Mechanisms for Improving Cognitive Outcome in Pediatric Epilepsy with ACTH

ACTH 改善小儿癫痫认知结果的机制

• 批准号: 10232148
• 负责人: Amanda Hernan
• 金额: $ 24.24万
• 依托单位: ALFRED I. DU PONT HOSP FOR CHILDREN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10232148
• 关键词: Acute; Address; Adrenal Cortex Hormones; Adult; Aftercare; Agonist; American; Animals; Anti-Inflammatory Agents; Anticonvulsants; Area; Attention; Behavioral; Belief; Benchmarking; Biological; Brain; Brain region; Child; Chronic; Clinical Data; Code; Cognition; Cognitive; Cognitive deficits; Communication; Control Animal; Critical Pathways; Data; Development; Disease Pathway; Disease model; Early treatment; Effectiveness; Epilepsy; Evolution; Executive Dysfunction; Extinction (Psychology); Flurothyl; Fright; Funding; Goals; Gold; Hippocampus (Brain); Hormones; Impaired cognition; Impairment; Incidence; Individual; Infantile spasms; Laboratories; Life; Link; Melanocortin 4 Receptor; Mentors; Methods; Modeling; Modification; Molecular; National Institute of Neurological Disorders and Stroke; Neurodevelopmental Disorder; Neuroglia; Neurons; Outcome; Patients; Pharmaceutical Preparations; Phase; Population; Prefrontal Cortex; Prevention; Property; Quality of life; Rattus; Receptor Activation; Receptor Signaling; Recording of previous events; Research; Rodent Model; Role; Seizures; Short-Term Memory; Signal Pathway; Societies; Specificity; Synaptic plasticity; System; Testing; Time; Training; aggressive therapy; behavioral impairment; cell type; childhood epilepsy; clinically relevant; comorbidity; computational neuroscience; design; experimental study; hypothalamic-pituitary-adrenal axis; improved; improved outcome; in vivo; information processing; knock-down; melanocortin receptor; nervous system disorder; network dysfunction; neural network; novel; prevent; psychiatric comorbidity; receptor; receptor expression; relating to nervous system; self organization; small hairpin RNA; standard care; therapeutic target; tool; treatment duration; treatment strategy

Epilepsy, particularly pediatric epilepsy, is associated with a very high incidence of cognitive, behavioral and psychiatric comorbidities that are often more detrimental to overall quality of life than the seizures themselves. Aggressive treatment of seizures has been the gold standard, with the belief that this will also minimize cognitive and psychiatric comorbidities. However, very little focus has been placed on treatment of these comorbidities directly and clinical data suggest that focusing on seizure treatment alone does not effectively treat cognitive impairment. We have recently found that ACTH, an endogenous part of the hypothalamic- pituitary-adrenal axis that is often exogenously administered to children with severe epilepsies, can improve cognitive outcome in rats without altering seizure parameters. While it was previously thought that the primary mechanism of action for ACTH was through the release of corticosteroids, new research suggests that melanocortin 4 receptor (MC4R) activation in neuronal and glial populations is neuroprotective and can improve outcomes in other disease models. We hypothesize that MC4R agonism in the CNS with ACTH is a key mechanism of action by which it can improve cognitive outcomes after early life seizures (ELS). We further hypothesize that early treatment with ACTH will normalized functional organization of neural networks within and between the prefrontal cortex and the hippocampus, and that this improvement will provide a systems-level mechanism underpinning its mechanism of action. Understanding how ACTH can prevent cognitive deficits without altering seizure parameters is crucial for finding novel treatment approaches for these deficits. Therefore, the scientific aims of this study are to: 1) (Phase I) determine the role of MC4R signaling in the brain on subsequent cognition in control animals and (Phase II) ELS animals, 2) (Phase I) determine the effect of early treatment with ACTH on synaptic plasticity in adult neuronal networks in the PFC after ELS and finally 3) (Phase II) determine the effect of early treatment with ACTH on adult neuronal networks in vivo and executive dysfunction associated with ELS. To achieve these goals, I require additional training, both formal through a “Methods in Computational Neuroscience” course at the Marine Biological Laboratory and informal with my co-mentor, Dr. Mahoney, in order to develop the neurocomputational modeling tools necessary for exploring the systems-level mechanisms of cognitive impairment after ELS and the prevention of such impairments with ACTH. The studies proposed are designed to understand the developmental role of ACTH and MC4Rs on cognitive networks in ELS. Successful completion of this project has the potential to change the way we think about treatment of pediatric epilepsy, and may have implications for the treatment of other neurodevelopmental disorders as well.

