Efficacy of flupirtine for treatment of neonatal hypoxic-ischemic encephalopathy

氟吡汀治疗新生儿缺氧缺血性脑病的疗效

• 批准号: 8663705
• 负责人: Yogendra H Raol
• 金额: $ 28.14万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8663705
• 关键词: Acute; Adult; Adverse effects; Affect; Age; Analgesics; Anatomy; Animal Model; Antiepileptic Agents; Antioxidants; Apoptotic; BCL2 gene; Behavioral; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Calcium; Cell Death; Cells; Child; Chronic Brain Injury; Clinic; Clinical; Clinical Treatment; Clinical Trials; Cognition; Cognitive; Degenerative Disorder; Development; Developmental Delay Disorders; Diazepam; Disease; Disease model; Drug usage; Elderly; Epilepsy; Etiology; Europe; Fibromyalgia; Focal Seizure; Frequencies; GABA-A Receptor; Genes; Glutathione; Health; Hour; Human; Infant; Injury; Intellectual functioning disability; Laboratories; Lead; Life; Mediating; Modeling; Multiple Sclerosis; Neonatal; Nervous System Physiology; Neurodevelopmental Deficit; Neurologic; Neurological outcome; Neuroprotective Agents; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Phenobarbital; Phenytoin; Play; Potassium; Potassium Channel; Principal Investigator; Property; Proteins; Rattus; Refractory; Role; Safety; Seizures; Survivors; Testing; Translating; Translations; age group; analog; caspase-3; common treatment; design; early childhood; effective therapy; experience; flupirtine; gamma-Aminobutyric Acid; improved; mind control; neonatal hypoxic-ischemic brain injury; neonate; neurochemistry; neurodevelopment; neuroprotection; novel; prevent; programs; treatment effect

DESCRIPTION (provided by applicant): The neonatal brain is different from mature brain anatomically and neurochemically, which can affect how the immature brain responds to both injury and treatment as compared to mature brain. Therefore, to find the most efficacious treatment for early childhood diseases, it is imperative to target age-specific mechanisms and test new therapies in neonatal disease models. Hypoxia-ischemia (HI) is a common cause of neonatal seizures and brain injury. Survivors of HI often experience neurological problems such as epilepsy and intellectual disability in later life. Studies suggest that seizures contribute to brain injury and affect long-term neurologic outcome. First-line drugs such as phenobarbital, which act by augmenting GABA(A) receptors, are poorly effective in treating neonatal seizures and are associated with many side effects. Potassium channels play a uniquely important role in controlling brain excitability in early life. Our recent study showed that unlike diazepam and phenobarbital, flupirtine a potassium channel opener, effectively treated chemoconvulsant- induced neonatal seizures. Flupirtine has been used clinically as an analgesic in Europe for decades with excellent safety record. Flupirtine is neuroprotective in animal models of various degenerative diseases and is currently in clinical trials as a neuroprotective therapy for multiple sclerosis. In the current proposal I hypothesize that flupirtine, with its potential neuroprotective action combined with strong efficacy to stop neonatal seizures, will treat HI-induced neonatal seizures, reduce brain injury and improve the long-term neurologic outcome. Specifically, I propose to: I. Determine whether flupirtine given after first HI-induced seizure will inhibit or reduce further HI-induced acute behavioral and electrographic seizure activity in 7 days old rats, II. Determine whether flupirtine prevents or reduces acute and chronic brain injury and identify the underlying mechanism of neuroprotection, III. Determine if treatment with flupirtine following neonatal HI alleviates behavioral deficits and inhibits epilepsy development in later life. These studies will determine if flupirtine effectively treats HI without adversely affecting development. If successful, these studies should rapidly translate into new effective treatment for neonatal HI.

描述（由申请人提供）：在解剖学和神经化学上，新生儿大脑与成熟的大脑不同，这可能会影响与成熟大脑相比，未成熟大脑对损伤和治疗的反应。因此，要找到针对幼儿疾病的最有效治疗方法，必须在新生儿疾病模型中靶向特定年龄的机制并测试新疗法。缺氧 - 缺血（HI）是新生儿癫痫发作和脑损伤的常见原因。 HI的幸存者经常在以后的生活中经常经历癫痫和智力残疾等神经问题。研究表明，癫痫发作会导致脑损伤并影响长期神经系统损伤。通过增强GABA（A）受体起作用的苯巴比妥等一线药物在治疗新生儿癫痫发作方面的有效性不佳，并且与许多副作用有关。钾通道在控制早期大脑兴奋性方面起着独特的重要作用。我们最近的研究表明，与地西ep和苯巴比妥不同，plupirtine a钾通道开瓶器有效地处理了化学磁空诱导的新生儿癫痫发作。数十年来，欧洲临床上一直在临床上用作镇痛药，并具有出色的安全记录。 Clupirtine在各种退化性疾病的动物模型中具有神经保护作用，目前正在临床试验中作为多发性硬化症的神经保护疗法。在当前的提案中，我假设其潜在的神经保护作用加上强大的疗效以阻止新生儿癫痫发作，将治疗高引起的新生儿癫痫发作，减少脑损伤并改善长期神经系统损伤。具体而言，我建议：I。确定第一次癫痫发作后给出的浮翼蛋白是否会抑制或减少7天大的大鼠的进一步HI诱导的急性急性行为和电学癫痫发作活性，II。确定浮力石是否可以防止或减少急性和慢性脑损伤，并确定神经保护的潜在机制，iii。确定新生儿HI后用浮力石治疗减轻行为缺陷并抑制后来的癫痫发育。这些研究将确定浮力石是否在不影响发展的情况下有效地治疗HI。如果成功，这些研究应迅速转化为新生儿HI的新有效治疗方法。

项目成果

Anticonvulsant effect of flupirtine in an animal model of neonatal hypoxic-ischemic encephalopathy.

• DOI: 10.1016/j.neuropharm.2017.06.002
• 发表时间: 2017-09-01
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: Sampath D;Valdez R;White AM;Raol YH
• 通讯作者: Raol YH

Searching for new targets for treatment of pediatric epilepsy.

寻找治疗小儿癫痫的新靶点。

• DOI: 10.1016/j.yebeh.2012.09.022
• 发表时间: 2013
• 期刊: Epilepsy & behavior : E&B
• 作者: Noam,Yoav;Raol,YogendraH;Holmes,GregoryL
• 通讯作者: Holmes,GregoryL

Repeated exposure to low doses of kainic acid activates nuclear factor kappa B (NF-κB) prior to seizure in transgenic NF-κB/EGFP reporter mice.

• DOI: 10.1016/j.neuro.2014.04.010
• 发表时间: 2014-09
• 期刊: Neurotoxicology
• 影响因子: 3.4
• 作者: Miller JA;Kirkley KA;Padmanabhan R;Liang LP;Raol YH;Patel M;Bialecki RA;Tjalkens RB
• 通讯作者: Tjalkens RB

Brain Distribution and Metabolism of Flupirtine, a Nonopioid Analgesic Drug with Antiseizure Effects, in Neonatal Rats.

氟吡汀（一种具有抗癫痫作用的非阿片类镇痛药）在新生大鼠中的脑分布和代谢。

• DOI: 10.3390/pharmaceutics10040281
• 发表时间: 2018
• 期刊: Pharmaceutics
• 影响因子: 5.4
• 作者: Patil,MadhoosudanA;Matter,BrockA;Raol,YogendraH;Bourne,DavidWA;Kelley,RyanA;Kompella,UdayB
• 通讯作者: Kompella,UdayB