Striatal Sequelae of Perinatal Anticonvulsant Drug Treatment

围产期抗惊厥药物治疗的纹状体后遗症

基本信息

批准号：
8013065
负责人：
Patrick Alexander Forcelli
金额：
$ 2.87万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8013065
关键词：
ARHGEF5 gene Acoustics Address Adult Anesthetics Animals Anticonvulsants Antiepileptic Agents Apoptosis Apoptotic Area Attenuated Behavior Behavioral Behavioral Assay Brain Brain region Cell Death Cells Cessation of life Corpus striatum structure Coupled Data Development Disease Dose Drug Exposure Educational process of instructing Epilepsy Exhibits Exposure to Fellowship Frequencies Goals Human Impairment Infant Institution Intervention Laboratories Lead Levetiracetam Measures Melatonin Mentors Motor Motor Seizures National Research Service Awards Neonatal Neurologic Neurons Outcome Pentylenetetrazole Performance Perinatal Pharmaceutical Preparations Pharmacotherapy Phenobarbital Phenytoin Physiological Pregnancy Pregnant Women Publishing Rattus Reflex action Regulation Research Rodent Seizures Sensory Series Slice Students Synapses Synaptic Transmission Techniques Testing Time Toxic effect Training adverse outcome attenuation career critical developmental period follow-up functional disability functional outcomes infancy interest lamotrigine lectures neonate neurodevelopment neuron apoptosis neuron loss patch clamp post-doctoral training postnatal prepulse inhibition prevent programs pup putamen research study response skills

项目摘要

DESCRIPTION (provided by applicant): The use of antiepileptic drugs (AEDs) in pregnancy and early infancy poses special challenges and concerns, as even transient exposure to certain drugs during CNS development may impede subsequent neuronal and synaptic development. Several AEDs, including phenobarbital and phenytoin, when given in therapeutically relevant doses to rats during the early postnatal period, cause a pronounced increase in apoptotic cell death in several brain regions. Other drugs such as lamotrigine (in low or moderate doses) and levetiracetam are devoid of this effect. We have recently discovered a single exposure to phenobarbital, at the time of peak vulnerability to the propapoptotic action (postnatal day 7 in the rat), resulted In the suppression of the normal, developmental increase in the frequency of inhibitory post-synaptic currents (IPSCs) recorded via patch clamp from striatal medium spiny neurons (MSNs) in slices taken between postnatal day 10 and 14. We have also identified impairments in adult rotorod performance in rats treated at P7 with a proapoptotic dose of phenytoin, a reduction in prepulse inhibition (a measure of sensory-motor gating) and a reduction in seizure threshold to pentylenetetrazol In animals treated in the first postnatal week with phenobarbital. Each of these behavioral assays are sensitive to damage or altered function in the striatum. The proposed experiments will follow up on these exciting preliminary findings to determine if there is a consistent and predictive (potentially causative) relationship between AED-induced neuronal apoptosis and impaired maturation of I PSC frequency in the striatum and/or adult behavioral toxicitiy. This will be assessed by comparing AED treatments that are proapoptotic with those that avoid this toxicity. We hypothesize that AEDs that do not cause cell death will not cause impaired maturation of IPSC frequency in striatal MSNs, nor will they result in impaired rotorod performance, reduced seizure threshold, and impaired prepulse inhibition ofthe acoustic starle response. Moreover, the extent to which a neuroprotective treatment can prevent impaired maturation of IPSC frequency in striatal MSNs and/or behavior will be evaluated to test the hypothesis that neuronal death is necessary for this adverse functional outcome. The results ofthe proposed experiments will allow us to better understand the potential functional outcomes of exposure to AEDs in late gestation or early infancy, and the extent to which induction of excessive neuronal death is a valid marker of subsequent functional impairment. Furthermore, it will identify strategies to avoid deleterious functional sequelae of AED therapy during critical developmental periods. GOALS FOR KIRSCHSTEIN-NRSA FELLOWSHIP TRAINING AND CAREER I am seeking this fellowship tp support my dissertation research in Dr. Karen Gale and Dr. Stefano Vicini's laboratories, investigating the impact of neonatal anticonvulsant drug exposure. My goal for dissertation research is to develop a broad skill set of experimental techniques that will allow me to address scientific questions at the level of molecules, cells, networks and behavior. The complementary expertise of my mentors provides such exposure. A limited portion of this support is also requested to allow me to continue to teach (present lectures to graduate and undergraduate students, and continue to direct a course entitled, "Diseases and Disorders of the Brain". A key goal of my training is to complete and publish a series of focused studies on outcomes following drug exposure during development. My long-term goals are predicated on the broad training I am receiving at Georgetown. Following Georgetown I will seek post-doctoral training and then I hope to develop an independent, productive research program at an academic institution where I can ask and answer questions of interest at multiple levels of function, to maintain an active Involvement in teaching and mentoring, and to contribute to scientific discourse.