癫痫，特别是小儿癫痫，与认知、行为和精神障碍的非常高的发病率相关。 精神病合并症，往往比癫痫发作本身对整体生活质量更有害。 积极治疗癫痫一直是金标准，相信这也将最大限度地减少 认知和精神共病。然而，很少有人关注这些疾病的治疗。 临床数据表明，仅关注癫痫发作治疗并不能有效地 治疗认知障碍。我们最近发现，促肾上腺皮质激素，下丘脑的内源性部分- 垂体-肾上腺轴，往往是外源性管理的儿童严重癫痫，可以改善 在不改变癫痫发作参数的情况下，大鼠的认知结果。虽然以前认为， 促肾上腺皮质激素的作用机制是通过释放皮质类固醇，新的研究表明， 黑皮质素4受体（MC 4 R）在神经元和神经胶质细胞群中的激活具有神经保护作用， 改善其他疾病模型的结果。 我们推测，促肾上腺皮质激素激动中枢神经系统中的MC 4 R是一个关键的作用机制， 可以改善早期癫痫发作（ELS）后的认知结果。我们进一步假设， ACTH治疗将使神经网络内部和之间的功能组织正常化， 前额叶皮层和海马体，这种改善将提供一个系统水平的 机制支撑其作用机制。了解ACTH如何预防认知功能障碍 在不改变癫痫发作参数的情况下减少癫痫发作是为这些缺陷找到新的治疗方法的关键。 因此，本研究的科学目的是：1）（第一阶段）确定MC 4 R信号在大脑中的作用 对对照动物和（II期）ELS动物随后认知的影响，2）（I期）确定 早期ACTH治疗对ELS后PFC中成人神经元网络的突触可塑性的影响，以及3） （II期）确定ACTH早期治疗对体内和执行神经元网络的影响。 与ELS相关的功能障碍。 为了实现这些目标，我需要额外的培训，无论是通过正式的“计算方法 在海洋生物实验室和非正式与我的共同导师，马奥尼博士， 为了开发探索系统级所需的神经计算建模工具， ELS后认知障碍的机制以及ACTH对此类障碍的预防。的 提出的研究旨在了解ACTH和MC 4 Rs在认知功能发育中的作用。 网络在ELS这个项目的成功完成有可能改变我们对 儿童癫痫的治疗，并可能对其他神经发育疾病的治疗产生影响 紊乱也是。

项目成果

Differential regulation of gene expression pathways with dexamethasone and ACTH after early life seizures.

• DOI: 10.1016/j.nbd.2022.105873
• 发表时间: 2022-11
• 期刊: NEUROBIOLOGY OF DISEASE
• 影响因子: 6.1
• 作者: Brabec, Jeffrey L.;Ouardouz, Mohamed;Mahoney, J. Matthew;Scott, Rod C.;Hernan, Amanda E.
• 通讯作者: Hernan, Amanda E.

Mechanisms for Cognitive Impairment in Epilepsy: Moving Beyond Seizures.

• DOI: 10.3389/fneur.2022.878991
• 发表时间: 2022
• 期刊: FRONTIERS IN NEUROLOGY
• 影响因子: 3.4
• 作者: Khalife, Mohamed R.;Scott, Rod C.;Hernan, Amanda E.
• 通讯作者: Hernan, Amanda E.