Alternative therapeutic approaches for the control of brain inflammation secondary to antihelminthic therapy in neurocysticercosis using a novel experimental pig model

使用新型实验猪模型控制神经囊尾蚴病抗蠕虫治疗继发脑炎症的替代治疗方法

• 批准号: 10364652
• 负责人: Gianfranco Arroyo
• 金额: $ 13.47万
• 依托单位: UNIVERSIDAD PERUANA CAYETANO HEREDIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-08 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10364652
• 关键词: Acute; Adrenal Cortex Hormones; Albendazole; Animal Model; Animals; Anthelmintics; Anti-Inflammatory Agents; Antiinflammatory Effect; Antimetabolites; Blood - brain barrier anatomy; Brain; Brain Edema; Central Nervous System Cysts; Clinical; Clinical Research; Controlled Study; Cyst; Deterioration; Developed Countries; Dexamethasone; Diagnosis; Dose; Early treatment; Edema; Encephalitis; Etanercept; Evaluation; Family suidae; Functional disorder; Genes; Goals; Histologic; Human; Human Pathology; Immigrant; Immune response; Infection; Inflammation; Inflammatory Response; Injections; Intracarotid; Intracranial Hypertension; Larva; Lead; Lesion; Life; Local Acute Inflammatory Response Pathway; Methotrexate; Modeling; Neurocysticercosis; Neurons; Outcome Measure; Parasites; Patients; Permeability; Pharmaceutical Preparations; Population; Praziquantel; Process; Recurrence; Regimen; Relapse; Resolution; Scheme; Secondary to; Seizures; Steroids; Study models; TNF gene; Taenia solium; Testing; Therapeutic; acquired epilepsy; appropriate dose; brain tissue; clinical practice; evidence base; improved; inflammatory marker; mind control; novel; novel therapeutic intervention; porcine model; response; side effect; tool; translational study; tumor necrosis factor-alpha inhibitor

Alternative therapeutic approaches for the control of brain inflammation secondary to antihelminthic therapy in neurocysticercosis using a novel experimental pig model PROJECT SUMMARY Neurocysticercosis (NCC) is the infection of the human brain by the larvae of the pork tapeworm Taenia solium and is a major cause of seizures in most of the world. Antihelminthic therapy induces cyst damage and activates the host immune response, which results in brain inflammation and edema. Corticosteroids are commonly administered concomitant with antihelminthic drugs to control the early treatment-induced inflammatory response. However, an ideal therapeutic scheme using corticosteroids has not been established, corticosteroid therapy is suboptimal in some forms of NCC, and its use may also lead to undesirable side- effects. A better understanding of the immunopathological processes associated with CNS cyst infection and in response to antihelminthic therapy is essential to improve the control of the treatment-induced brain inflammation and to evaluate potential corticosteroid-sparing/replacing agents. The lack of an appropriate animal model for NCC has however, limited our ability to achieve these goals. We recently demonstrated that intra-carotid injection of T. solium activated oncospheres in pigs reproduces CNS cyst infection efficiently, thus providing a suitable animal model for the study of NCC. In this proposal, we will optimize the intra-carotid injection model by determining the number of activated oncospheres required to consistently reproduce NCC in pigs, as well as to characterize the immunopathological processes associated with CNS cyst infection and in response to antihelminthic therapy with albendazole plus praziquantel. Subsequently, we will conduct two trials in pigs with experimental NCC: In the first trial, we will determine the optimal dose of two alternative anti-inflammatory drugs: etanercept (ETN) or methotrexate (MTX) in the control of the brain inflammatory response that results from antihelminthic therapy; the second trial will compare the optimal dose of ETN and MTX versus the wide-spectrum, corticosteroid dexamethasone (DEX) in the control of pericystic brain inflammation after antihelminthic therapy. We expect that our findings will provide the base evidence for translational studies testing ETN or MTX in controlled studies in NCC patients.

继发性脑炎控制的替代治疗方法 一种新的猪脑囊虫病模型的抗蠕虫治疗 项目总结 脑囊虫病(NCC)是猪带绦虫幼虫对人脑的感染 Solium是世界上大多数地区癫痫发作的主要原因。抗蠕虫治疗导致囊性损伤和 激活宿主免疫反应，导致脑部发炎和浮肿。皮质类固醇是 常规用药配合抗寄生虫药物控制早期治疗诱发 炎症反应。然而，使用皮质类固醇的理想治疗方案尚未建立， 皮质类固醇治疗在某些形式的NCC中是次优的，它的使用也可能导致不良的副作用- 效果。更好地了解与中枢神经系统囊性感染相关的免疫病理过程 抗寄生虫治疗的反应是改善治疗引起的脑控制的关键 炎症和评估潜在的皮质类固醇节约剂/替代剂。缺乏一个合适的 然而，NCC的动物模型限制了我们实现这些目标的能力。 我们最近证实，颈动脉内注射沙门氏菌激活的六钩虫球体在猪身上可以繁殖 为NCC的研究提供了一种合适的动物模型。在这项提案中，我们 将通过确定所需的激活六肽球数量来优化颈动脉内注射模型 在猪身上持续复制NCC，并表征相关的免疫病理过程 合并中枢神经系统囊性感染，对阿苯达唑联合吡喹酮抗寄生虫治疗有效。 随后，我们将在实验性NCC猪身上进行两项试验：在第一次试验中，我们将确定 两种替代抗炎药：依那西普(ETN)或甲氨蝶呤(MTX)在对照中的最佳剂量 抗寄生虫治疗引起的脑部炎症反应；第二项试验将比较 ETN和MTX的最佳剂量与广谱皮质类固醇地塞米松(DEX)的比较 抗寄生虫治疗后的囊周脑炎。我们希望我们的发现将提供基础 NCC患者对照研究中检测ETN或MTX的翻译研究的证据。