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Acute Treatment with Nicotinamide Riboside Chloride Reduces Hippocampal Damage and Preserves the Cognitive Function of Mice with Ischemic Injury

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Abstract

Nicotinamide adenine dinucleotide (NAD) is a critical cosubstrate for enzymes involved in supplying energy to the brain. Nicotinamide riboside (NR), an NAD+ precursor, emerges as a neuroprotective factor after chronic brain insults. However, researchers have not determined whether it improves cognition after acute ischemia. In the present study, mice with middle cerebral artery occlusion were treated with NR chloride (NRC, 300 mg/kg, IP., 20 min after reperfusion). The results of the Morris water maze test revealed better recovery of learning and memory function in the NRC-treated group. Acute NRC treatment decreased hippocampal infarct volume, reduced neuronal loss and apoptosis in the hippocampus. Western blot and high-performance liquid chromatography assays of hippocampal tissues revealed that the activation of Sirtin-1 and adenosine 5′ monophosphate-activated protein kinase was increased, the NAD content was elevated, and the production of adenosine triphosphate was strengthened by NRC. Collectively, acute NRC treatment increased the energy supply, reduced the neuronal loss and apoptosis, protected the hippocampus and ultimately promoted the recovery of cognitive function after brain ischemia.

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Data Availability

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Code Availability

Not applicable.

Abbreviations

NAD:

Nicotinamide adenine dinucleotide

NR:

Nicotinamide riboside

NRC:

Nicotinamide riboside chloride

HPLC:

High-performance liquid chromatography

Sirt1:

Sirtin-1

AMPK:

Adenosine 5′ monophosphate-activated protein kinase

ATP:

Adenosine triphosphate

MCAO:

Middle cerebral artery occlusion

PARP1:

(ADP ribose) polymerase 1

PGC1α:

Proliferator-activated receptor-γ coactivator 1α

AI:

Apoptosis index

BDNF:

Brain-derived neurotrophic factor

iPSC:

Induced pluripotent stem cells

LKB1:

Liver kinase B1

References

  1. Katan M, Luft A (2018) Global burden of stroke. Semin Neurol. https://doi.org/10.1055/s-0038-1649503

    Article  PubMed  Google Scholar 

  2. Kathner-Schaffert C, Karapetow L, Günther M et al (2019) Early stroke induces long-term impairment of adult neurogenesis accompanied by hippocampal-mediated cognitive decline. Cells. https://doi.org/10.3390/cells8121654

    Article  PubMed  PubMed Central  Google Scholar 

  3. Guo X, Qun Xue Q, Zhao J et al (2020) Clinical diagnostic and therapeutic guidelines of stroke neurorestoration (2020 China version). J Neurorestorat. https://doi.org/10.26599/JNR.2020.9040026

    Article  Google Scholar 

  4. Braidy N, Grant R, Sachdev PS (2018) Nicotinamide adenine dinucleotide and its related precursors for the treatment of Alzheimer’s disease. Curr Opin Psychiatry

  5. Hosseini L, Mahmoudi J, Pashazadeh F, et al (2021) Protective effects of nicotinamide adenine dinucleotide and related precursors in alzheimer’s disease: a systematic review of preclinical studies. J Mol Neurosci

  6. Hosseini L, Vafaee MS, Mahmoudi J, Badalzadeh R (2019) Nicotinamide adenine dinucleotide emerges as a therapeutic target in aging and ischemic conditions. Biogerontology

  7. Covarrubias AJ, Perrone R, Grozio A, Verdin E (2021) NAD+ metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol

  8. Xie X, Gao Y, Zeng M et al (2019) Nicotinamide ribose ameliorates cognitive impairment of aged and Alzheimer’s disease model mice. Metab Brain Dis. https://doi.org/10.1007/s11011-018-0346-8

    Article  PubMed  Google Scholar 

  9. Braidy N, Liu Y (2020) Can nicotinamide riboside protect against cognitive impairment? Curr Opin Clin Nutr Metab Care. https://doi.org/10.1097/MCO.0000000000000691

