Department of Anatomy, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05030, Republic of Korea.
College of Veterinary Medicine and Veterinary Science Research Institute, Konkuk University, Seoul, 05030, Republic of Korea.
Biol Trace Elem Res. 2019 Aug;190(2):446-456. doi: 10.1007/s12011-018-1572-y. Epub 2018 Nov 28.
We investigated the effects of lead (Pb) and ascorbic acid co-administration on rat cerebellar development. Prior to mating, rats were randomly divided into control, Pb, and Pb plus ascorbic acid (PA) groups. Pregnant rats were administered Pb in drinking water (0.3% Pb acetate), and ascorbic acid (100 mg/kg) via oral intubation until the end of the experiment. Offspring were sacrificed at postnatal day 21, the age at which the morphology of the cerebellar cortex in developing pups is similar to that of the adult brain. In the cerebellum, Pb exposure significantly reduced Purkinje cells and ascorbic acid prevented their reduction. Along with the change of the Purkinje cells, long-term Pb exposure significantly reduced the expression of the synaptic marker (synaptophysin), γ-aminobutyric acid (GABA)-synthesizing enzyme (glutamic acid decarboxylase 67), and axonal myelin basic protein while ascorbic acid co-treatment attenuated Pb-mediated reduction of these proteins in the cerebellum of pups. However, glutamatergic N-methyl-D-aspartate receptor subtype 1 (NMDAR1), anchoring postsynaptic density protein 95 (PSD95), and antioxidant superoxide dismutases (SODs) were adversely changed; Pb exposure increased the expression of NMDAR1, PSD95, and SODs while ascorbic acid co-administration attenuated Pb-mediated induction. Although further studies are required about the neurotoxicity of the Pb exposure, the results presented here suggest that developmental Pb exposure disrupted normal development of Purkinje cells by increasing glutamatergic and oxidative stress in the cerebellum. Additionally, ascorbic acid co-treatment is beneficial in attenuating prenatal and postnatal Pb exposure-induced maldevelopment of Purkinje cells in the developing cerebellum.
我们研究了铅（Pb）和抗坏血酸联合给药对大鼠小脑发育的影响。在交配前，将大鼠随机分为对照组、Pb 组和 Pb 加抗坏血酸（PA）组。给孕鼠饮用含 0.3%醋酸铅的水，并通过口服插管给予抗坏血酸（100mg/kg），直至实验结束。在出生后第 21 天处死后代，此时发育中小鼠小脑皮质的形态与成年大脑相似。在小脑内，Pb 暴露显著减少了浦肯野细胞，而抗坏血酸则阻止了它们的减少。随着浦肯野细胞的变化，长期 Pb 暴露显著降低了突触标记物（突触小体蛋白）、γ-氨基丁酸（GABA）合成酶（谷氨酸脱羧酶 67）和轴突髓鞘碱性蛋白的表达，而抗坏血酸联合处理减轻了 Pb 对幼鼠小脑内这些蛋白的下调。然而，谷氨酸能 N-甲基-D-天冬氨酸受体亚型 1（NMDAR1）、突触后密度蛋白 95（PSD95）和抗氧化超氧化物歧化酶（SODs）的表达则受到不利影响；Pb 暴露增加了 NMDAR1、PSD95 和 SODs 的表达，而抗坏血酸联合处理减轻了 Pb 介导的诱导作用。虽然需要进一步研究 Pb 暴露的神经毒性，但这里呈现的结果表明，发育性 Pb 暴露通过增加小脑内的谷氨酸能和氧化应激，破坏了浦肯野细胞的正常发育。此外，抗坏血酸联合处理有利于减轻产前和产后 Pb 暴露诱导的发育中小脑浦肯野细胞的发育不良。
