HISTAMINE, IL-1 & NITRIC OXIDE IN WERNICKE LESIONS

人类硫胺素缺乏引起的病理性损伤与韦尼克脑病（WE）、korsakoff综合征和混合性感觉运动神经病变有关。WE在所有尸体解剖中的患病率为1.7% - 2.8%，在慢性酗酒者中高达12- 18%。在一些非酒精人群中，包括患有阿尔茨海默病、获得性免疫缺陷综合征（艾滋病）、白血病和胃肠道疾病的人，也被临床和死后诊断出WE。这些硫胺素缺乏症（TD）疾病的一个重要特征是特定脑区域对病理损伤的选择性脆弱性。丘脑、乳腺、身体和某些脑干核区域特别容易受到td引起的病变。尽管其在WE中的病因学作用已被接受，但td诱导的脑损伤的生化、分子和生理机制仍不清楚。因此，目前没有治疗性干预措施可以在硫胺素缺乏期间提供突然停止或中断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，以预防或减少脑部病变，特别是丘脑内的病变，以及由硫胺素缺乏引起的相关认知和记忆缺陷。当前的目标是测试关于组胺、细胞因子和一氧化氮在td诱导的丘脑病变中的作用的特定假设。具体目标是研究药理学和遗传学操作对TD大鼠早期血管变化（即终足突肿胀、血管周围水肿和肥大细胞脱颗粒）和晚期变化（即丘脑内凋亡和坏死神经元的数量）的定量测量的影响。将不同组的大鼠进行硫胺素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alphaFMH （i.c.v）抑制组胺合成，双侧损伤组胺能结节乳头核，给予甲胺（H1受体拮抗剂）或西咪替丁（H2受体拮抗剂）；ii) 7-硝基吲哚唑抑制神经元型一氧化氮合酶（nNOS），氨基胍抑制诱导型一氧化氮合酶（nNOS）；Iii)给药重组人白细胞介素-1受体拮抗剂（icv）；iv)突变，肥大细胞缺陷（Ws/Ws）大鼠。10天后进行早期血管变化的定量测量，15天后进行晚期神经退行性变化的定量测量。

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.