Age Related Seizure Suppression

年龄相关的癫痫发作抑制

基本信息

批准号：
8122116
负责人：
SOLOMON L. MOSHE
金额：
$ 50.56万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8122116
关键词：
6-Cyano-7-nitroquinoxaline-2,3-dione Abbreviations Acids Acute Adult Affinity Age Agonist Androgen Receptor Animals Anticonvulsants Antiepileptic Agents Appearance Applications Grants Attenuated Autistic Disorder Behavior Control Benzodiazepines Bicuculline Brain Bromodeoxyuridine CLC-2 protein CREB1 gene Calcium Channel Cells Chloride Ion Chlorides Clonic Seizure Cognition Cognition Disorders Cyclic AMP-Responsive DNA-Binding Protein Data Development Developmental Process Diazepam Disease Down-Regulation Epidemiologic Studies Epigenetic Process Exposure to Failure Female Fluorescein Flurothyl GABA transporter Gender Genetic Glutamate Decarboxylase Goals Health Hematoxylin and Eosin Staining Method Human Hydrochloride Salt Immunochemistry Immunohistochemistry Impact Seizures In Situ Hybridization In Vitro Infant Infusion procedures Intervention KCC2 cotransporter Kainic Acid Kainic Acid Receptors Lead Life Long-Term Effects Mediating Messenger RNA Methods Modification Motor Muscimol NMDA receptor antagonist Nature Network-based Neuronal Differentiation Neuronal Injury Neurons Nifedipine Nipecotic Acids Outcome Output Parvalbumins Pattern Pentylenetetrazole Perinatal Phenotype Pilocarpine Polymerase Chain Reaction Predisposition Proliferating Rattus Receptor Signaling Recording of previous events Recurrence Reverse Transcription Role S-nitro-N-acetylpenicillamine Seizures Sexual Development Site Sodium Channel Sodium-Potassium-Chloride Symporters Staining method Stains Status Epilepticus Substantia nigra structure Synapses System Testing Tetrodotoxin Time Tyrosine 3-Monooxygenase Work age related base carbonate dehydratase chloride-cotransporter potassium experience fluoro jade gabazine gamma-Aminobutyric Acid immunoreactivity in vivo inhibitor/antagonist male mature animal poly(L-glutamic acid(60)-L-alanine(30)-L-tyrosine(10))postnatal postsynaptic pregnane-20-one prevent receptor response sex tetrahydrodeoxycorticosterone therapy design treatment duration uptake voltage zolpidem

项目摘要

DESCRIPTION (provided by applicant): Epidemiological studies suggest that early in life, the brain is very susceptible to seizures and especially status epilepticus (SE). Understanding the spectrum and progressive nature of SE-induced changes in brain function may have important implications in the design of treatments aimed at disease modification. The substantia nigra pars reticulata (SNR) is one of the brain sites critically involved in the control of seizures. Preliminary data indicate that the development of the SNR is distorted if infant rats experience 3 episodes of SE (3SE) prior to postnatal day (PN) 6 by preventing the emergence of the SNR GABA-sensitive anticonvulsant region at PN30. 3SE are not associated with acute neuronal injury in SNR but increase the expression of the chloride cotransporter KCC2 mRNA and accelerate the switch of synaptic GABAAergic responses from depolarizing to hyperpolarizing; induce changes in GABAA receptor subunit composition; and attenuate the responsiveness of SNRanterior neurons to GABAA agents in vivo and in vitro at PN30. Because the depolarizing effects of GABA are important for neuronal differentiation, the data suggest that, during a specific developmental window, the 3SE- induced increases in KCC2 expression and the resultant early appearance of hyperpolarizing responses may shorten the period during which the normal GABA-mediated differentiation of SNR occurs. The specific aims are to determine: 1. The discrete developmental periods during which exposure to 3SE prevents the expression of SNR GABAA-sensitive anticonvulsant region; 2. The effects of 3SE during the susceptible developmental period on GABAA-related function in SNR; 3. The identification of agents that can restore the normal developmental pattern of GABAA receptor signaling and avert the 3SE-induced long-term detrimental effects on SNRanterior GABAA-sensitive anticonvulsant region. Male and female rats will be used. Methods include induction of SE using kainic acid or pilocarpine, intracranial microinfusions of GABAA agents and seizure testing using flurothyl or pentylenetetrazole, immunohistochemistry, qRT-PCR, in situ hybridization, in vivo and in vitro electrophysiological recordings. PUBLIC HEALTH RELEVANCE The overall goal is to identify mechanisms involved in the suppression of seizures as a function of age, gender and prior history of seizures. Recurrent prolonged seizures may prevent the normal maturation of the brain. Understanding the impact of these seizures on the development of effective seizure suppressing mechanisms in animals may lead to the identification of new time-sensitive treatments to prevent the long-term effects of status epilepticus in human infants.

描述（由申请人提供）：流行病学研究表明，在生命的早期，大脑非常容易受到癫痫发作，尤其是状态癫痫症（SE）。了解SE诱导的脑功能变化的频谱和渐进性可能对旨在疾病修饰的治疗的设计具有重要意义。黑质nigra pars reticulata（SNR）是严重涉及癫痫发作的大脑部位之一。初步数据表明，如果婴儿大鼠在产后（pn）6（pn）6（pn）6（pn）6（pn）6发作，通过防止SNR GABA对PN30的SNR GABA敏感抗惊厥区的出现，则SNR的发展会扭曲。 3SE与SNR中的急性神经元损伤无关，而是增加氯化物共转运蛋白KCC2 mRNA的表达，并加速了突触GabaAagagic反应从去极化到超极化的转换；诱导GABAA受体亚基组成的变化；并减轻Snranterior神经元对体内Gabaa剂和PN30的体外的反应性。由于GABA的去极化作用对于神经元分化很重要，因此数据表明，在特定的发育窗口中，3SE诱导的KCC2表达增加以及超极化反应的早期出现可能会缩短正常GABA介导的SNR分化的时期。具体目的是确定：1。暴露于3SE的离散发育周期阻止了SNR GABAA敏感的抗惊厥区域的表达； 2。在易感性发育时期3SE对SNR中与GABAA相关功能的影响； 3。鉴定可以恢复GABAA受体信号传导正常发育模式的药物，并避免3SE诱导的长期有害作用对SN旋转GABAA敏感的抗惊厥区域。将使用雄性和雌性大鼠。方法包括使用Kainic Acid或Pilocarpine诱导SE，GABAA药物的颅内微吸收以及使用Flurothyl或氯噻酯或氯乙酸酯或氯乙酸酯的癫痫发作测试，免疫组织化学，QRT-PCR，QRT-PCR，QRT-PCR，原位杂交，体内和体内杂交。公共卫生相关性的总体目标是确定抑制癫痫发作的机制，这是年龄，性别和先前癫痫发作历史的功能。复发性延长的癫痫发作可能会阻止大脑正常成熟。了解这些癫痫发作对动物有效癫痫发作机制的发展的影响可能会导致鉴定新的时间敏感治疗方法，以防止癫痫癫痫病在人类婴儿中的长期影响。