Oleksii Shandra , Yongjun Wang , Lisa D. Coles , Wenzhu B. Mowrey , Qianyun Li , Wei Liu , Solomon L. Moshé , Aristea S. Galanopoulou
{"title":"赛拉司琼和依达拉奉在婴儿痉挛症多发大鼠模型中的疗效和耐受性。","authors":"Oleksii Shandra , Yongjun Wang , Lisa D. Coles , Wenzhu B. Mowrey , Qianyun Li , Wei Liu , Solomon L. Moshé , Aristea S. Galanopoulou","doi":"10.1016/j.yebeh.2024.110159","DOIUrl":null,"url":null,"abstract":"<div><h3>Objective</h3><div>To test whether anti-inflammatory and antioxidant drugs that inhibit the nuclear factor kappa light chain enhancer of activated B cells (NF-kB), celastrol and edaravone, suppress spasms and improve developmental outcomes in the multiple-hit rat model of refractory infantile spasms (IS) due to structural lesions.</div></div><div><h3>Methods</h3><div>Postnatal day 3 (PN3) Sprague-Dawley rats were treated according to the multiple-hit IS model protocol. Using a randomized, blinded, vehicle-controlled, dose- and time-response study design, we tested the effects of single celastrol [1, 2, or 4 mg/kg intraperitoneally (i.p.), 10–14 rats/group] or edaravone (1, 10 or 30 mg/kg i.p., 14–17 rats/group) injections vs their vehicles on behavioral and electroclinical spasms and developmental milestones. Video-EEG monitoring was done on PN6-7 (n = 11–12 rats/group). Pulse celastrol treatment effects (PN4: 4 mg/kg, PN5-6: 2 mg/kg/day i.p.) were determined on spasms, developmental milestones and Barnes maze. Celastrol and edaravone pharmacokinetics in plasma and neocortex were assessed. Linear mixed model analysis of raw or normalized log-transformed spasm frequencies, considering repeated observations was used.</div></div><div><h3>Results</h3><div>Single (2–4 mg/kg i.p) or pulse celastrol, but not edaravone, reduced behavioral and electroclinical spasms frequencies within 5hrs. Pulse celastrol did not affect spasm-freedom, survival, developmental milestones or Barnes maze performance. Celastrol had erratic i.p. absorption with maximum concentrations observed between 2–4 h, when effects on spasms were seen. Edaravone had low blood-to-brain permeability.</div></div><div><h3>Conclusions</h3><div>Celastrol’s efficacy on spasms is partially explained by its better brain penetration than edaravone’s. NFkB inhibitors may be useful in treating drug-resistant IS but delivery methods with improved bioavailability and brain permeability are needed.</div></div>","PeriodicalId":11847,"journal":{"name":"Epilepsy & Behavior","volume":"162 ","pages":"Article 110159"},"PeriodicalIF":2.3000,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Efficacy and tolerability of celastrol and edaravone in the multiple-hit rat model of infantile spasms\",\"authors\":\"Oleksii Shandra , Yongjun Wang , Lisa D. Coles , Wenzhu B. Mowrey , Qianyun Li , Wei Liu , Solomon L. Moshé , Aristea S. Galanopoulou\",\"doi\":\"10.1016/j.yebeh.2024.110159\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Objective</h3><div>To test whether anti-inflammatory and antioxidant drugs that inhibit the nuclear factor kappa light chain enhancer of activated B cells (NF-kB), celastrol and edaravone, suppress spasms and improve developmental outcomes in the multiple-hit rat model of refractory infantile spasms (IS) due to structural lesions.</div></div><div><h3>Methods</h3><div>Postnatal day 3 (PN3) Sprague-Dawley rats were treated according to the multiple-hit IS model protocol. Using a randomized, blinded, vehicle-controlled, dose- and time-response study design, we tested the effects of single celastrol [1, 2, or 4 mg/kg intraperitoneally (i.p.), 10–14 rats/group] or edaravone (1, 10 or 30 mg/kg i.p., 14–17 rats/group) injections vs their vehicles on behavioral and electroclinical spasms and developmental milestones. Video-EEG monitoring was done on PN6-7 (n = 11–12 rats/group). Pulse celastrol treatment effects (PN4: 4 mg/kg, PN5-6: 2 mg/kg/day i.p.) were determined on spasms, developmental milestones and Barnes maze. Celastrol and edaravone pharmacokinetics in plasma and neocortex were assessed. Linear mixed model analysis of raw or normalized log-transformed spasm frequencies, considering repeated observations was used.