Protective Effects of 1-Methylnicotinamide on Aβ1–42-Induced Cognitive Deficits, Neuroinflammation and Apoptosis in Mice

  • Lili Fu
  • Caihong Liu
  • Liang Chen
  • Yangge Lv
  • Guoliang Meng
  • Mei Hu
  • Yan Long
  • Hao HongEmail author
  • Susu TangEmail author


The neurotoxicity of Aβ peptides has been well documented, but effective neuroprotective approaches against Aβ neurotoxicity are unavailable. In the present study, we investigated effects of 1-Methylnicotinamide (MNA), known as a main metabolite of nicotinamide (NA), on the impairment of learning and memory induced by Aβ and the underlying mechanisms. We found that intragastric administration of MNA at 100 or 200 mg/kg for 3 weeks significantly reversed bilateral intrahippocampal injection of Aβ1–42-induced cognitive impairments in the Morris water maze (MWM), Y-maze and Novel object recognition tests. Furthermore, MNA suppressed Aβ1–42-induced neuroinflammation, characterized by suppressed activation of microglia, decreased the expression of IL-6, TNF-α and nuclear translocation of NF-κB p65, as well as attenuated neuronal apoptosis as indicated by decreased TUNEL-positive cells and ratio of caspase-3 fragment to procaspase-3, and increased ratio of Bcl-2/Bax in the hippocampus. Our results show that MNA may ameliorate Aβ1–42-induced cognition deficits, which is involved in inhibition of neuroinflammation and apoptosis mediated by NF-κB signaling, suggesting that MNA could have potential therapeutic value for AD.

Graphical Abstract

Neuroprotective affect of MNA on Aβ1–42-induced cognitive deficits.


1-Methylnicotinamide 1–42 Cognition deficits Neuroinflammation Apoptosis 



This work was supported by grants from the National Natural Science Foundation of China (81573413, 81773714 and 81273497 to Hao Hong, 81603113 to Su Su Tang), the Natural Science Foundation of Jiangsu Province (BK20150705 to Su Su Tang), and the Fundamental Research Funds for the Central Universities (2632017PT01).

Compliance with Ethical Standards

The National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80–23, revised, 1996) was used for the experiments and the procedures were approved by the Animal Care and Use Committee, China Pharmaceutical University.

