HISTAMINE, IL-1 & NITRIC OXIDE IN WERNICKE LESIONS

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。 在所有尸检中，WE的患病率为1.7%-2.8%，在慢性酗酒者中高达12%-18%。 WE也在临床和尸检中被诊断为非酒精人群，包括阿尔茨海默病，获得性免疫缺陷综合征（AIDS），白血病和胃肠道疾病。 这些硫胺素缺乏症（TD）疾病的一个重要特征是特定脑区对病理损伤的选择性脆弱性。 丘脑、乳头体、身体和某些脑干核团的区域特别容易受到TD诱导的病变的影响。 尽管其公认的病因学作用，在WE，生化，分子和生理机制负责TD诱导的脑病变仍然未知。 因此，目前没有治疗干预，这将提供一个突然停止或中断正在进行的病理事件在硫胺素缺乏症。这一正在进行的项目的长期目标是开发有效的治疗方法，以预防或减少大脑病变，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。当前的目标是测试特定的假设组胺，细胞因子和一氧化氮在TD引起的丘脑病变的作用。 具体目标是检查药理学和遗传操作对早期血管变化定量测量的影响，即，足端突肿胀、血管周围水肿和肥大细胞脱颗粒以及晚期变化，即，TD大鼠丘脑内神经元凋亡和坏死的数量。 将单独的大鼠组进行吡硫胺诱导的硫胺素缺乏（PTD）或成对喂养（PFC），并接受以下操作：i）使用α FMH（i.c.v.）抑制组胺合成，组胺能结节乳头核的双侧损伤，施用美托咪胺（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），和诱导型NOS，使用氨基胍（i.p.）; iii）施用重组人白细胞介素-1受体拮抗剂（i.c.v.）;和iv）突变型肥大细胞缺陷（Ws/Ws）大鼠。 将在治疗10天后进行早期血管变化的定量测量，并在治疗15天后进行晚期神经退行性变化的测量。

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.