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NMN Alleviates NP-Induced Learning and Memory Impairment Through SIRT1 Pathway in PC-12 Cell

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Abstract

Nonylphenol (NP) is widely used in the chemical industry; it accumulates in organisms through environmental contamination and causes learning memory impairment. Nicotinamide mononucleotide (NMN) has been found to have a positive effect on the treatment of central nervous-related diseases. This study aimed to investigate the protective effect of NMN on NP-induced learning memory-related impairment in vitro and to further identify the underlying mechanisms. The results showed that NP induced oxidative stress and impaired the cholinergic system, 5-HT system in PC-12 cells. NMN alleviated NP-induced learning and memory impairment at the molecular level through alleviating oxidative stress and protective effects on the 5-HT system and cholinergic system. The 50 μM NP group significantly reduced the NAD+ content, and the relative expression of SIRT1, PGC-1α, Nrf2, MAOA, BDNF, and p-TrkB were significantly downregulated. Co-treatment of NMN with NP significantly reduced oxidative stress, improved the homeostasis of 5-HT and cholinergic system, enhanced the intracellular NAD+ content, and significantly upregulated the expression of SIRT1 pathway proteins. SIRT1 inhibitors reduced the expression of SIRT1 pathway-related proteins, which implied the impairment of learning and memory by NP and the protective effect of NMN might be achieved through the SIRT1-mediated PGC-1α/MAOA/BDNF signaling pathway. Overall, this study not only help us to understand the toxic mechanism of NP on learning memory impairment in vitro, but also have important reference significance to further explore the health care value of NMN and promote the development of related functional foods.

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Data Availability

All data generated during this study are available from the corresponding author on reasonable request.

References

  1. Squire LR (2004) Memory systems of the brain: a brief history and current perspective. Neurobiol Learn Mem 82(3):171–177

    Article  PubMed  Google Scholar 

  2. de Bruin W et al (2019) Occurrence, fate and toxic effects of the industrial endocrine disrupter, nonylphenol, on plants - a review. Ecotoxicol Environ Safety 181:419–427

    Article  PubMed  Google Scholar 

  3. Langford KH et al (2005) The partitioning of alkylphenolic surfactants and polybrominated diphenyl ether flame retardants in activated sludge batch tests. Chemosphere 61(9):1221–1230

    Article  CAS  PubMed  Google Scholar 

  4. Fries E, Puttmann W (2003) Occurrence and behaviour of 4-nonylphenol in river water of Germany. J Environ Monit 5(4):598–603

    Article  CAS  PubMed  Google Scholar 

  5. Sabik H et al (2003) Occurrence of alkylphenol polyethoxylates in the St. Lawrence River and their bioconcentration by mussels (Elliptio complanata). Chemosphere 51(5):349–356

    Article  CAS  PubMed  Google Scholar 

  6. Nowak KM et al (2008) Effect of sludge treatment on the bioaccumulation of nonylphenol in grass grown on sludge-amended soil. Environ Chem Lett 6(1):53–58

    Article  CAS  Google Scholar 

  7. Ying GG, Williams B, Kookana R (2002) Environmental fate of alkylphenols and alkylphenol ethoxylates - a review. Environ Int 28(3):215–226

    Article  CAS  PubMed  Google Scholar 

  8. Vieira WT et al (2020) Removal of endocrine disruptors in waters by adsorption, membrane filtration and biodegradation. A review. Environ Chem Lett 18(4):1113–1143

    Article  CAS  Google Scholar 

  9. Dsikowitzky L, Schwarzbauer J (2014) Industrial organic contaminants: identification, toxicity and fate in the environment. Environ Chem Lett 12(3):371–386

    Article  CAS  Google Scholar 

  10. Zhou et al. (2018) Easier removal of nonylphenol and naphthalene pollutants in wet weather revealed by Markov chains modeling. Environ Chem Lett 16(3):1089–1093. https://doi.org/10.1007/s10311-018-0728-5

  11. Snedeker SM, Hay AG (2014) The alkylphenols nonylphenol and octylphenol in food contact materials and household items: exposure and health risk considerations. Springer, London

    Google Scholar 

  12. Park JH et al (2016) Nicotinamide mononucleotide inhibits post-ischemic NAD+ degradation and dramatically ameliorates brain damage following global cerebral ischemia. Neurobiol Dis 95:102–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang X et al (2016) Nicotinamide mononucleotide protects against beta-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res 1643:1–9

    Article  CAS  PubMed  Google Scholar 

  14. Yao ZW et al (2017) Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease. Neurosci Lett 647:133–140

    Article  CAS  PubMed  Google Scholar 

  15. Diao P et al (2017) Phenolic endocrine-disrupting compounds in the Pearl River Estuary: occurrence, bioaccumulation and risk assessment. Sci Total Environ 584–585:1100–1107