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. Antunes M, Biala G (2012) The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process 13:93–110CrossRefGoogle Scholar
  2. Bar A, Olkowicz M, Tyrankiewicz U, Kus E, Jasinski K, Smolenski RT, Skorka T, Chlopicki S (2017) Functional and biochemical endothelial profiling in vivo in a murine model of endothelial dysfunction; comparison of effects of 1-Methylnicotinamide and angiotensin-converting enzyme inhibitor. Front Pharmacol 8:183CrossRefGoogle Scholar
  3. Bryniarski K, Biedron R, Jakubowski A, Chlopicki S, Marcinkiewicz J (2008) Anti-inflammatory effect of 1-methylnicotinamide in contact hypersensitivity to oxazolone in mice; involvement of prostacyclin. Eur J Pharmacol 578:332–338CrossRefGoogle Scholar
  4. Chlopicki S, Swies J, Mogielnicki A, Buczko W, Bartus M, Lomnicka M, Adamus J, Gebicki J (2007) 1-Methylnicotinamide (MNA), a primary metabolite of nicotinamide, exerts anti-thrombotic activity mediated by a cyclooxygenase-2/prostacyclin pathway. Br J Pharmacol 152:230–239CrossRefGoogle Scholar
  5. Chong ZZ, Lin SH, Maiese K (2002) Nicotinamide modulates mitochondrial membrane potential and cysteine protease activity during cerebral vascular endothelial cell injury. J Vasc Res 39:131–147CrossRefGoogle Scholar
  6. Chong ZZ, Lin SH, Maiese K (2004) The NAD+ precursor nicotinamide governs neuronal survival during oxidative stress through protein kinase B coupled to FOXO3a and mitochondrial membrane potential. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism 24:728–743CrossRefGoogle Scholar
  7. Ding HG, Deng YY, Yang RQ, Wang QS, Jiang WQ, Han YL, Huang LQ, Wen MY, Zhong WH, Li XS, Yang F, Zeng HK (2018) Hypercapnia induces IL-1beta overproduction via activation of NLRP3 inflammasome: implication in cognitive impairment in hypoxemic adult rats. J Neuroinflammation 15:4CrossRefGoogle Scholar
  8. DiPalma JR, Thayer WS (1991) Use of niacin as a drug. Annu Rev Nutr 11:169–187CrossRefGoogle Scholar
  9. Dragun P, Makarewicz D, Wojcik L, Ziemka-Nalecz M, Slomka M, Zalewska T (2008) Matrix metaloproteinases activity during the evolution of hypoxic-ischemic brain damage in the immature rat. The effect of 1-methylnicotinamide (MNA). Journal of Physiology and Pharmacology : an Official Journal of the Polish Physiological Society 59:441–455Google Scholar
  10. Echeverria V, Yarkov A, Aliev G (2016) Positive modulators of the alpha7 nicotinic receptor against neuroinflammation and cognitive impairment in Alzheimer's disease. Prog Neurobiol 144:142–157CrossRefGoogle Scholar
  11. Erb C, Seidel A, Frank H, Platt KL, Oesch F, Klein J (1999) Formation of N-methylnicotinamide in the brain from a dihydropyridine-type prodrug: effect on brain choline. Biochem Pharmacol 57:681–684CrossRefGoogle Scholar
  12. Frost JL, Le KX, Cynis H, Ekpo E, Kleinschmidt M, Palmour RM, Ervin FR, Snigdha S, Cotman CW, Saido TC, Vassar RJ, St George-Hyslop P, Ikezu T, Schilling S, Demuth HU, Lemere CA (2013) Pyroglutamate-3 amyloid-beta deposition in the brains of humans, non-human primates, canines, and Alzheimer disease-like transgenic mouse models. Am J Pathol 183:369–381CrossRefGoogle Scholar
  13. Garcez ML, Mina F, Bellettini-Santos T, da Luz AP, Schiavo GL, Macieski JMC, Medeiros EB, Marques AO, Magnus NQ, Budni J (2018) The involvement of NLRP3 on the effects of minocycline in an AD-like pathology induced by beta-amyloid oligomers administered to mice. Mol NeurobiolGoogle Scholar
  14. Huang Y, Zhao Z, Wei X, Zheng Y, Yu J, Zheng J, Wang L (2016) Long-term trihexyphenidyl exposure alters neuroimmune response and inflammation in aging rat: relevance to age and Alzheimer's disease. J Neuroinflammation 13:175CrossRefGoogle Scholar
  15. Hurley MJ, Deacon RMJ, Beyer K, Ioannou E, Ibáñez A, Teeling JL, Cogram P (2018) The long-lived Octodon degus as a rodent drug discovery model for Alzheimer's and other age-related diseases. Pharmacol Ther 188:36–44CrossRefGoogle Scholar
  16. Je JH, Lee JY, Jung KJ, Sung B, Go EK, Yu BP, Chung HY (2004) NF-kappaB activation mechanism of 4-hydroxyhexenal via NIK/IKK and p38 MAPK pathway. FEBS Lett 566:183–189CrossRefGoogle Scholar
