neonatal seizures by ANA12(Scientific Reports. 8 Article number: 11987).https:\/\/doi.org\/10.1038\/s41598-018-30486-7","DOI":"10.1038\/s41598-018-30486-7"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0057148"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mehy.2014.10.008"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1301"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21229"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02229070"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2017.03.006"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2016.06.042"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00944.2004"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5821-09.2010"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00015.2009"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3819"},{"key":"e_1_2_9_16_1","article-title":"Age and gender dependent severity of ischemic neonatal seizures: response to phenobarbital + bumetanide combination therapy in a mouse model","author":"Kadam S.D.","year":"2011","journal-title":"AES Annual Meeting #3.035"},{"key":"e_1_2_9_17_1","first-page":"1026","article-title":"Pre\u2010clinical models of acquired neonatal seizures: differential effects of injury on function of chloride co\u2010transporters","volume":"1","author":"Kang S.K.","year":"2014","journal-title":"Austin Journal of Cerebrovascular Disease & Stroke"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.13094"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2015.00173"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3154-10.2010"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2011.03128.x"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2012.05.045"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1159\/000443782"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2015.10.007"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1990.tb07887.x"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.55.4.506"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2017.06.008"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e31820af91a"},{"key":"e_1_2_9_29_1","unstructured":"NCT00830531. 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