Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, China.
PLoS One. 2012;7(8):e43924. doi: 10.1371/journal.pone.0043924. Epub 2012 Aug 31.
Exposure of Lead (Pb), a known neurotoxicant, can impair spatial learning and memory probably via impairing the hippocampal long-term potentiation (LTP) as well as hippocampal neuronal injury. Activation of hippocampal microglia also impairs spatial learning and memory. Thus, we raised the hypothesis that activation of microglia is involved in the Pb exposure induced hippocampal LTP impairment and neuronal injury. To test this hypothesis and clarify its underlying mechanisms, we investigated the Pb-exposure on the microglia activation, cytokine release, hippocampal LTP level as well as neuronal injury in in vivo or in vitro model. The changes of these parameters were also observed after pretreatment with minocycline, a microglia activation inhibitor. Long-term low dose Pb exposure (100 ppm for 8 weeks) caused significant reduction of LTP in acute slice preparations, meanwhile, such treatment also significantly increased hippocampal microglia activation as well as neuronal injury. In vitro Pb-exposure also induced significantly increase of microglia activation, up-regulate the release of cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β) and inducible nitric oxide synthase (iNOS) in microglia culture alone as well as neuronal injury in the co-culture with hippocampal neurons. Inhibiting the microglia activation with minocycline significantly reversed the above-mentioned Pb-exposure induced changes. Our results showed that Pb can cause microglia activation, which can up-regulate the level of IL-1β, TNF-α and iNOS, these proinflammatory factors may cause hippocampal neuronal injury as well as LTP deficits.
铅（Pb）暴露是一种已知的神经毒物，可能通过损害海马长时程增强（LTP）以及海马神经元损伤来损害空间学习和记忆。海马小胶质细胞的激活也会损害空间学习和记忆。因此，我们提出假说，即小胶质细胞的激活参与了 Pb 暴露引起的海马 LTP 损伤和神经元损伤。为了验证这一假说并阐明其潜在机制，我们在体内和体外模型中研究了 Pb 暴露对小胶质细胞激活、细胞因子释放、海马 LTP 水平以及神经元损伤的影响。在预先用米诺环素（一种小胶质细胞激活抑制剂）处理后，观察到这些参数的变化。长期低剂量 Pb 暴露（8 周 100ppm）导致急性切片制备中 LTP 明显降低，同时，这种处理也显著增加了海马小胶质细胞激活和神经元损伤。体外 Pb 暴露也导致小胶质细胞激活显著增加，上调细胞因子的释放，包括肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和诱导型一氧化氮合酶（iNOS），无论是在小胶质细胞培养物中还是在与海马神经元共培养物中都诱导了明显的神经元损伤。用米诺环素抑制小胶质细胞激活可显著逆转上述 Pb 暴露引起的变化。我们的结果表明，Pb 可引起小胶质细胞激活，进而上调 IL-1β、TNF-α 和 iNOS 的水平，这些促炎因子可能导致海马神经元损伤和 LTP 缺陷。
