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NMDA Receptor Antagonist MK801 Protects Against 1-Bromopropane-Induced Cognitive Dysfunction

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Abstract

Occupational exposure to 1-bromopropane (1-BP) induces learning and memory deficits. However, no therapeutic strategies are currently available. Accumulating evidence has suggested that N-methyl-D-aspartate receptors (NMDARs) and neuroinflammation are involved in the cognitive impairments in neurodegenerative diseases. In this study we aimed to investigate whether the noncompetitive NMDAR antagonist MK801 protects against 1-BP-induced cognitive dysfunction. Male Wistar rats were administered with MK801 (0.1 mg/kg) prior to 1-BP intoxication (800 mg/kg). Their cognitive performance was evaluated by the Morris water maze test. The brains of rats were dissected for biochemical, neuropathological, and immunological analyses. We found that the spatial learning and memory were significantly impaired in the 1-BP group, and this was associated with neurodegeneration in both the hippocampus (especially CA1 and CA3) and cortex. Besides, the protein levels of phosphorylated NMDARs were increased after 1-BP exposure. MK801 ameliorated the 1-BP-induced cognitive impairments and degeneration of neurons in the hippocampus and cortex. Mechanistically, MK801 abrogated the 1-BP-induced disruption of excitatory and inhibitory amino-acid balance and NMDAR abnormalities. Subsequently, MK801 inhibited the microglial activation and release of pro-inflammatory cytokines in 1-BP-treated rats. Our findings, for the first time, revealed that MK801 protected against 1-BP-induced cognitive dysfunction by ameliorating NMDAR function and blocking microglial activation, which might provide a potential target for the treatment of 1-BP poisoning.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81872654, 81703264); Fundamental Research Funds of Shandong University (2016JC020), China, and Natural Science Foundation of Shandong Province (ZR2017MH002), China.

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Authors and Affiliations

  1. School of Public Health, Shandong University, Jinan, 250012, China

    Lin Xu, Xiaofei Qiu & Xiu-Lan Zhao

  2. School of Public Health, Dalian Medical University, Dalian, 116044, China

    Qingshan Wang

  3. School of Pharmacy, Liaocheng University, Liaocheng, 252000, China

    Shuo Wang

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  1. Lin Xu
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Xu, L., Qiu, X., Wang, S. et al. NMDA Receptor Antagonist MK801 Protects Against 1-Bromopropane-Induced Cognitive Dysfunction. Neurosci. Bull. 35, 347–361 (2019). https://doi.org/10.1007/s12264-018-0321-8

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