  17. Jiao H, Guan F, Yang B, Li J, Song L, Hu X, Du Y (2012) Human amniotic membrane derived-mesenchymal stem cells induce C6 glioma apoptosis in vivo through the Bcl-2/caspase pathways. Mol Biol Rep 39:467–473CrossRefGoogle Scholar
  18. Kempuraj D, Thangavel R, Selvakumar GP, Zaheer S, Ahmed ME, Raikwar SP, Zahoor H, Saeed D, Natteru PA, Iyer S, Zaheer A (2017) Brain and peripheral atypical inflammatory mediators potentiate Neuroinflammation and neurodegeneration. Front Cell Neurosci 11:216CrossRefGoogle Scholar
  19. Kerr JS, Adriaanse BA, Greig NH, Mattson MP, Cader MZ, Bohr VA, Fang EF (2017) Mitophagy and Alzheimer's disease: cellular and molecular mechanisms. Trends Neurosci 40:151–166CrossRefGoogle Scholar
  20. Khan M, Im YB, Shunmugavel A, Gilg AG, Dhindsa RK, Singh AK, Singh I (2009) Administration of S-nitrosoglutathione after traumatic brain injury protects the neurovascular unit and reduces secondary injury in a rat model of controlled cortical impact. J Neuroinflammation 6:32CrossRefGoogle Scholar
  21. Kimura R, Devi L, Ohno M (2010) Partial reduction of BACE1 improves synaptic plasticity, recent and remote memories in Alzheimer's disease transgenic mice. J Neurochem 113:248–261CrossRefGoogle Scholar
  22. Kuchmerovska T, Shymanskyy I, Chlopicki S, Klimenko A (2010) 1-methylnicotinamide (MNA) in prevention of diabetes-associated brain disorders. Neurochem Int 56:221–228CrossRefGoogle Scholar
  23. Lai J, Hu M, Wang H, Hu M, Long Y, Miao MX, Li JC, Wang XB, Kong LY, Hong H (2014) Montelukast targeting the cysteinyl leukotriene receptor 1 ameliorates Abeta1-42-induced memory impairment and neuroinflammatory and apoptotic responses in mice. Neuropharmacology 79:707–714CrossRefGoogle Scholar
  24. Lawrence T, Gilroy DW, Colville-Nash PR, Willoughby DA (2001) Possible new role for NF-kappaB in the resolution of inflammation. Nat Med 7:1291–1297CrossRefGoogle Scholar
  25. Li F, Chong ZZ, Maiese K (2006) Cell life versus cell longevity: the mysteries surrounding the NAD+ precursor nicotinamide. Curr Med Chem 13:883–895CrossRefGoogle Scholar
  26. Lin S-J, Guarente L (2003) Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease. Curr Opin Cell Biol 15:241–246CrossRefGoogle Scholar
  27. Lin N, Xiong L-L, R-p Z, Zheng H, Wang L, Qian Z-Y, Zhang P, Z-w C, Gao F-B, Wang T-H (2016) Injection of Aβ1-40 into hippocampus induced cognitive lesion associated with neuronal apoptosis and multiple gene expressions in the tree shrew. Apoptosis : an International Journal on Programmed Cell Death 21:621–640CrossRefGoogle Scholar
  28. Lin JR, Fang SC, Tang SS, Hu M, Long Y, Ghosh A, Sun HB, Kong LY, Hong H (2017) Hippocampal CysLT1R knockdown or blockade represses LPS-induced depressive behaviors and neuroinflammatory response in mice. Acta Pharmacol Sin 38:477–487CrossRefGoogle Scholar
  29. Liu D, Pitta M, Jiang H, Lee JH, Zhang G, Chen X, Kawamoto EM, Mattson MP (2013) Nicotinamide forestalls pathology and cognitive decline in Alzheimer mice: evidence for improved neuronal bioenergetics and autophagy procession. Neurobiol Aging 34:1564–1580CrossRefGoogle Scholar
  30. Liu H, Wang J, Wang J, Wang P, Xue Y (2015) Paeoniflorin attenuates Abeta1-42-induced inflammation and chemotaxis of microglia in vitro and inhibits NF-kappaB- and VEGF/Flt-1 signaling pathways. Brain Res 1618:149–158CrossRefGoogle Scholar
  31. Lowry JR, Klegeris A (2018) Emerging roles of microglial Cathepsins in neurodegenerative disease. Brain Res Bull 139:144–156CrossRefGoogle Scholar
  32. Magni G, Amici A, Emanuelli M, Orsomando G, Raffaelli N, Ruggieri S (2004) Enzymology of NAD+ homeostasis in man. Cellular and Molecular Life Sciences : CMLS 61:19–34CrossRefGoogle Scholar
  33. Maurice T, Lockhart BP, Privat A (1996) Amnesia induced in mice by centrally administered beta-amyloid peptides involves cholinergic dysfunction. Brain Res 706:181–193CrossRefGoogle Scholar
  34. Nasoohi S, Ismael S, Ishrat T (2018) Thioredoxin-interacting protein (TXNIP) in cerebrovascular and neurodegenerative diseases: regulation and implication. Mol NeurobiolGoogle Scholar