描述（由申请人提供）：在怀孕和婴儿早期期间使用抗癫痫药（AED）提出了特殊的挑战和关注，因为即使在中枢神经系统发育过程中暂时暴露于某些药物也可能妨碍随后的神经元和突触发育。当在产后早期对大鼠进行治疗相关剂量时，几种AED，包括苯巴比妥和苯妥英，在几个大脑区域都显着增加了凋亡细胞死亡的明显增加。其他药物（例如低剂量或中等剂量）和左旋乙酰氨基苯二甘氨酸的药物没有这种作用。最近，我们发现了一次暴露于苯巴尔滨的暴露，在高峰易受倾向作用时（大鼠的第7天后），导致抑制正常的抑制后突触后电流（IPSC）的发育率增加，这也是通过斑点中的斑点神经元（IPSC）记录的。在P7治疗的大鼠成年rotorod性能的损害，苯妥英钠的促凋亡剂量，降低预硫酸抑制作用（一种感觉运动门控的量度）以及在第一个在近头一周中治疗的动物中戊戊酸术的癫痫发作阈值降低。这些行为测定中的每一个都对纹状体中的损伤或功能改变敏感。提出的实验将跟进这些令人兴奋的初步发现，以确定AED诱导的神经元细胞凋亡和IPSC频率成熟和/或成人行为毒理中I PSC频率的成熟之间是否存在一致且预测的（潜在的病因）关系。这将通过将促凋亡的AED治疗与避免这种毒性的AED治疗进行比较。我们假设不会导致细胞死亡的AED不会导致纹状体MSN中IPSC频率成熟的受损，也不会导致Rotorod的性能受损，癫痫发作阈值降低以及对声学星球反应的预硫抑制作用受损。此外，将评估神经保护治疗可防止IPSC频率成熟和/或行为的成熟程度，以检验以下假设：神经元死亡对于这种不良功能结果是必要的。提出的实验的结果将使我们能够更好地了解妊娠或早期婴儿期暴露于AED的潜在功能结果，以及过度神经元死亡的诱导程度是随后功能障碍的有效标志。此外，它将确定避免在关键发育期间AED治疗的有害功能后遗症的策略。 Kirschstein-NRSA奖学金培训和职业生涯的目标我正在寻求TP TP支持我在Karen Gale博士和Stefano Vicini博士实验室中的论文研究，并调查了新生儿抗惊厥药物暴露的影响。我的论文研究的目标是开发一系列广泛的实验技术，使我能够在分子，细胞，网络和行为水平上解决科学问题。我的导师的互补专业知识提供了这种曝光。还要求我继续教书（目前的毕业和本科生讲座，并继续指导一门题为“大脑的疾病和疾病”的课程。我的培训的关键目标是完成并发布一系列专注于发展的培训后，我的长期培训是我的培训。博士后培训，然后我希望在一个学术机构中制定一项独立的，生产的研究计划，在该计划中，我可以在多个功能层面上询问和回答感兴趣的问题，以保持积极参与教学和指导，并为科学话语做出贡献。