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.

用于控制继发脑炎症的替代治疗方法 使用新型实验性猪模型，在神经囊肿中的抗胆汁疗法 项目摘要 神经囊虫病（NCC）是猪肉tapeeworm taenia的幼虫对人脑的感染 在世界上大多数地区是癫痫发作的主要原因。抗固有疗法会诱导囊肿损伤和 激活宿主免疫反应，从而导致脑部炎症和水肿。皮质类固醇是 通常与抗固有药物同时给药，以控制早期治疗诱导的 炎症反应。但是，尚未建立使用皮质类固醇的理想治疗方案， 皮质类固醇治疗在某些形式的NCC中是次优的，其使用也可能导致不良的侧面 效果。更好地了解与中枢神经系统囊肿感染相关的免疫病理过程和 对抗固有疗法的反应对于改善治疗诱导的大脑的控制至关重要 炎症并评估潜在的皮质类固醇药物剂量/替代剂。缺乏适当的 但是，NCC的动物模型限制了我们实现这些目标的能力。 最近，我们证明了钩状物内注射猪牛t。在猪中激活的肠圈会繁殖 CNS囊肿感染有效，因此为NCC研究提供了合适的动物模型。在这个建议中，我们 将通过确定所需的激活的肿瘤座的数量来优化 - 偶然注射模型 一贯再现猪中的NCC，并表征相关的免疫病理过程 伴有中枢神经系统囊肿感染，并响应阿苯达唑和praziquantel的抗静脉治疗。 随后，我们将在具有实验NCC的猪中进行两项试验：在第一次试验中，我们将确定 两种替代性抗炎药的最佳剂量：对照中的依那耐（ETN）或甲氨蝶呤（MTX） 由抗Niminthic疗法引起的脑炎症反应；第二次审判将比较 ETN和MTX的最佳剂量与宽光谱，皮质类固醇激素（DEX）的最佳剂量 抗胆汁疗法后，周细胞性脑炎症。我们希望我们的发现将提供基础 NCC患者对照研究中转化研究测试ETN或MTX的证据。