Bioenergetics and Neuronal Network Remodeling in a Rodent Model of Temporal Lobe Epilepsy

颞叶癫痫啮齿动物模型中的生物能量学和神经元网络重塑

• 批准号: 10550184
• 负责人: Yijen Lin Wu
• 金额: $ 19.49万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10550184
• 关键词: 2,4-Dinitrophenol; Acute; Adult; Affect; Anesthesia procedures; Animals; Anticonvulsants; Attenuated; Bioenergetics; Biological Assay; Biological Markers; Brain; Brain Injuries; Child; Childhood; Chronic; Clinical; Complex; Data; Defect; Development; Diffusion Magnetic Resonance Imaging; Dinitrophenols; Disease; Early Intervention; Energy-Generating Resources; Epilepsy; Epileptogenesis; Evolution; Functional Magnetic Resonance Imaging; Functional disorder; Future; Genes; Genetic; Goals; Hypoxia; Impairment; Inherited; Injury; Kainic Acid; Knowledge; Legal patent; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Membrane Potentials; Metabolic; Methods; Mitochondria; Modeling; Molecular; Monitor; Motor Seizures; Mus; N-acetylaspartate; Neuronal Injury; Neurons; Oxidative Phosphorylation; Patients; Pharmaceutical Preparations; Play; Positioning Attribute; Process; Protocols documentation; Proxy; Pyruvate; Rattus; Refractory; Respiration; Respiratory Chain; Rodent; Rodent Model; Rotenone; Route; Seizures; Severities; Signal Transduction; Site; Spirometry; Status Epilepticus; Temporal Lobe Epilepsy; Testing; Time; Tissues; Translating; Validation; acquired epilepsy; epileptic encephalopathies; experience; genomic locus; in vivo; mitochondrial dysfunction; neural network; novel; oxidation; pharmacologic; predictive marker; resilience; risk stratification; spatiotemporal; tool; valproate

Epilepsy affects 3 million adults and 450,000 children in the US. One-third of chronic epilepsy is intractable to current antiseizure medications. Temporal lobe epilepsy (TLE), the most frequent form of acquired epilepsy, is typically initiated by brain injury, such as status epilepticus (SE), followed by a latent period wherein molecular and cellular remodeling occurs leading to chronic epilepsy. The process of remodeling is poorly understood. Not every patient who experiences episodic SE will progress to TLE, and the latent period of epileptogenesis can vary from weeks to years. There is a critical need for new mechanistic understanding and early recognition of post-SE TLE for risk stratification and better management. Mitochondrial dysfunction is increasingly recognized as an inciting factor for TLE, not only acutely after SE, but also contributing to epileptogenesis for refractory TLE. However, there are major knowledge gaps in disease thresholds and a lack of sensitive in vivo tools to detect and monitor the subclinical epileptogenesis process for early intervention before epilepsy is established. Our long-term goal is to understand the remodeling process that leads from SE to TLE. As an important step towards this, we are now in a strong position to test the HYPOTHESIS that a novel 4D oxy-wavelet MRI can be a proxy to detect foci with mitochondrial dysfunctions in post-SE injury that can contribute to TLE development. The focus of the current proposal is to validate and establish 4D oxy-wavelet MRI as a biomarker for identifying brain foci with mitochondrial dysfunctions. We will first validate 4D oxy-wavelet MRI as a non-invasive, region-specific means of monitoring mitochondrial function in the brain. We will use the well-known mitochondrial drugs, rotenone and 2,4-dinitrophenol, to pharmacologically impair or enhance mitochondrial respiration, respectively. Then we will monitor spatiotemporal evolution of region-specific changes in mitochondrial functions with 4D oxy-wavelet MRI in a post-SE TLE rat model. The 4D oxy-wavelet MRI signal will be correlated with ex vivo mitochondrial functional assays, including Oroboros respirometry, and brain metabolic profiling with in vivo MR spectroscopy. Our study will validate 4D oxy-wavelet MRI as a non-invasive method for monitoring mitochondrial activity in the brain. Using a rat model of post-SE TLE, we will use the new MRI tool to observe temporal and region- specific changes of mitochondrial function. These data can advance use of the 4D oxy-wavelet MRI as a non- invasive biomarker for predicting post-SE TLE. As this method is non-invasive, it can be translated to clinical setting in the future.

在美国，癫痫会影响300万成人和450,000名儿童。慢性癫痫的三分之一是 对当前的毒药很棘手。颞叶癫痫（TLE），最常见的形式 癫痫，通常是由脑损伤引发的，例如状态癫痫症（SE），然后是一个潜在时期 分子和细胞重塑发生导致慢性癫痫。重塑的过程很差 理解。并非每个经历情节性SE的患者都会发展为TLE，而潜在时期 癫痫发生可能因几周到几年而异。迫切需要新的机械理解和 早期认识到风险分层和更好的管理。 线粒体功能障碍越来越多地被认为是TLE的刺激因素，不仅是敏锐的 SE，但也有助于癫痫生成的耐火性TLE。但是，有主要的知识差距 疾病阈值和缺乏敏感的体内工具来检测和监测亚临床癫痫发生 建立癫痫之前的早期干预过程。我们的长期目标是了解重塑 从SE到TLE的过程。作为朝着这一目标的重要一步，我们现在处于强大的位置来测试 假设新型的4D氧气小波MRI可以是检测用线粒体功能障碍检测焦点的代理 SE后伤害可能有助于TLE的发展。当前建议的重点是验证和 建立4D氧小波MRI作为一种生物标志物，用于鉴定有线粒体功能障碍的脑焦点。我们将 首先验证4D氧波MRI作为一种非侵入性，特定区域特定的线粒体功能的手段 在大脑中。我们将使用众所周知的线粒体药物，烤面包酮和2,4-二硝基苯酚 药理学上分别损害或增强线粒体呼吸。然后，我们将监视时空 线粒体函数中区域特异性变化的演变，其4D氧气大鼠MRI 模型。 4D氧波小波MRI信号将与离体线粒体功能分析相关，包括 Oroboros呼吸测定法和体内MR光谱法进行脑代谢分析。 我们的研究将验证4D氧波MRI作为监测线粒体活性的非侵入性方法 在大脑中。使用新的大鼠模型，我们将使用新的MRI工具观察时间和区域 - 线粒体功能的特定变化。这些数据可以提高4D氧大波MRI作为非 - 侵入性生物标志物用于预测后的tle。由于这种方法是非侵入性的，因此可以翻译成临床 将来设置。