    Article  PubMed  Google Scholar 

  10. Vaur P, Brugg B, Mericskay M et al (2017) Nicotinamide riboside, a form of Vitamin B3, protects against excitotoxicity-induced axonal degeneration. FASEB J. https://doi.org/10.1096/fj.201700221RR

    Article  PubMed  Google Scholar 

  11. Gong B, Pan Y, Vempati P et al (2013) Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer’s mouse models. Neurobiol Aging 34:1581–1588. https://doi.org/10.1016/j.neurobiolaging.2012.12.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lee HJ, Yang SJ (2019) Supplementation with nicotinamide riboside reduces brain inflammation and improves cognitive function in diabetic mice. Int J Mol Sci. https://doi.org/10.3390/ijms20174196

    Article  PubMed  PubMed Central  Google Scholar 

  13. Cantó C, Gerhart-Hines Z, Feige JN et al (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458(7241):1056–1060. https://doi.org/10.1038/nature07813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91. https://doi.org/10.1161/01.STR.20.1.84

    Article  CAS  PubMed  Google Scholar 

  15. Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods. https://doi.org/10.1016/0165-0270(84)90007-4

    Article  PubMed  Google Scholar 

  16. Zhang H, Ryu D, Wu Y et al (2016) NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. https://doi.org/10.1126/science.aaf2693

    Article  PubMed  PubMed Central  Google Scholar 

  17. Brenner C (2019) Maternal nicotinamide riboside enhances postpartum weight loss, juvenile offspring development, and neurogenesis of adult offspring (P11–003-19). Curr Dev Nutr. https://doi.org/10.1093/cdn/nzz048.p11-003-19

    Article  PubMed Central  Google Scholar 

  18. Jiang Y, Liu Y, Gao M et al (2020) Nicotinamide riboside alleviates alcohol-induced depression-like behaviours in C57BL/6J mice by altering the intestinal microbiota associated with microglial activation and BDNF expression. Food Funct. https://doi.org/10.1039/c9fo01780a

    Article  PubMed  Google Scholar 

  19. Schöndorf DC, Ivanyuk D, Baden P et al (2018) The NAD+ precursor nicotinamide riboside rescues mitochondrial defects and neuronal loss in iPSC and Fly models of parkinson’s disease. Cell Rep. https://doi.org/10.1016/j.celrep.2018.05.009

    Article  PubMed  Google Scholar 

  20. Trammell SAJ, Schmidt MS, Weidemann BJ et al (2016) Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun. https://doi.org/10.1038/ncomms12948

    Article  PubMed  PubMed Central  Google Scholar 

  21. Martens CR, Denman BA, Mazzo MR et al (2018) Chronic nicotinamide riboside supplementation is well-Tolerated and elevates NAD+ in healthy middle-Aged and older adults. Nat Commun. https://doi.org/10.1038/s41467-018-03421-7

    Article  PubMed  PubMed Central  Google Scholar 

  22. Airhart SE, Shireman LM, Risler LJ et al (2017) An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS ONE. https://doi.org/10.1371/journal.pone.0186459

    Article  PubMed  PubMed Central  Google Scholar 

  23. Cantó C, Menzies KJ, Auwerx J (2015) NAD+ Metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab

  24. Imai S, Guarente L (2014) NAD+ and sirtuins in aging and disease. Trends Cell Biol 24:464–471. https://doi.org/10.1016/j.tcb.2014.04.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Johnson S, Wozniak DF, Imai S (2018) CA1 Nampt knockdown recapitulates hippocampal cognitive phenotypes in old mice which nicotinamide mononucleotide improves. NPJ Aging Mech Dis. https://doi.org/10.1038/s41514-018-0029-z

    Article  PubMed  PubMed Central  Google Scholar 

  26. Guo JM, Shu H, Wang L et al (2017) SIRT1-dependent AMPK pathway in the protection of estrogen against ischemic brain injury. CNS Neurosci Ther. https://doi.org/10.1111/cns.12686