  35. Nitta A, Fukuta T, Hasegawa T, Nabeshima T (1997) Continuous infusion of beta-amyloid protein into the rat cerebral ventricle induces learning impairment and neuronal and morphological degeneration. Jpn J Pharmacol 73:51–57CrossRefGoogle Scholar
  36. Pandey R, Rai V, Mishra J, Mandrah K, Kumar Roy S, Bandyopadhyay S (2017) From the cover: arsenic induces hippocampal neuronal apoptosis and cognitive impairments via an up-regulated BMP2/Smad-dependent reduced BDNF/TrkB signaling in rats. Toxicological Sciences : an Official Journal of the Society of Toxicology 159:137–158CrossRefGoogle Scholar
  37. Pfau ML, Russo SJ (2016) Neuroinflammation regulates cognitive impairment in socially defeated mice. Trends Neurosci 39:353–355CrossRefGoogle Scholar
  38. Piirainen S, Youssef A, Song C, Kalueff AV, Landreth GE, Malm T, Tian L (2017) Psychosocial stress on neuroinflammation and cognitive dysfunctions in Alzheimer's disease: the emerging role for microglia? Neurosci Biobehav Rev 77:148–164CrossRefGoogle Scholar
  39. Przygodzki T, Kazmierczak P, Sikora J, Watala C (2010) 1-methylnicotinamide effects on the selected markers of endothelial function, inflammation and haemostasis in diabetic rats. Eur J Pharmacol 640:157–162CrossRefGoogle Scholar
  40. Pujadas L, Rossi D, Andres R, Teixeira CM, Serra-Vidal B, Parcerisas A, Maldonado R, Giralt E, Carulla N, Soriano E (2014) Reelin delays amyloid-beta fibril formation and rescues cognitive deficits in a model of Alzheimer's disease. Nat Commun 5:3443CrossRefGoogle Scholar
  41. Qian Y, Yin J, Hong J, Li G, Zhang B, Liu G, Wan Q, Chen L (2016) Neuronal seipin knockout facilitates Abeta-induced neuroinflammation and neurotoxicity via reduction of PPARgamma in hippocampus of mouse. J Neuroinflammation 13:145CrossRefGoogle Scholar
  42. Rahimifard M, Maqbool F, Moeini-Nodeh S, Niaz K, Abdollahi M, Braidy N, Nabavi SM, Nabavi SF (2017) Targeting the TLR4 signaling pathway by polyphenols: a novel therapeutic strategy for neuroinflammation. Ageing Res Rev 36:11–19CrossRefGoogle Scholar
  43. Rubio-Perez JM, Morillas-Ruiz JM (2012) A review: inflammatory process in Alzheimer's disease, role of cytokines. TheScientificWorldJournal 2012:756357CrossRefGoogle Scholar
  44. Ruiz-Vela A, Opferman JT, Cheng EHY, Korsmeyer SJ (2005) Proapoptotic BAX and BAK control multiple initiator caspases. EMBO Rep 6:379–385CrossRefGoogle Scholar
  45. Russo I, Caracciolo L, Tweedie D, Choi SH, Greig NH, Barlati S, Bosetti F (2012) 3,6′-Dithiothalidomide, a new TNF-alpha synthesis inhibitor, attenuates the effect of Abeta1-42 intracerebroventricular injection on hippocampal neurogenesis and memory deficit. J Neurochem 122:1181–1192CrossRefGoogle Scholar
  46. Sethi G, Sung B, Aggarwal BB (2008) Nuclear factor-kappaB activation: from bench to bedside. Exp Biol Med 233:21–31CrossRefGoogle Scholar
  47. Slomka M, Zieminska E, Lazarewicz J (2008a) Nicotinamide and 1-methylnicotinamide reduce homocysteine neurotoxicity in primary cultures of rat cerebellar granule cells. Acta Neurobiol Exp 68:1–9Google Scholar
  48. Slomka M, Zieminska E, Salinska E, Lazarewicz JW (2008b) Neuroprotective effects of nicotinamide and 1-methylnicotinamide in acute excitotoxicity in vitro. Folia Neuropathol 46:69–80Google Scholar
  49. Song D, Jiang X, Liu Y, Sun Y, Cao S, Zhang Z (2018) Asiaticoside attenuates cell growth inhibition and apoptosis induced by Abeta1-42 via inhibiting the TLR4/NF-kappaB signaling pathway in human brain microvascular endothelial cells. Front Pharmacol 9:28CrossRefGoogle Scholar
  50. Sternak M, Khomich TI, Jakubowski A, Szafarz M, Szczepanski W, Bialas M, Stojak M, Szymura-Oleksiak J, Chlopicki S (2010) Nicotinamide N-methyltransferase (NNMT) and 1-methylnicotinamide (MNA) in experimental hepatitis induced by concanavalin a in the mouse. Pharmacological Reports : PR 62:483–493CrossRefGoogle Scholar
  51. Sternak M, Jakubowski A, Czarnowska E, Slominska EM, Smolenski RT, Szafarz M, Walczak M, Sitek B, Wojcik T, Jasztal A, Kaminski K, Chlopicki S (2015) Differential involvement of IL-6 in the early and late phase of 1-methylnicotinamide (MNA) release in Concanavalin A-induced hepatitis. Int Immunopharmacol 28:105–114CrossRefGoogle Scholar
