Neuropeptides in the pathogenesis of neurocysticercosis

神经肽在神经囊尾蚴病发病机制中的作用

• 批准号: 6751680
• 负责人: PREMA ROBINSON
• 金额: $ 24.24万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6751680
• 关键词: Cestoda; clinical research; enzyme linked immunosorbent assay; epilepsy; gene targeting; genetically modified animals; helminthiasis; high performance liquid chromatography; host organism interaction; human tissue; immunocytochemistry; interleukin 1; interleukin 6; laboratory mouse; leukocyte activation /transformation; neurologic manifestations; neuropeptide receptor; parasite infection mechanism; polymerase chain reaction; protein quantitation /detection; receptor expression; somatostatin; substance P; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Neurocysticercosis (NCC) is a parasitic infection of the human central nervous system caused by the helminth Taenia solium. NCC is recognized as a leading cause of seizures worldwide. Seizures in NCC are evoked by localized granulomatous responses to dying parasites in the brain. The mediators of the seizures are unknown, identification of seizure mediator(s) in NCC may result in treatment with specific antagonists. The neuropeptide substance P (SP) stimulates granuloma growth and Th1 cytokine production. Another neuropeptide, somatostatin, stimulates Th2 cytokine production and impairs granuloma formation. SP evokes epileptiform responses in neurons, whereas, somatostatin has anticonvulsant properties. We divided granulomas associated with murine cysticercosis into 4 stages based on the histologic appearance of the degenerating parasite. Early stage granulomas expressed Th1 cytokines and SP, whereas Th2 cytokines and somatostatin were only expressed in later stages. Preliminary results also noted that behavioral seizures and increased hippocampal activity were induced when extracts from early granulomas were injected into brain of rats. Pretreatment with SP receptor antagonist inhibited these effects. Similarly, injection of SP into rat brain also induced seizures and altered hippocampal activity that was completely blocked by pretreatment with SP receptor antagonist or somatostatin. We hypothesize that SP mediates and somatostatin inhibits the granulomatous response and seizures in NCC. Specific aim 1: To test the hypothesis that SP and somatostatin modulate granulomatous responses in cysticercosis. Granuloma size, Th1/Th2 and pro-inflammatory cytokine levels in infected, wildtype mice, SP knockout mice (SP KO), SP receptor KO mice and somatostatin KO mice will be compared. Specific aim 2: To determine if SP and somatostatin are respectively responsible for the mediation and modulation of seizure responses in NCC. SP protein expression will be examined in brain biopsies from NCC patients with seizures. Epileptogenic activity of granuloma extracts from infected, SP KO and somatostatin KO mice will be compared to that from wildtype mice. Specific aim 3: To determine if seizures in NCC are directly due to SP and/or indirectly due to SP induced cytokines. Epileptogenic activity of early granuloma extracts will be tested with or without inhibition or blocking of SP, IL-1beta, TNF-alpha or IL-6. Also epileptogenic activity of early granulomas from infected IL-1beta, TNF-alpha or IL-6 knockouts will be tested. Specific aim 4: To test the hypothesis that somatostatin inhibits seizures in NCC. Epileptogenic activity of early granuloma extracts with or without somatostatin analogues or SOM antagonist will be studied. These studies will determine the importance of SP and SOM in pathogenesis of NCC, and may lead to future use of SP antagonist and SOM analogues as anti-epileptic agents for treatment of seizures in NCC and other seizure related diseases.

描述（由申请人提供）： 神经囊尾蚴病（NCC）是由蠕虫猪带绦虫引起的人类中枢神经系统的寄生虫感染。 NCC 被认为是全世界癫痫发作的主要原因。 NCC 的癫痫发作是由大脑中垂死寄生虫的局部肉芽肿反应引起的。癫痫发作的介质尚不清楚，NCC 中癫痫发作介质的识别可能导致使用特定拮抗剂进行治疗。神经肽物质 P (SP) 刺激肉芽肿生长和 Th1 细胞因子产生。另一种神经肽生长抑素可刺激 Th2 细胞因子的产生并损害肉芽肿的形成。 SP 在神经元中引起癫痫样反应，而生长抑素具有抗惊厥特性。我们根据退化寄生虫的组织学外观将与小鼠囊尾蚴病相关的肉芽肿分为 4 个阶段。早期肉芽肿表达Th1细胞因子和SP，而Th2细胞因子和生长抑素仅在后期表达。初步结果还指出，当将早期肉芽肿的提取物注射到大鼠大脑中时，会诱发行为性癫痫发作和海马活动增加。 SP受体拮抗剂预处理可抑制这些作用。同样，将 SP 注射到大鼠大脑中也会诱发癫痫发作并改变海马活动，而用 SP 受体拮抗剂或生长抑素预处理可完全阻断这种活动。我们假设 SP 介导且生长抑素抑制 NCC 中的肉芽肿反应和癫痫发作。具体目标 1：检验 SP 和生长抑素调节囊尾蚴病肉芽肿反应的假设。将比较受感染的野生型小鼠、SP 敲除小鼠 (SP KO)、SP 受体 KO 小鼠和生长抑素 KO 小鼠的肉芽肿大小、Th1/Th2 和促炎细胞因子水平。具体目标 2：确定 SP 和生长抑素是否分别负责 NCC 癫痫反应的介导和调节。将在癫痫发作的 NCC 患者的脑活检中检查 SP 蛋白表达。将来自感染的 SP KO 和生长抑素 KO 小鼠的肉芽肿提取物的致癫痫活性与野生型小鼠的致癫痫活性进行比较。具体目标 3：确定 NCC 的癫痫发作是否直接由 SP 引起和/或间接由 SP 诱导的细胞因子引起。将在抑制或阻断 SP、IL-1β、TNF-α 或 IL-6 的情况下测试早期肉芽肿提取物的致癫痫活性。还将测试感染 IL-1β、TNF-α 或 IL-6 敲除的早期肉芽肿的致癫痫活性。具体目标 4：检验生长抑素抑制 NCC 癫痫发作的假设。将研究含有或不含生长抑素类似物或 SOM 拮抗剂的早期肉芽肿提取物的致癫痫活性。这些研究将确定 SP 和 SOM 在 NCC 发病机制中的重要性，并可能导致未来使用 SP 拮抗剂和 SOM 类似物作为抗癫痫药来治疗 NCC 癫痫发作和其他癫痫相关疾病。