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: 8732496
• 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/8732496
• 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; Fibroblast Growth Factor 2; 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; Pharmaceutical Preparations; 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）： 项目总结细胞移植策略能够减少慢性颞叶癫痫（TLE）患者的自发性复发性癫痫发作（SRS）、学习和记忆功能障碍以及抑郁，这具有重要意义，因为约35%的TLE患者患有对抗癫痫药物（AED）耐药的SRS，AED治疗不能减轻认知和情绪功能障碍。由于TLE与分泌抗惊厥蛋白质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对于抑制SRS似乎很有吸引力。事实上，我们最近的研究已经表明，移植的内侧神经节隆起（MGE）衍生的神经干细胞（NSC）到表现出慢性TLE大鼠的海马实质上减少SRS的频率和强度，增加新的GABA能神经元和GDNF+星形胶质细胞。然而，海马神经发生或认知功能没有改善。移植物的分析显示，移植物来源的细胞的总产量仅为注射细胞的28%，并且细胞植入到神经源性颗粒下区（SGZ）中的量极少。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物衍生细胞的产量较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给予神经源性化合物将大大减少SRS以及逆转慢性TLE中观察到的记忆功能障碍和抑郁症。我们认为，这种改善的功能恢复将与移植物衍生的细胞移植到SGZ的显着数量，产生更多的新的GABA能神经元和GDNF+星形胶质细胞的移植物，恢复宿主海马GDNF浓度，增加海马神经发生，并在认知和情绪功能和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，我们将调查是否联合海马内移植MGE-NSCs和神经源性药物治疗策略将大大减少SRS，认知功能障碍和抑郁症在慢性TLE大鼠模型。在具体目标1中，我们将确定MGE-NSC和皮下（S.C.）FGF-2治疗14天。在具体目标2中，我们将检查MGE-NSC与S. C.给予神经类固醇类似物加奈索酮。我们将测试这些联合治疗介导的神经功能抑制和改善的认知和情绪功能是否与移植物衍生的GABA能神经元和GDNF阳性星形胶质细胞的产量增加、将更多数量的移植物衍生的NSC移植到神经源性SGZ中、内源性NSC和海马神经发生的活性增加以及对认知和情绪功能至关重要的蛋白质/基因的表达增强有关。我们还将这些结果与在存在或不存在FGF-2/加奈索酮治疗的情况下从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。拟议的研究有希望提供关键的基准考虑NSC移植策略治疗慢性TLE的临床应用必不可少。这些研究也与退伍军人的医疗保健需求有关，因为在伊拉克和阿富汗战争中服役的士兵中与战斗有关的中度至重度头部受伤可能会导致未来几年的慢性TLE。