HISTAMINE, IL-1 & NITRIC OXIDE IN WERNICKE LESIONS

组胺，IL-1

• 批准号: 6321365
• 负责人: Philip Joseph Langlais
• 金额: $ 4万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6321365
• 关键词: Wernicke Korsakoff syndrome; antihistamines; cerebrovascular system; enzyme inhibitors; histamine; interleukin 1; laboratory rat; mast cell; molecular pathology; neural degeneration; neuropathology; nitric oxide; nitric oxide synthase; nutrition related tag; thalamus; thiamine deficiency

Thiamine deficiency-induced pathologic damage in humans is associated with Wernicke's encephalopathy (WE), Korsakoffs syndrome, and mixed sensory motor neuropathy. The prevalence of WE ranges from 1.7-2.8 percent among all autopsies to as high as 12-18 percent among chronic alcoholics. WE has also been diagnosed clinically and at postmortem in a number of non-alcoholic populations including those with Alzheimer's disease, acquired immunodeficiency syndrome (AIDS), leukemia, and gastrointestinal disorders. An important feature of these thiamine deficiency (TD) disorders is the selective vulnerability of specific brain regions to pathologic damage. Regions of thalamus, mammillary, body, and certain brainstem nuclei are particularly vulnerable to TD-induced lesions. Despite its accepted etiological role in WE, the biochemical, molecular, and physiological mechanisms responsible for TD-induced brain lesions remain unknown. Consequently, there is currently no therapeutic intervention which will provide an abrupt cessation or interruption of the ongoing pathologic events during thiamine deficiency. The long-term objective of this ongoing project is to develop effective treatments for the prevention or reduction of brain lesions, particularly within the thalamus, and associated cognitive and memory deficits produced by thiamine deficiency. The immediate goal is to test specific hypotheses regarding the role of histamine, cytokines and nitric oxide in TD-induced lesions to the thalamus. The specific goals are to examine the effects of pharmacological and genetic manipulations on quantitative measures of early vascular changes, i.e., swelling of endfoot processes, perivascular edema, and mast cell degranulation and the late changes, i.e., number of apoptotic and necrotic of neurons within the thalamus of TD rats. Separate groups of rats will be subjected to pyrithiamine-induced thiamine deficiency (PTD) or pairfeeding (PFC) and receive the following manipulations; i) inhibition of histamine synthesis using alphaFMH (i.c.v.), bilateral lesions of the histaminergic tuberomammillary nucleus, administration of mepyramine (H1 receptor antagonist) or cimetidine (H2 receptor antagonist); ii) inhibition of both neuronal nitric oxide synthase (nNOS), using 7-nitroindazole (i.p.), and inducible NOS using aminoguanidine (i.p.); iii) administration of a recombinant human interleukin-1 receptor antagonist (i.c.v.); and iv) mutant, mast cell deficient (Ws/Ws) rats. Quantitative measures of early vascular changes will be performed after 10 days and measures of late neurodegenerative changes performed after 15 days of treatment.

硫胺素缺乏引起的人类病理损伤与韦尼克脑病 (WE)、科萨科夫综合征和混合感觉运动神经病有关。 WE 的患病率在所有尸检中为 1.7-2.8%，而在慢性酗酒者中则高达 12-18%。 在许多非酒精人群中，包括患有阿尔茨海默氏病、获得性免疫缺陷综合症（艾滋病）、白血病和胃肠道疾病的人群中，也已通过临床和尸检诊断出 WE。 这些硫胺素缺乏 (TD) 疾病的一个重要特征是特定大脑区域选择性地易受病理损伤。 丘脑、乳头、身体和某些脑干核团的区域特别容易受到 TD 引起的损伤。 尽管其在 WE 中的病因学作用已被接受，但 TD 引起的脑损伤的生化、分子和生理机制仍然未知。 因此，目前尚无治疗干预能够突然停止或中断硫胺素缺乏期间正在进行的病理事件。这个正在进行的项目的长期目标是开发有效的治疗方法来预防或减少脑损伤，特别是丘脑内的损伤，以及由硫胺素缺乏引起的相关认知和记忆缺陷。近期目标是测试关于组胺、细胞因子和一氧化氮在 TD 引起的丘脑损伤中的作用的具体假设。 具体目标是检查药理学和基因操作对早期血管变化（即足底突起肿胀、血管周围水肿和肥大细胞脱粒）和晚期变化（即 TD 大鼠丘脑内神经元凋亡和坏死数量）的定量测​​量的影响。 不同组的大鼠将遭受吡硫胺诱导的硫胺素缺乏症（PTD）或配对喂养（PFC），并接受以下操作； i) 使用αFMH（静脉注射）抑制组胺合成，组胺能结节乳头核双侧损伤，给予美吡拉明（H1受体拮抗剂）或西咪替丁（H2受体拮抗剂）； ii) 使用 7-硝基吲唑（腹腔注射）抑制神经元一氧化氮合酶（nNOS），并使用氨基胍（腹腔注射）抑制诱导型 NOS； iii) 给予重组人白细胞介素-1受体拮抗剂（静脉注射）； iv) 突变肥大细胞缺陷 (Ws/Ws) 大鼠。 早期血管变化的定量测量将在治疗 10 天后进行，晚期神经退行性变化的测量将在治疗 15 天后进行。