Combined NSC Grafting and Neurogenic Drug Therapy for Temporal Lobe Epilepsy

NSC 移植和神经源性药物联合治疗颞叶癫痫

• 批准号: 8967096
• 负责人: ASHOK K SHETTY
• 金额: --
• 依托单位: OLIN TEAGUE VETERANS CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8967096
• 关键词: Address; Adverse effects; Affect; Afghanistan; Allopregnanolone; Alternative Therapies; Anticonvulsants; Antiepileptic Agents; Astrocytes; BDNF gene; Behavior; Benchmarking; Cell Differentiation process; Cell Therapy; Cell Transplantation; Cells; Chronic; Cognition; Cognitive; Combined Modality Therapy; Comorbidity; Complex; Craniocerebral Trauma; Data; Development; Embryo; Epilepsy; Excision; Exhibits; FGF2 gene; Focal Seizure; Frequencies; Future; Gene Proteins; Generations; Genes; Goals; Healthcare; Hippocampus (Brain); Impaired cognition; Interneurons; Intractable Epilepsy; Iraq; Lead; Learning; Link; Medial; Mediating; Memory; Memory impairment; Mental Depression; Modeling; Moods; Neurons; Neurotransmitters; Operative Surgical Procedures; Patients; Pattern; Peripheral; Pharmacotherapy; Proteins; Rattus; Recovery; Recovery of Function; Recurrence; Resistance; Seizures; Soldier; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Veterans; War; analog; arm; clinical application; cognitive function; combat; depressive symptoms; disturbance in affect; gamma-Aminobutyric Acid; ganaxolone; glial cell-line derived neurotrophic factor; graft failure; improved; improved functioning; kainate; memory recognition; migration; nerve stem cell; neurogenesis; neurosteroids; neurotrophic factor; protein expression; public health relevance; restoration; standard of care; subcutaneous; treatment strategy

DESCRIPTION (provided by applicant): PROJECT SUMMARY Cell transplantation strategies capable of diminishing spontaneous recurrent seizures (SRS), learning and memory dysfunction and depression in chronic temporal lobe epilepsy (TLE) have great significance because ~35% of patients with TLE have SRS that are resistant to antiepileptic drugs (AEDs) and AED therapy does not reduce cognitive and mood dysfunction. As TLE is associated with a paucity of inhibitory GABA-ergic neurons and astrocytes secreting the anticonvulsant protein glial cell line-derived neurotrophic factor (GDNF), cell grafts that have the ability to give rise to both GABA-ergic neurons and GDNF+ astrocytes appear attractive for restraining SRS. Indeed, our recent study has shown that grafting of the medial ganglionic eminence (MGE) derived neural stem cells (NSCs) into the hippocampus of rats exhibiting chronic TLE substantially reduces the frequency and intensity of SRS with additions of new GABA-ergic neurons and GDNF+ astrocytes. However, no improvements were seen in the hippocampal neurogenesis or cognitive function. Analyses of grafts revealed that the overall yield of graft-derived cells was only 28% of injected cells and engrafting of cells into th neurogenic subgranular zone (SGZ) was minimal. This finding suggested that lack of improvements in neurogenesis and cognition after MGE-NSC grafting is a consequence of both lower yield and reduced migration of graft- derived cells. We hypothesize that combined grafting of MGE-NSCs into the hippocampus and peripheral administration of neurogenic compounds will greatly diminish SRS as well as reverse memory dysfunction and depression seen in chronic TLE. We propose that such improved functional recovery will be associated with engrafting of significant numbers of graft-derived cells into the SGZ, generation of greater numbers of new GABA-ergic neurons and GDNF+ astrocytes from grafts, restoration of the host hippocampal GDNF concentration, increased hippocampal neurogenesis, and normalization in the concentration/expression of proteins/genes important for cognitive and mood function and neurogenesis. In this project, we will investigate whether combined intrahippocampal grafting of MGE-NSCs and neurogenic drug treatment strategies would greatly diminish SRS, cognitive dysfunction and depression in a rat model of chronic TLE. In Specific Aim 1, we will ascertain the effects of combined intrahippocampal grafting of MGE-NSCs and subcutaneous (S.C.) FGF-2 treatment for 14 days. In Specific Aim 2, we will examine the effects of combined intrahippocampal grafting of MGE-NSCs with S.C. administration of neurosteroid analog ganaxolone. We will test whether seizure-suppression and improved cognitive and mood function mediated by these combination therapies are linked to an increased yield of graft-derived GABA-ergic neurons and GDNF-positive astrocytes, engrafting of greater numbers of graft-derived NSCs into the neurogenic SGZ, increased activity of endogenous NSCs and hippocampal neurogenesis, and enhanced expression of proteins/genes vital for cognitive and mood functions. We will also compare these results with data obtained from grafts of MGE-derived GABA-ergic cells and MGE-NSC derived astrocyte grafts in the presence or absence of FGF-2/Ganaxolone treatment. The proposed studies have promise for providing the critical benchmarks essential for considering clinical application of NSC grafting strategies for treating chronic TLE. The studies are also relevant to the health care needs of Veterans, as combat related moderate to severe head injuries among soldiers who served in Iraq and Afghanistan wars might lead to chronic TLE in the coming years.

