HISTAMINE, IL-1 & NITRIC OXIDE IN WERNICKE LESIONS

硫胺素缺乏导致的人类病理损害与韦尼克脑病(WE)、Korsakoff综合征和混合感觉运动神经病有关。在所有尸检中，WE的患病率从1.7-2.8%到慢性酗酒者中高达12-18%不等。我们还在一些非酒精人群的临床和尸检中被诊断出来，包括阿尔茨海默病、获得性免疫缺陷综合征(艾滋病)、白血病和胃肠道疾病。这些硫胺素缺乏(TD)障碍的一个重要特征是特定大脑区域对病理损伤的选择性易损性。丘脑、乳头体、体部和某些脑干核团的区域特别容易受到TD引起的损害。尽管TD在WE中起了公认的病因学作用，但TD引起的脑损伤的生化、分子和生理机制仍不清楚。因此，目前还没有治疗干预措施，可以在硫胺素缺乏期间突然停止或中断正在进行的病理事件。这一正在进行的项目的长期目标是开发有效的治疗方法，以预防或减少脑损伤，特别是丘脑内的损伤，以及因硫胺素缺乏而产生的相关认知和记忆障碍。目前的目标是测试组胺、细胞因子和一氧化氮在TD诱导的丘脑损伤中所起作用的具体假设。具体目的是研究药物和遗传操作对TD大鼠早期血管变化的定量测量的影响，这些变化包括内足突起肿胀、血管周围水肿和肥大细胞脱颗粒，以及晚期的变化，即丘脑内神经元的凋亡和坏死数量。不同组的大鼠将受到吡硫胺诱导的硫胺缺乏症(PTD)或配对喂养(PFC)的影响，并接受以下操作：i)使用α-FMH(i.c.v)抑制组胺合成，双侧组胺能结节乳头核损毁，给予甲吡拉明(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(i.p)抑制神经元型一氧化氮合酶(NNOS)，以及使用氨基胍(i.p.)诱导NOS；iii)注射重组人白介素1受体拮抗剂(i.c.v)；以及iv)突变的肥大细胞缺陷(Ws/Ws)大鼠。早期血管变化的定量测量将在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。

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.