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Excessive Activation of NMDA Receptors Induced Neurodevelopmental Brain Damage and Cognitive Deficits in Rats Exposed to Intrauterine Hypoxia

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Abstract

Intrauterine hypoxia is one of the most common stressors in fetuses, which can lead to abnormal brain development and permanent neurological deficits in adulthood. Neurological disorder excitotoxicity induced by hypoxia or ischemia may involve N-methyl-d-aspartate receptors (NMDARs), which are known to participate in the maturation and plasticity of developmental neurons. Inhibition of NMDARs has been reported to improve neurological outcomes in traumatic brain injuries and Alzheimer’s disease. Here, we investigated if antenatal blockade of NMDARs induced by memantine could alleviate neurodevelopmental brain damage and long-term cognitive deficits in intrauterine hypoxia rats. Pregnant rats were assigned to four groups: air control, air + memantine, hypoxia, and hypoxia + memantine. The rats were exposed to hypoxic conditions (FiO2 = 0.095–0.115) for 8 h/day (hypoxia group) or given a daily memantine injection (5 mg/kg, i.p.) before hypoxia exposure from pregnant day 19 (G19) to G20 (hypoxia + memantine group).The influence of NMDARs antenatal blockade by memantine on intrauterine hypoxia-induced brain developmental damage and cognitive function was then studied. Intrauterine hypoxia resulted in decreased fetal body weight, brain weight, cognitive function, hippocampal neuron numbers, and Ki-67 proliferation index in the hippocampus. Memantine preventive treatment in pregnant rats before hypoxia exposure alleviated the aforementioned damage in vivo. Excessive activation of NMDARs contributes to fetal brain developmental damage and cognitive ability impairment induced by intrauterine hypoxia, which could be alleviated by antenatal memantine preventative treatment.

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Acknowledgements

The authors acknowledge all colleagues of the Department of Physiology, Xiangya Medical College, Central South University for technical assistance.

Funding

Funding was provided by National Science Foundation of China (Grant No. 81270121).

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Authors and Affiliations

  1. Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China

    Ting Li, Yang Liu, Mingjie Wang, Xiaohe Yu, Chuanding Cao, Zhengchang Liao, Ying Ding & Shaojie Yue

  2. Department of Physiology, Xiangya Medical School, Central South University, Changsha, 410008, Hunan, China

    Ziqiang Luo

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  1. Ting Li
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Correspondence to Shaojie Yue.

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Li, T., Luo, Z., Liu, Y. et al. Excessive Activation of NMDA Receptors Induced Neurodevelopmental Brain Damage and Cognitive Deficits in Rats Exposed to Intrauterine Hypoxia. Neurochem Res 43, 566–580 (2018). https://doi.org/10.1007/s11064-017-2451-1

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