</div></div><div><h3>Results</h3><div>Single (2–4 mg/kg i.p) or pulse celastrol, but not edaravone, reduced behavioral and electroclinical spasms frequencies within 5hrs. Pulse celastrol did not affect spasm-freedom, survival, developmental milestones or Barnes maze performance. Celastrol had erratic i.p. absorption with maximum concentrations observed between 2–4 h, when effects on spasms were seen. Edaravone had low blood-to-brain permeability.</div></div><div><h3>Conclusions</h3><div>Celastrol’s efficacy on spasms is partially explained by its better brain penetration than edaravone’s. NFkB inhibitors may be useful in treating drug-resistant IS but delivery methods with improved bioavailability and brain permeability are needed.</div></div>\",\"PeriodicalId\":11847,\"journal\":{\"name\":\"Epilepsy & Behavior\",\"volume\":\"162 \",\"pages\":\"Article 110159\"},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2024-11-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Epilepsy & Behavior\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1525505024005419\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BEHAVIORAL SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Epilepsy & Behavior","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1525505024005419","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BEHAVIORAL SCIENCES","Score":null,"Total":0}
Efficacy and tolerability of celastrol and edaravone in the multiple-hit rat model of infantile spasms
Objective
To test whether anti-inflammatory and antioxidant drugs that inhibit the nuclear factor kappa light chain enhancer of activated B cells (NF-kB), celastrol and edaravone, suppress spasms and improve developmental outcomes in the multiple-hit rat model of refractory infantile spasms (IS) due to structural lesions.
Methods
Postnatal day 3 (PN3) Sprague-Dawley rats were treated according to the multiple-hit IS model protocol. Using a randomized, blinded, vehicle-controlled, dose- and time-response study design, we tested the effects of single celastrol [1, 2, or 4 mg/kg intraperitoneally (i.p.), 10–14 rats/group] or edaravone (1, 10 or 30 mg/kg i.p., 14–17 rats/group) injections vs their vehicles on behavioral and electroclinical spasms and developmental milestones. Video-EEG monitoring was done on PN6-7 (n = 11–12 rats/group). Pulse celastrol treatment effects (PN4: 4 mg/kg, PN5-6: 2 mg/kg/day i.p.) were determined on spasms, developmental milestones and Barnes maze. Celastrol and edaravone pharmacokinetics in plasma and neocortex were assessed. Linear mixed model analysis of raw or normalized log-transformed spasm frequencies, considering repeated observations was used.
Results
Single (2–4 mg/kg i.p) or pulse celastrol, but not edaravone, reduced behavioral and electroclinical spasms frequencies within 5hrs. Pulse celastrol did not affect spasm-freedom, survival, developmental milestones or Barnes maze performance. Celastrol had erratic i.p. absorption with maximum concentrations observed between 2–4 h, when effects on spasms were seen. Edaravone had low blood-to-brain permeability.
Conclusions
Celastrol’s efficacy on spasms is partially explained by its better brain penetration than edaravone’s. NFkB inhibitors may be useful in treating drug-resistant IS but delivery methods with improved bioavailability and brain permeability are needed.
期刊介绍:
Epilepsy & Behavior is the fastest-growing international journal uniquely devoted to the rapid dissemination of the most current information available on the behavioral aspects of seizures and epilepsy.
Epilepsy & Behavior presents original peer-reviewed articles based on laboratory and clinical research. Topics are drawn from a variety of fields, including clinical neurology, neurosurgery, neuropsychiatry, neuropsychology, neurophysiology, neuropharmacology, and neuroimaging.
From September 2012 Epilepsy & Behavior stopped accepting Case Reports for publication in the journal. From this date authors who submit to Epilepsy & Behavior will be offered a transfer or asked to resubmit their Case Reports to its new sister journal, Epilepsy & Behavior Case Reports.