    Article  PubMed  Google Scholar 

  16. Lotfi M et al (2021) The investigation into neurotoxicity mechanisms of nonylphenol: a narrative review. Curr Neuropharmacol 19(8):1345–1353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ravni A et al (2006) The neurotrophic effects of PACAP in PC12 cells: control by multiple transduction pathways. J Neurochem 98(2):321–329

    Article  CAS  PubMed  Google Scholar 

  18. Vaudry D, et al (2002) PC12 cells as a model to study the neurotrophic activities of PACAP, D.T. OConnor and L.E. Eiden, D.T. OConnor and L.E. Eiden^Editors. 11th International Symposium on Chromaffin Cell Biology. 491–496

  19. Mussina K, Toktarkhanova D, Filchakova O (2021) Nicotinic acetylcholine receptors of PC12 cells. Cell Mol Neurobiol 41(1):17–29

    Article  CAS  PubMed  Google Scholar 

  20. Nishimura Y, Nagao T, Fukushima N (2014) Long-term pre-exposure of pheochromocytoma PC12 cells to endocrine-disrupting chemicals influences neuronal differentiation. Neurosci Lett 570:1–4

    Article  CAS  PubMed  Google Scholar 

  21. Huang RX, Tao J (2020) Nicotinamide mononucleotide attenuates glucocorticoid-induced osteogenic inhibition by regulating the SIRT1/PGC-1 alpha signaling pathway. Mol Med Rep 22(1):145–154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yoo KH et al (2021) Nicotinamide mononucleotide prevents cisplatin-induced cognitive impairments. Can Res 81(13):3727–3737

    Article  CAS  Google Scholar 

  23. Mills KF et al (2016) Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab 24(6):795–806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sharma M, Gupta YK (2002) Chronic treatment with trans resveratrol prevents intracerebroventricular streptozotocin induced cognitive impairment and oxidative stress in rats. Life Sci (1973) 71(21):2489–2498

    Article  CAS  Google Scholar 

  25. Glade MJ (2010) Oxidative stress and cognitive longevity. Nutrition 26(6):595–603

    Article  CAS  PubMed  Google Scholar 

  26. Ito S et al (2020) Protective effects of nicotinamide mononucleotide against oxidative stress-induced PC12 cell death via mitochondrial enhancement. PharmaNutrition 11:100175

    Article  Google Scholar 

  27. Deng X et al (2021) Nicotinamide mononucleotide (NMN) protects bEnd.3 cells against H2 O2 -induced damage via NAMPT and the NF-kappaB p65 signalling pathway. FEBS Open Bio 11(3):866–879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Al-Zahrani SSA et al (1996) Effect of destruction of the 5-hydroxytryptaminergic pathways on the acquisition of temporal discrimination and memory for duration in a delayed conditional discrimination task. Psychopharmacologia 123(1):103–110

    Article  CAS  Google Scholar 

  29. Blazevic S et al (2012) Anxiety-like behavior and cognitive flexibility in adult rats perinatally exposed to increased serotonin concentrations. Behav Brain Res 230(1):175–181

    Article  CAS  PubMed  Google Scholar 

  30. Gold CA, Budson AE (2008) Memory loss in Alzheimer’s disease: implications for development of therapeutics. Expert Rev Neurother 8(12):1879–1891

    Article  PubMed  PubMed Central  Google Scholar 

  31. Haam J, Yakel JL (2017) Cholinergic modulation of the hippocampal region and memory fuction. J Neurochem 142:111–121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Berger-Sweeney J et al (2001) Selective immunolesions of cholinergic neurons in mice: effects on neuroanatomy, neurochemistry, and behavior. J Neurosci 21(20):8164–8173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Parent MJ et al (2013) Cholinergic depletion in Alzheimer’s disease shown by [(18) F]FEOBV autoradiography. Int J Mol Imaging 2013:205045–205045

    Article  PubMed  PubMed Central  Google Scholar 

  34. Wu D et al (2020) Neuroprotective function of a novel hexapeptide QMDDQ from shrimp via activation of the PKA/CREB/BNDF signaling pathway and its structure–activity relationship. J Agric Food Chem 68(24):6759–6769

    Article  CAS  PubMed  Google Scholar 

  35. Das A et al (2018) Impairment of an endothelial NAD+-H2S signaling network is a reversible cause of vascular aging. Cell 173(1):74-89.e20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Di Stefano M et al (2015) A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration. Cell Death Differ 22(5):731–742

