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）： 能够减少自发复发性癫痫发作（SRS），学习和记忆力障碍和慢性颞叶癫痫（TLE）的项目摘要细胞移植策略具有很大的意义，因为〜35％的TLE患者的TLE患者的SR具有对抗抗血症药物的耐药性（AEDS）的耐药性（AEDS）和AED疗法的耐药性。因为TLE与抑制性GABA - 凝胶神经元和星形胶质细胞的缺乏有关，分泌抗惊厥蛋白神经胶质细胞系衍生的神经营养因子（GDNF）， 具有引起GABA - 凝胶神经元和GDNF+星形胶质细胞同时产生的能力的细胞移植物似乎在限制SRS方面有吸引力。实际上，我们最近的研究表明，内侧神经节敏锐度（MGE）衍生的神经干细胞（NSC）纳入表现出慢性TLE的大鼠的海马，大大降低了SRS的频率和强度，并添加了新的GABA-ergigic神经元和GABA-ergic神经元和GDNF+星形镜。但是，在海马神经发生或认知功能中没有看到改善。对移植物的分析表明，移植细胞的总收率仅为注射细胞的28％，并将细胞灌输到神经源性下粒区（SGZ）中最小。这一发现表明，MGE-NSC嫁接后神经发生和认知缺乏改善是由于较低的产率和降低移植细胞的迁移而导致的。我们假设将MGE-NSC嫁接到海马和神经源性化合物的周围给药会大大减少SR，以及在慢性TLE中看到的反向记忆功能障碍和抑郁症。我们建议，这种改善的功能恢复将与将大量的移植细胞植入SGZ中有关，从而产生更多的GABA - 凝胶神经元和GDNF+星形胶质细胞，从而恢复宿主的Hampocal GDNF浓度，并增加了海马神经形成和海马神经形成的浓度和正常化的浓度，并增加了海马GDNF的浓度和正常化的素养。神经发生。 在该项目中，我们将研究MGE-NSC的汉普科内接枝和神经源性药物治疗策略是否会大大减少SR，认知功能障碍和抑郁症在慢性TLE的大鼠模型中。在特定的目标1中，我们将确定MGE-NSC和皮下（S.C.）FGF-2治疗的综合植物内移植的影响14天。在特定的目标2中，我们将研究MGE-NSC与S.C.施用神经类固醇类似物Ganaxolone的联合疗法的效果。我们将测试这些组合疗法介导的癫痫抑制以及改善的认知和情绪功能是否与移植衍生的GABA - 热神经元和GDNF阳性星形胶质层的产量增加有关，植入了更多的NSC的NSC和NEUREGIS SGZ的NESERIC SGZ和HIMPALIC SSSS的活性，并增加蛋白质/基因对认知和情绪功能至关重要。我们还将将这些结果与在存在或不存在FGF-2/Ganaxolone处理的情况下从MGE衍生的GABA - 凝胶细胞和MGE-NSC衍生的星形胶质细胞移植物中获得的数据进行比较。拟议的研究有望提供为考虑用于治疗慢性TLE的NSC移植策略所必需的关键基准。这项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相关的中度至重度头部受伤可能会导致未来几年的慢性TLE。