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）：神经囊虫病（NCC）是由Helminth Taenia ilium引起的人类中枢神经系统的寄生虫感染。 NCC被认为是全球癫痫发作的主要原因。 NCC中的癫痫发作是通过对大脑垂死的寄生虫的局部肉芽肿反应引起的。癫痫发作的介体是未知的，NCC中癫痫发作介质的鉴定可能会导致特定拮抗剂的治疗。神经肽物质P（SP）刺激肉芽肿的生长和Th1细胞因子产生。另一种神经肽生长抑素刺激Th2细胞因子的产生并损害肉芽肿的形成。 SP唤起神经元中的癫痫样反应，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鼠囊肿相关的肉芽肿分为4个阶段。早期肉芽肿表达了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，当将早期肉芽肿提取物注入大鼠大脑中时，行为癫痫发作和海马活性增加。用SP受体拮抗剂预处理抑制了这些作用。同样，将SP注射到大鼠脑中还会诱导癫痫发作并改变海马活性，这被SP受体拮抗剂或生长抑素完全阻塞。我们假设SP介导和生长抑素抑制了NCC中的颗粒状反应和癫痫发作。具体目的1：检验以下假设：SP和生长抑素调节囊肿中的肉芽肿反应。将比较受感染，野生型小鼠，SP基因敲除小鼠（SP KO），SP受体KO小鼠和生长抑素KO小鼠的肉芽肿大小，Th1/Th2和促炎性细胞因子水平。具体目的2：确定SP和生长抑素是否分别负责NCC中癫痫发作反应的中介和调节。 SP蛋白表达将在NCC癫痫发作的NCC患者的大脑活检中检查。将受感染，SP KO和生长抑素KO小鼠的肉芽肿提取物的癫痫发作与野生型小鼠的癫痫活性进行比较。特定目标3：确定NCC中的癫痫发作是否直接是由于SP和/或间接造成的，这是由于SP诱导的细胞因子。早期肉芽肿提取物的癫痫活性将在有或不抑制SP，IL-1BETA，TNF-ALPHA或IL-6的情况下进行测试。还将测试来自感染的IL-1BETA，TNF-ALPHA或IL-6敲除的早期肉芽肿的癫痫活性。特定目的4：测试生长抑素抑制NCC癫痫发作的假设。将研究具有或没有生长抑素类似物或SOM拮抗剂的早期肉芽肿提取物的癫痫发作活性。这些研究将确定SP和SOM在NCC发病机理中的重要性，并可能导致SP拮抗剂和SOM类似物作为抗癫痫剂在NCC和其他癫痫发作相关疾病中的癫痫发作。