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完整哺乳动物中铝的神经行为毒性研究。

Studies of aluminum neurobehavioral toxicity in the intact mammal.

作者信息

Yokel R A, Allen D D, Meyer J J

机构信息

Division of Pharmacology & Experimental Therapeutics, College of Pharmacy, University of Kentucky, Lexington 40536-0082, USA.

出版信息

Cell Mol Neurobiol. 1994 Dec;14(6):791-808. doi: 10.1007/BF02088685.

Abstract
  1. Aluminum (Al) has been implicated in neurotoxic syndromes in several conditions, including Alzheimer's disease (AD). The developmental stage of the mammalian brain most susceptible to Al was determined in rabbits systematically exposed to Al during the prenatal, postnatal, or second month or for 1 month as adults or as aged subjects. Eyeblink reflex classical conditioning showed an Al-induced learning deficit only in the adult and aged rabbits. 2. 4-Aminopyridine, which was reported to improve learning in AD subjects, attenuated the Al-induced learning deficit. 3. Conditioned eyeblink acquisition is slower in AD subjects than controls, supporting the Al-loaded rabbit as a model of some AD effects. 4. To determine if the Al-loaded rabbit modeled the AD cholinergic deficit, acetylcholine (Ach) overflow was measured in rabbit hippocampus using microdialysis. Aluminum pretreatment reduced basal and potassium-stimulated Ach overflow compared to controls. 5. Acetylcholine overflow increased as control rabbits acquired the conditioned eyeblink reflex, then subsequently decreased, although conditioned eyeblink performance continued. In contrast, Al-loaded rabbits showed a delay in conditioned eyeblink acquisition and greatly attenuated Ach overflow. The Al-induced attenuation of Ach overflow may contribute to the Al-induced learning deficit. 6. Brain Al entry was studied using microdialysis of blood, brain, and lateral ventricle. Aluminum rapidly entered the brain and lateral ventricle. Frontal cortical Al was greater than lateral ventricular Al, suggesting that Al primarily enters the brain through the cerebral microvasculature. 7. The brain/blood Al ratio was always significantly less than 1. This ratio was influenced by the Al form administered, brain site and animal species. Thus, there appears to be an active process moving Al out of brain extracellular fluid (ECF). 8. Brain and blood dialysate Ach concentrations were not different after cyanide addition to the dialysate, supporting the conclusion that an active process moves Al out of brain ECF.
摘要
  1. 铝(Al)在包括阿尔茨海默病(AD)在内的多种病症中都与神经毒性综合征有关。通过对在产前、产后、第二个月系统性暴露于铝的兔子,以及成年或老年时暴露1个月的兔子进行研究,确定了哺乳动物大脑中对铝最敏感的发育阶段。眨眼反射经典条件反射显示,仅成年和老年兔子存在铝诱导的学习缺陷。2. 据报道,4-氨基吡啶可改善AD患者的学习能力,它可减轻铝诱导的学习缺陷。3. AD患者的条件性眨眼习得比对照组慢,这支持了铝负荷兔子可作为某些AD效应模型的观点。4. 为了确定铝负荷兔子是否模拟了AD胆碱能缺陷,使用微透析法测量了兔子海马体中的乙酰胆碱(Ach)溢出。与对照组相比,铝预处理降低了基础和钾刺激的Ach溢出。5. 随着对照兔子习得条件性眨眼反射,乙酰胆碱溢出增加,随后减少,尽管条件性眨眼表现仍在持续。相比之下,铝负荷兔子在条件性眨眼习得方面出现延迟,且Ach溢出大幅减弱。铝诱导的Ach溢出减弱可能导致铝诱导的学习缺陷。6. 使用血液、大脑和侧脑室的微透析法研究了大脑对铝的摄取。铝迅速进入大脑和侧脑室。额叶皮质中的铝含量高于侧脑室中的铝,这表明铝主要通过脑微血管系统进入大脑。7. 大脑/血液铝比值始终显著小于1。该比值受给药铝的形式、脑部位和动物物种的影响。因此,似乎存在一个将铝从脑细胞外液(ECF)中移出的活跃过程。8. 向透析液中添加氰化物后,大脑和血液透析液中的Ach浓度没有差异,这支持了存在一个将铝从脑ECF中移出的活跃过程的结论。

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