    Article  PubMed  Google Scholar 

  37. Chen H et al (2013) NAD+-carrying mesoporous silica nanoparticles can prevent oxidative stress-induced energy failures of both rodent astrocytes and PC12 cells. PLoS ONE 8(9):e74100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chen D et al (2008) The role of calorie restriction and SIRT1 in prion-mediated neurodegeneration. Exp Gerontol 43(12):1086–1093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yoshino J et al (2011) Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab 14(4):528–536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Auberval N, et al (2014) Metabolic and oxidative stress markers in Wistar rats after 2 months on a high-fat diet. Diabetol Metab Syndr 6(1):130. https://doi.org/10.1186/1758-5996-6-130

  41. Thapa I, Fox HS, Bastola D (2015) Coexpression network analysis of miRNA-142 overexpression in neuronal cells. Biomed Res Int 2015:1–9

    Article  Google Scholar 

  42. Arevalo JC, Wu SH (2006) Neurotrophin signaling: many exciting surprises. Cell Mol Life Sci 63(13):1523–1537

    Article  CAS  PubMed  Google Scholar 

  43. Lin J et al (2002) Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 418(6899):797–801

    Article  CAS  PubMed  Google Scholar 

  44. Cho HY, Reddy SP, Kleeberger SR (2006) Nrf2 defends the lung from oxidative stress. Antioxid Redox Signal 8(1–2):76–87

    Article  CAS  PubMed  Google Scholar 

  45. Gong W et al (2017) Polydatin promotes Nrf2-ARE anti-oxidative pathway through activating CKIP-1 to resist HG-induced up-regulation of FN and ICAM-1 in GMCs and diabetic mice kidneys. Free Radic Biol Med 106:393–405

    Article  CAS  PubMed  Google Scholar 

  46. Huang K et al (2013) Sirt1 resists advanced glycation end products-induced expressions of fibronectin and TGF-beta 1 by activating the Nrf2/ARE pathway in glomerular mesangial cells. Free Radic Biol Med 65:528–540

    Article  CAS  PubMed  Google Scholar 

  47. Yang Y et al (2014) Alpha-lipoic acid improves high-fat diet-induced hepatic steatosis by modulating the transcription factors SREBP-1, FoxO1 and Nrf2 via the SIRT1/LKB1/AMPK pathway. J Nutr Biochem 25(11):1207–1217

    Article  CAS  PubMed  Google Scholar 

  48. Naoi M et al (2011) Type A monoamine oxidase regulates life and death of neurons in neurodegeneration and neuroprotection. Int Rev Neurobiol 100:85

    Article  CAS  PubMed  Google Scholar 

  49. Libert S et al (2011) SIRT1 activates MAO-A in the brain to mediate anxiety and exploratory drive. Cell 147(7):1459–1472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kang H et al (1997) Neurotrophins and time: different roles for TrkB signaling in hippocampal long-term potentiation. Neuron (Cambridge Mass) 19(3):653–664

    Article  CAS  Google Scholar 

  51. Croll SD et al (1998) Expression of BDNF and trkB as a function of age and cognitive performance. Brain Res 812(1):200–208

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We appreciate the contribution of all the members participating in this study.

Funding

This study was supported by the Natural Science Foundation of Guangdong Province (2021A1515010825), Guangdong Key R&D Program, Department of Science and Technology of Guangdong Province (2019B020210002), Generic Technique Innovation Team Construction of Modern Agriculture of Guangdong Province (2021KJ130), and Guangdong Provincial Key Laboratory of Food Quality and Safety (2020B1212060059).

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Authors and Affiliations

  1. College of Food Science, South China Agricultural University, 483#, Wu-Shan Ave., Tian-He District, Guangzhou, 510642, China

    Zhongyi Li, Huan Liu, Wenna Han, Siyu Zhu & Chunhong Liu

  2. Guangdong Provincial Key Laboratory of Food Quality and Safety, Guangzhou, 510642, China

    Zhongyi Li, Huan Liu, Wenna Han, Siyu Zhu & Chunhong Liu

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  1. Zhongyi Li
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  2. Huan Liu
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  4. Siyu Zhu
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Contributions

Zhongyi Li: design and conduct of the cell cultural experiments, analysis of the data, and writing the manuscript.

Huan Liu: conduct the Western blotting experiments.

Wenna Han: conduct the cell cultural experiments, and analysis of the relevant data.

Siyu Zhu: conceptualization, writing-review and editing, and funding acquisition.

Chunhong Liu: supervision and funding acquisition.

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Correspondence to Chunhong Liu.

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Li, Z., Liu, H., Han, W. et al. NMN Alleviates NP-Induced Learning and Memory Impairment Through SIRT1 Pathway in PC-12 Cell. Mol Neurobiol 60, 2871–2883 (2023). https://doi.org/10.1007/s12035-023-03251-9

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