    Article  PubMed  PubMed Central  Google Scholar 

  27. Cattelan A, Ceolotto G, Bova S et al (2015) NAD+-dependent SIRT1 deactivation has a key role on ischemia-reperfusion-induced apoptosis. Vascul Pharmacol. https://doi.org/10.1016/j.vph.2015.02.004

    Article  PubMed  Google Scholar 

  28. Ruderman NB, Xu XJ, Nelson L, et al (2010) AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol Metab

  29. Ke R, Xu Q, Li C, et al (2018) Mechanisms of AMPK in the maintenance of ATP balance during energy metabolism. Cell Biol Int

  30. Wang Y, Guo X, Liu J et al (2020) Olfactory ensheathing cells in chronic ischemic stroke: A phase 2, double-blind, randomized, controlled trial. J Neurorestorat. https://doi.org/10.26599/JNR.2020.9040019

    Article  Google Scholar 

  31. Lunt SY, Vander Heiden MG (2011) Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol. https://doi.org/10.1146/annurev-cellbio-092910-154237

    Article  PubMed  Google Scholar 

  32. Alano CC, Garnier P, Ying W et al (2010) NAD+ depletion is necessary and sufficient for poly(ADP-ribose) polymerase-1-mediated neuronal death. J Neurosci. https://doi.org/10.1523/JNEUROSCI.5552-09.2010

    Article  PubMed  PubMed Central  Google Scholar 

  33. Klimova N, Kristian T (2019) Multi-targeted effect of nicotinamide mononucleotide on brain bioenergetic metabolism. Neurochem Res. https://doi.org/10.1007/s11064-019-02729-0

    Article  PubMed  Google Scholar 

  34. Mehmel M, Jovanović N, Spitz U (2020) Nicotinamide riboside—the current state of research and therapeutic uses. Nutrients 12(6):1616. https://doi.org/10.3390/nu12061616

    Article  CAS  PubMed Central  Google Scholar 

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Funding

This work was supported by the Natural Science Foundation of China (81400977 to Wen-sheng Qu and 81771341 to Xiang Luo), Fund for Returnees of Tongji Hospital (2018hgry013 to Wen-sheng Qu), and the open project of Henan Key Laboratory of Neurorestoratology (HNSJXF-2018-012 to Wen-sheng Qu).

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Author notes

  1. Yin-hong Cheng and Wei-feng Zong are co-contributors.

Authors and Affiliations

  1. Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Ave., Wuhan, 430030, Hubei, People’s Republic of China

    Yin-hong Cheng, Wei-feng Zong, Yi-fan Jiang, Xiang Luo, Wei Wang & Wen-sheng Qu

  2. Henan Key Laboratory of Neurorestoratology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453100, China

    Yin-hong Cheng & Jian-hua Zhao

  3. The No. 1 People’s Hospital of Jingzhou City; No. 1 Hospital Affiliated with Yangtze University, Jingzhou, 434000, China

    Yin-hong Cheng

  4. The Second Clinical College, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Xian-jie Wei, Zhe Xu & Yuan Yuan

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  1. Yin-hong Cheng
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Contributions

All authors contributed to the study conception and design. YHC performed the HPLC and staining experiments. WFZ performed the western blot assay; JHZ prepared the reagents. XJW, ZX and YY prepared the mice and performed the Morris water maze test under the instruction of YHC. YFJ generated the animal model. XL and WW supervised the experiments and obtained financial support, and WSQ performed the analysis and prepared the manuscript. All authors read and approved the final manuscript.

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Correspondence to Wen-sheng Qu.

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Cheng, Yh., Zhao, Jh., Zong, Wf. et al. Acute Treatment with Nicotinamide Riboside Chloride Reduces Hippocampal Damage and Preserves the Cognitive Function of Mice with Ischemic Injury. Neurochem Res 47, 2244–2253 (2022). https://doi.org/10.1007/s11064-022-03610-3

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