脑室输注喹啉酸可损害幼鼠的空间学习和记忆：铅诱导神经毒性的新机制。
Intraventricular infusion of quinolinic acid impairs spatial learning and memory in young rats: a novel mechanism of lead-induced neurotoxicity.
机构信息
Department of Food Science and Nutrition, College of Life Sciences, Kuwait University, Kuwait City, Kuwait.
Department of Anatomy, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
出版信息
J Neuroinflammation. 2018 Sep 14;15(1):263. doi: 10.1186/s12974-018-1306-2.
BACKGROUND
Lead (Pb), a heavy metal, and quinolinic acid (QA), a metabolite of the kynurenine pathway of tryptophan metabolism, are known neurotoxicants. Both Pb and QA impair spatial learning and memory. Pb activates astrocytes and microglia, which in turn induce the synthesis of QA. We hypothesized increased QA production in response to Pb exposure as a novel mechanism of Pb-neurotoxicity.
METHODS
Two experimental paradigms were used. In experiment one, Wistar rat pups were exposed to Pb via their dams' drinking water from postnatal day 1 to 21. Control group was given regular water. In the second protocol, QA (9 mM) or normal saline (as Vehicle Control) was infused into right lateral ventricle of 21-day old rats for 7 days using osmotic pumps. Learning and memory were assessed by Morris water maze test on postnatal day 30 or 45 in both Pb- and QA-exposed rats. QA levels in the Pb exposed rats were measured in blood by ELISA and in the brain by immunohistochemistry on postnatal days 45 and 60. Expression of various molecules involved in learning and memory was analyzed by Western blot. Means of control and experimental groups were compared with two-way repeated measure ANOVA (learning) and t test (all other variables).
RESULTS
Pb exposure increased QA level in the blood (by ~ 58%) and increased (p < 0.05) the number of QA-immunoreactive cells in the cortex, and CA1, CA3 and dentate gyrus regions of the hippocampus, compared to control rats. In separate experiments, QA infusion impaired learning and short-term memory similar to Pb. PSD-95, PP1, and PP2A were decreased (p < 0.05) in the QA-infused rats, whereas tau phosphorylation was increased, compared to vehicle infused rats.
CONCLUSION
Putting together the results of the two experimental paradigms, we propose that increased QA production in response to Pb exposure is a novel mechanism of Pb-induced neurotoxicity.
背景
铅（Pb）是一种重金属，喹啉酸（QA）是色氨酸代谢犬尿氨酸途径的一种代谢产物，均为神经毒性物质。Pb 和 QA 均可损害空间学习和记忆。Pb 可激活星形胶质细胞和小胶质细胞，进而诱导 QA 的合成。我们假设，Pb 暴露后 QA 产生增加是 Pb 神经毒性的新机制。
方法
采用了两种实验方案。在实验一中，Wistar 幼鼠通过母鼠饮用水在出生后第 1 天至 21 天期间暴露于 Pb。对照组给予普通水。在第二个方案中，通过渗透泵将 QA（9mM）或生理盐水（作为载体对照）输注到 21 日龄大鼠的右侧侧脑室，持续 7 天。在 Pb 和 QA 暴露大鼠的出生后第 30 或 45 天，通过 Morris 水迷宫试验评估学习和记忆能力。在出生后第 45 天和第 60 天，通过 ELISA 法测定 Pb 暴露大鼠血液中的 QA 水平，通过免疫组化法测定大脑中的 QA 水平。通过 Western blot 分析参与学习和记忆的各种分子的表达。采用双因素重复测量方差分析（学习）和 t 检验（所有其他变量）比较对照组和实验组的平均值。
结果
与对照组大鼠相比，Pb 暴露使血液中的 QA 水平升高（约 58%），并使大脑皮质、CA1、CA3 和海马齿状回的 QA 免疫反应性细胞数量增加（p<0.05）。在单独的实验中，与载体输注大鼠相比，QA 输注损害了学习和短期记忆。与载体输注大鼠相比，QA 输注大鼠的 PSD-95、PP1 和 PP2A 减少（p<0.05），而 tau 磷酸化增加。
结论
综合两个实验方案的结果，我们提出，Pb 暴露后 QA 产生增加是 Pb 诱导神经毒性的新机制。
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