Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, PR China.
NPFPC Key Laboratory of Contraceptives and Devices, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai 200032, PR China.
J Trace Elem Med Biol. 2019 Mar;52:199-208. doi: 10.1016/j.jtemb.2018.12.014. Epub 2018 Dec 31.
Excess copper exposure is a risk factor of neurodegeneration related to Alzheimer's disease (AD). Evidence indicates that, besides promoting amyloid β aggregation, activation of neuroinflammation and oxido-nitrosative stress (two key pathophysiological processes of AD) may also play important roles in Cu(II)-induced neuronal injury. Therefore, the copper-chelating strategy has gained attention in search for new anti-AD drugs. We previously reported a novel multifunctional compound N,N-bis(3-(S)-meptazinol-propyl) oxalamide (ZLA), a bis-(-)-nor-meptazinol-oxalamide hybrid with properties of dual binding site acetylcholinesterase (AChE) inhibition and Cu(II)/Zn(II) chelation. The present study was aimed to explore its effect on cognitive deficits caused by intrahippocampal injection of Cu(II) in mice. Results showed that ZLA (2, 5 mg/kg; i.p.) treatment significantly ameliorated the Cu(II)-induced impairment of hippocampus-dependent learning and memory, whereas rivastigmine, an AChE inhibitor showing a similar potency of enzyme inhibition to ZLA, had no obvious effect. Immunohistochemical and Western blot analyses revealed that ZLA attenuated the decrease in hippocampal expression of microtubule-associated protein 2 (MAP2, a dendritic marker) in Cu(II)-challenged mice. Further analysis showed that ZLA suppressed the Cu(II)-evoked microglial activation. Moreover, it inhibited the Cu(II)-evoked production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1β and expression of inducible nitric oxide synthase in the hippocampus. The Cu(II)-induced oxidative and nitrosative stress in the hippocampus was also attenuated after ZLA treatment. Collectively, these results suggest that ZLA ameliorates the Cu(II)-caused cognitive deficits. Inhibition of neuroinflammation and oxido-nitrosative stress, and thus ameliorating neuronal injury, may be the potential mechanism for the anti-amnesic effect of ZLA.
过量的铜暴露是与阿尔茨海默病（AD）相关的神经退行性变的危险因素。有证据表明，除了促进淀粉样β聚合外，神经炎症和氧化硝化应激（AD 的两个关键病理生理过程）的激活也可能在 Cu（II）诱导的神经元损伤中发挥重要作用。因此，铜螯合策略在寻找新的抗 AD 药物方面引起了关注。我们之前报道了一种新型多功能化合物 N,N-双（3-（S）-美普他酚丙基）草酰亚胺（ZLA），这是一种具有双（-）-诺美普他酚-草酰亚胺混合结构的化合物，具有双重结合部位乙酰胆碱酯酶（AChE）抑制和 Cu（II）/Zn（II）螯合的特性。本研究旨在探讨其对小鼠海马内注射 Cu（II）引起的认知功能障碍的影响。结果表明，ZLA（2、5mg/kg；ip）治疗显著改善了 Cu（II）诱导的海马依赖性学习和记忆损伤，而 rivastigmine 是一种 AChE 抑制剂，其对酶的抑制作用与 ZLA 相似，没有明显作用。免疫组织化学和 Western blot 分析表明，ZLA 减轻了 Cu（II）刺激小鼠海马内微管相关蛋白 2（MAP2，树突标记物）表达的减少。进一步分析表明，ZLA 抑制了 Cu（II）诱导的小胶质细胞激活。此外，它抑制了 Cu（II）诱导的促炎细胞因子如肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和白细胞介素-1β的产生以及海马中诱导型一氧化氮合酶的表达。ZLA 处理后，海马中 Cu（II）诱导的氧化和硝化应激也得到了减轻。综上所述，这些结果表明 ZLA 改善了 Cu（II）引起的认知功能障碍。抑制神经炎症和氧化硝化应激，从而改善神经元损伤，可能是 ZLA 抗健忘作用的潜在机制。