描述（由申请人提供）： 项目摘要 能够减少慢性颞叶癫痫 (TLE) 自发性复发性癫痫发作 (SRS)、学习记忆功能障碍和抑郁症的细胞移植策略具有重要意义，因为约 35% 的 TLE 患者患有抗癫痫药物 (AED) 耐药的 SRS ）并且 AED 治疗不会减少认知和情绪功能障碍。由于 TLE 与分泌抗惊厥蛋白胶质细胞系源性神经营养因子 (GDNF) 的抑制性 GABA 能神经元和星形胶质细胞的缺乏有关， 能够产生 GABA 能神经元和 GDNF+ 星形胶质细胞的细胞移植物似乎对抑制 SRS 很有吸引力。事实上，我们最近的研究表明，将内侧神经节隆起 (MGE) 衍生的神经干细胞 (NSC) 移植到表现出慢性 TLE 的大鼠海马中，通过添加新的 GABA 能神经元和 GDNF+，显着降低了 SRS 的频率和强度星形胶质细胞。然而，海马神经发生或认知功能没有改善。移植物分析表明，移植物衍生细胞的总产量仅为注射细胞的 28%，并且植入神经源性颗粒下区 (SGZ) 的细胞最少。这一发现表明，MGE-NSC 移植后神经发生和认知缺乏改善是移植来源细胞产量降低和迁移减少的结果。我们假设将 MGE-NSC 联合移植到海马和外周施用神经源性化合物将大大减少 SRS，并逆转慢性 TLE 中出现的记忆功能障碍和抑郁。我们认为，这种功能恢复的改善与将大量移植源性细胞移植到 SGZ、从移植物中产生更多数量的新 GABA 能神经元和 GDNF+ 星形胶质细胞、恢复宿主海马 GDNF 浓度、增加海马神经发生，以及对认知和情绪功能以及神经发生重要的蛋白质/基因的浓度/表达的正常化。 在这个项目中，我们将研究 MGE-NSC 的海马内移植和神经源性药物治疗策略相结合是否会大大减少慢性 TLE 大鼠模型中的 SRS、认知功能障碍和抑郁症。在具体目标 1 中，我们将确定海马内 MGE-NSC 移植和皮下 (S.C.) FGF-2 联合治疗 14 天的效果。在具体目标 2 中，我们将检查 MGE-NSC 海马内联合移植与皮下注射神经类固醇类似物加奈索酮的效果。我们将测试这些联合疗法介导的癫痫发作抑制以及认知和情绪功能的改善是否与移植源性 GABA 能神经元和 GDNF 阳性星形胶质细胞产量的增加有关，以及将更多数量的移植源性 NSC 植入神经源性神经元中。 SGZ，增加内源性 NSC 和海马神经发生的活性，并增强对认知和情绪功能至关重要的蛋白质/基因的表达。我们还将这些结果与在存在或不存在 FGF-2/Ganaxolone 治疗的情况下从 MGE 衍生的 GABA 能细胞移植物和 MGE-NSC 衍生的星形胶质细胞移植物获得的数据进行比较。拟议的研究有望为考虑 NSC 移植策略临床应用治疗慢性 TLE 提供必要的关键基准。这些研究还与退伍军人的医疗保健需求相关，因为在伊拉克和阿富汗战争中服役的士兵中与战斗相关的中度至重度头部受伤可能会在未来几年导致慢性 TLE。