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Reactive Oxygen Species-mediated Loss of Phenotype of Parvalbumin Interneurons Contributes to Long-term Cognitive Impairments After Repeated Neonatal Ketamine Exposures

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Abstract

Ketamine, a common anesthetic used for pediatric patients, has been shown to induce neurotoxicity and alter adolescent behaviors in rats when administered during neonatal period. However, the mechanisms underlying this kind of neurotoxicity remain largely to be determined. Herein, we studied whether the reactive oxygen species (ROS) due to the increased NOX2 mediates loss of phenotype of PV interneurons and thus contributes to long-term cognitive impairments after repeated ketamine exposures. Sprague–Dawley male rat pups received a daily administration of ketamine intraperitoneally (75 mg/kg) from postnatal day 6 (P6) to P8 for three consecutive days. For the interventional study, pups were treated with a NADPH oxidase inhibitor, apocynin (Apo). Learning and memory abilities were tested by the open field, fear conditioning, and Morris water maze on P40, P42–44, and P50–56, respectively. For histological and biochemical assays, a separate cohort of rats was killed on P9 or P60, and the brain tissues were harvested. Our results showed the upregulation of 8-OHdG and gp91/NOX2 and downregulation of PV and glutamic acid decarboxylase 67 (GAD67) after repeated ketamine exposures, which co-occurred with the long-term cognitive impairments as evidenced by the decreased freezing time to context. However, Apo treatment attenuated these abnormalities. Our results suggest that oxidative damage, probably due to the increased NOX2, mediates loss of phenotype of PV interneurons and thus contributes to long-term cognitive impairments after repeated ketamine exposures. Moreover, the inhibition of NADPH oxidase may protect against cognitive dysfunction.

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Acknowledgments

This work was supported by the grants from the National Natural Science Foundation of China (Nos. 81300946 and 81471105).

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Authors and Affiliations

  1. Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, China

    Hui Zhang, Xiao-ru Sun & Jing Wang

  2. Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, 22 Hankou Road, Nanjing, 210093, China

    Hong-ting Zhao, Hui-hui Li & Kuan-yu Li

  3. Department of Anesthesiology, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao Road, Nanjing, 210009, China

    Zhen-zhen Zhang, Mu-huo Ji & Jian-jun Yang

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  1. Hui Zhang
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  2. Xiao-ru Sun
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Correspondence to Kuan-yu Li or Jian-jun Yang.

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Zhang, H., Sun, Xr., Wang, J. et al. Reactive Oxygen Species-mediated Loss of Phenotype of Parvalbumin Interneurons Contributes to Long-term Cognitive Impairments After Repeated Neonatal Ketamine Exposures. Neurotox Res 30, 593–605 (2016). https://doi.org/10.1007/s12640-016-9653-1

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  • DOI: https://doi.org/10.1007/s12640-016-9653-1

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