  52. Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, Lacy-Hulbert A, El Khoury J, Golenbock DT, Moore KJ (2010) CD36 ligands promote sterile inflammation through assembly of a toll-like receptor 4 and 6 heterodimer. Nat Immunol 11:155–161CrossRefGoogle Scholar
  53. Takeda K, Akira S (2004) TLR signaling pathways. Semin Immunol 16:3–9CrossRefGoogle Scholar
  54. Tanaka Y, Kume S, Araki H, Nakazawa J, Chin-Kanasaki M, Araki S, Nakagawa F, Koya D, Haneda M, Maegawa H, Uzu T (2015) 1-Methylnicotinamide ameliorates lipotoxicity-induced oxidative stress and cell death in kidney proximal tubular cells. Free Radic Biol Med 89:831–841CrossRefGoogle Scholar
  55. Tang SS, Wang XY, Hong H, Long Y, Li YQ, Xiang GQ, Jiang LY, Zhang HT, Liu LP, Miao MX, Hu M, Zhang TT, Hu W, Ji H, Ye FY (2013) Leukotriene D4 induces cognitive impairment through enhancement of CysLT(1) R-mediated amyloid-beta generation in mice. Neuropharmacology 65:182–192CrossRefGoogle Scholar
  56. Tang SS, Hong H, Chen L, Mei ZL, Ji MJ, Xiang GQ, Li N, Ji H (2014a) Involvement of cysteinyl leukotriene receptor 1 in Abeta1-42-induced neurotoxicity in vitro and in vivo. Neurobiol Aging 35:590–599CrossRefGoogle Scholar
  57. Tang SS, Ji MJ, Chen L, Hu M, Long Y, Li YQ, Miao MX, Li JC, Li N, Ji H, Chen XJ, Hong H (2014b) Protective effect of pranlukast on Abeta(1)(−)(4)(2)-induced cognitive deficits associated with downregulation of cysteinyl leukotriene receptor 1. Int J Neuropsychopharmacol 17:581–592CrossRefGoogle Scholar
  58. Tang R, Lin YM, Liu HX, Wang ES (2018) Neuroprotective effect of docosahexaenoic acid in rat traumatic brain injury model via regulation of TLR4/NF-kappa B signaling pathway. Int J Biochem Cell Biol 99:64–71CrossRefGoogle Scholar
  59. Tusi SK, Ansari N, Amini M, Amirabad AD, Shafiee A, Khodagholi F (2010) Attenuation of NF-kappaB and activation of Nrf2 signaling by 1,2,4-triazine derivatives, protects neuron-like PC12 cells against apoptosis. Apoptosis : an International Journal on Programmed Cell Death 15:738–751CrossRefGoogle Scholar
  60. Ungerstedt JS, Blomback M, Soderstrom T (2003) Nicotinamide is a potent inhibitor of proinflammatory cytokines. Clin Exp Immunol 131:48–52CrossRefGoogle Scholar
  61. Wang WY, Tan MS, Yu JT, Tan L (2015) Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease. Annals of Translational Medicine 3:136Google Scholar
  62. Wang SW, Liu DQ, Zhang LX, Ji M, Zhang YX, Dong QX, Liu SY, Xie XX, Liu RT (2017) A vaccine with Abeta oligomer-specific mimotope attenuates cognitive deficits and brain pathologies in transgenic mice with Alzheimer's disease. Alzheimers Res Ther 9:41CrossRefGoogle Scholar
  63. Williams AC, Cartwright LS, Ramsden DB (2005) Parkinson's disease: the first common neurological disease due to auto-intoxication? QJM : Monthly Journal of the Association of Physicians 98:215–226CrossRefGoogle Scholar
  64. Wyss-Coray T (2006) Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 12:1005–1015Google Scholar
  65. Xie X, Liu H, Wang Y, Zhou Y, Yu H, Li G, Ruan Z, Li F, Wang X, Zhang J (2016) Nicotinamide N-methyltransferase enhances resistance to 5-fluorouracil in colorectal cancer cells through inhibition of the ASK1-p38 MAPK pathway. Oncotarget 7:45837–45848Google Scholar
  66. Ye SM, Johnson RW (2001) Regulation of interleukin-6 gene expression in brain of aged mice by nuclear factor kappaB. J Neuroimmunol 117:87–96CrossRefGoogle Scholar
  67. Zhang CT, Lin JR, Wu F, Ghosh A, Tang SS, Hu M, Long Y, Sun HB, Hong H (2016) Montelukast ameliorates streptozotocin-induced cognitive impairment and neurotoxicity in mice. Neurotoxicology 57:214–222CrossRefGoogle Scholar
  68. Zhang Z, Li X, Li D, Luo M, Li Y, Song L, Jiang X (2017) Asiaticoside ameliorates beta-amyloid-induced learning and memory deficits in rats by inhibiting mitochondrial apoptosis and reducing inflammatory factors. Experimental and Therapeutic Medicine 13:413–420CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Pharmacology, Key Laboratory of Neuropsychiatric DiseasesChina Pharmaceutical UniversityNanjingChina
  2. 2.School of PharmacyNantong UniversityNantongChina

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