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Combination of NAD+ and NADPH Offers Greater Neuroprotection in Ischemic Stroke Models by Relieving Metabolic Stress

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Abstract

Both reduced nicotinamide adenine dinucleotide phosphate (NADPH) and β-nicotinamide adenine dinucleotide hydrate (NAD+) have been reported to have potent neuroprotective effects against ischemic neuronal injury. Both NADPH and NAD+ are essential cofactors for anti-oxidation and cellular energy metabolism. We investigated if combined NADPH and NAD+ could offer better neuroprotective effects on cellular and animal models of ischemic stroke. In vitro studies with primary cultured neurons demonstrated that NAD+ was effective in protecting neurons against oxygen–glucose deprivation/reoxygenation (OGD/R) injury when given during the early time period of reoxygenation. In vivo studies in mice also suggested that NAD+ was effective for ameliorating ischemic brain damage when administered within 2 h after reperfusion. The combination of NADPH and NAD+ provided not only greater beneficial effects but also larger therapeutic window in both cellular and animal models of stroke. The combination of NADPH and NAD+ significantly increased the levels of adenosine triphosphate (ATP) and reduced the levels of reactive oxygen species (ROS) and oxidative damage of macromolecules. Furthermore, the combined medication significantly reduced long-term mortality, improved the functional recovery, and inhibited signaling pathways involved in apoptosis and necroptosis after ischemic stroke. The present study indicates that the combination of NAD+ and NADPH can produce greater therapeutic effects with smaller dose of NADPH; on the other hand, NADPH can significantly prolong the therapeutic window of NAD+. The current results suggest that the combination of NADPH and NAD+ may provide a novel effective therapy for ischemic stroke.

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Funding

This study was supported by the Natural Science 583 foundation of China (Nos. 31500822, 81730092, 81271459, 31030034), the Priority Academic Program Development of Jiangsu Higher Education Institutes (PAPD), the Graduate Education Innovation Project of Jiangsu Province (CXZZ12_0850), and the Jiangsu Provincial Medical Youth Talent (QNRC2016762).

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Author notes

  1. Qiao Huang and Meiling Sun contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, College of Pharmaceutical Science, Soochow University, Suzhou, 215123, China

    Qiao Huang, Meiling Sun, Dingmei Zhang, Jun Chao Wu & Zheng-Hong Qin

  2. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan

    Meiling Sun & Kohji Fukunaga

  3. Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, 215025, China

    Mei Li

  4. Institute of Toxicology and Biochemical Pharmaceutics, School of Pharmaceutical Science, Zhejiang University, Hangzhou, 310058, China

    Feng Han

  5. Institute of Pharmacology, School of Pharmaceutical Science, Zhejiang University, Hangzhou, 310058, China

    Zhong Chen

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  1. Qiao Huang
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  2. Meiling Sun
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  3. Mei Li
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  9. Zheng-Hong Qin
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Corresponding author

Correspondence to Zheng-Hong Qin.

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All animal experiments were performed in accordance with the institutional guidelines for animal use and care, and the study protocol was approved by the ethical committee of Soochow University.

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The authors declare that they have no conflict of interest.

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Huang, Q., Sun, M., Li, M. et al. Combination of NAD+ and NADPH Offers Greater Neuroprotection in Ischemic Stroke Models by Relieving Metabolic Stress. Mol Neurobiol 55, 6063–6075 (2018). https://doi.org/10.1007/s12035-017-0809-7

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  • DOI: https://doi.org/10.1007/s12035-017-0809-7

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