Wikipedia

1-Methylnicotinamide

1-Methylnicotinamide (1-MNA, trigonellamide) is a prototypic organic cation.[1] 1-Methylnicotinamide is the methylated amide of Nicotinamide (niacinamide, vitamin B3).

1-Methylnicotinamide
Names
Preferred IUPAC name
3-Carbamoyl-1-methylpyridin-1-ium
Other names
Trigonellamide; N1-Methylnicotinamide; NMN
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
UNII
  • C[N+]1=CC=CC(=C1)C(=O)N
Properties
C7H9N2O+
Molar mass 137.161 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

1-Methylnicotinamide is an endogenic substance that is produced in the liver when Nicotinamide is metabolized. It is a typical substance secreted in the kidney. It participates in the nicotinamide salvage pathway within the NAD+ (nicotinamide adenine dinucleotide) metabolic pathway, thereby contributing to optimizing NAD+ levels.[2]

Occurrence

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To date, the highest natural concentration of 1-methylnicotinamide has been found in the alga Undaria pinnatifida (3.2 mg/100 g of dried algae) and green tea leaves (3 mg/100 g of product). Other products with notable 1-MNA content include celery (1.6 mg/100 g of product), Chinese black mushrooms (shiitake, 1.3 mg/100 g), and fermented soybeans (natto, 1.0 mg/100 g).[3]

Biosynthesis

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1-Methylnicotinamide can be produced in the liver by nicotinamide N-methyltransferase (NNMT). The reaction takes place during the metabolism of NAD+ (nicotinamide adenine dinucleotide). NNMT is also present in brain tissue, adipose tissue, muscle tissue, kidneys, and skin.[4][5]

NNMT (nicotinamide N-methyltransferase) is an enzyme that in humans is encoded by the NNMT gene.[6] NNMT catalyzes the methylation of nicotinamide and similar compounds using the methyl donor S-adenosyl methionine (SAM-e) to produce S-adenosyl-L-homocysteine (SAH) and 1-methylnicotinamide.[7] NNMT is highly expressed in the human liver.[7]

Role in the body

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Scientific research highlights numerous therapeutic and health-promoting properties of 1-MNA, including vascular protective,[8][9] anticoagulant,[10] anti-atherosclerotic,[11] anti-inflammatory,[12][13][14] neuroprotective,[15] and endurance-enhancing effects.[16]

Vascular Protective Effects

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1-MNA exerts beneficial effects on blood vessels through its action on the vascular endothelium. It improves the bioavailability of nitric oxide (NO), which is crucial for vasodilation, and regulates the activity of endothelial nitric oxide synthase (eNOS), the enzyme responsible for NO synthesis.[8][9]

These effects have been demonstrated in both in vivo and in vitro studies. Oral administration of 1-MNA has been shown to increase the diameter of the brachial artery (as measured by flow-mediated dilation, FMD) and stimulate NO release from human endothelial cells in both healthy individuals and those with hypercholesterolemia increased.[9]

Additionally, in cases of vascular dysfunction (e.g., hypertriglyceridemia or diabetes), 1-MNA restored normal NO-dependent vasodilation.[8] By increasing NO bioavailability, 1-MNA may counteract endothelial dysfunction, support endothelial regeneration, and improve vascular function, particularly in the context of cardiovascular risk.[8][9]

Anticoagulant Effects

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1-Methylnicotinamide is an endogenous activator of prostacyclin synthesis and can therefore regulate thrombolytic[check spelling] and inflammatory processes in the cardiovascular system.[8] It inhibits platelet-dependent thrombosis through a mechanism involving[10] cyclooxygenase-2 and prostacyclin and increases nitric oxide bioavailability in the endothelium.[9][7] Endogenous prostacyclin (PGI2) plays a critical role in preventing platelet aggregation and thrombus formation. A deficiency in PGI2 can lead to increased platelet aggregation and arterial thrombi.

Anti-atherosclerotic and Anti-inflammatory Effects

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1-MNA exhibits anti-atherosclerotic and anti-inflammatory properties by improving the prostacyclin- and NO-dependent secretory function of the vascular endothelium, inhibiting platelet activation, reducing inflammation within atherosclerotic plaques, and lowering systemic inflammation and TNF-α levels.[11]

The anti-inflammatory effects of 1-MNA are linked to its ability to stimulate endogenous PGI2 secretion and reduce IL-4 and TNF-α levels.[12] These effects are mediated by endothelial mechanisms rather than a direct impact on immune cell function, ensuring that the body’s immune response is not weakened.[13][14]

NAD+ Optimization

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1-MNA is an inhibitor of nicotinamide N-methyltransferase (NNMT). By inhibiting NNMT activity, it regulates NAD+ biosynthesis via the nicotinamide salvage pathway, the primary route for NAD+ synthesis in mammals. By participating in this pathway, 1-MNA optimizes NAD+ levels.[2]

Impact on SIRT1

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Research published in Nature Medicine indicates that 1-MNA enhances SIRT1 expression and stability.[17] SIRT1 is an enzyme associated with longevity.

Studies using the nematode Caenorhabditis elegans indicate that 1-MNA supplementation may extend lifespan. These studies also link 1-MNA to SIRT1.[18]

Neuroprotective Effects

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Animal experiments with diabetic rats have shown that 1-methylnicotinamide positively effects degenerative changes in the brain, allowing cognitive performance to be maintained longer.[19] It also prevents depressive behavior with efficacy comparable to the common antidepressant fluoxetine. This effect is attributed to the reduction of neuroinflammation, pro-inflammatory cytokines (IL-6, TNF-α), and increased expression of BDNF (brain-derived neurotrophic factor), a protein supporting neuron survival and growth.[20]

The neuroprotective effects of 1-MNA involve shielding against neurotoxins, amyloid-beta plaques in the brain, neuroinflammatory responses, and neuronal apoptosis. It has been shown to improve memory deficits and cognitive functions, suggesting potential for treating neurodegenerative disorders.[15][21]

Enhancement of Physical Performance

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1-MNA acts as a myokine, supporting the utilization of amino acids for gluconeogenesis in the liver and stimulating lipolysis in adipose tissue, thereby providing energy for muscles.[22] Studies indicate that 1-MNA supplementation improves exercise tolerance and reduces fatigue. After one month of supplementation with 58 mg of 1-MNA, post-COVID-19 patients reported improved distances in a 6-minute walk test (6MWT), with 92% of participants experiencing better outcomes compared to controls.[16]

Additional studies highlight 1-MNA’s ability to enhance physical performance by stimulating PGI2 release, protecting microcirculation, and ensuring adequate blood flow to muscle tissues. This mechanism may reduce cardiovascular risks associated with physical exertion, particularly in individuals with impaired endothelial response.[23]

Commercialization

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1-MNA has been approved for use in food products in the form of 1-MNA chloride. The approval process in the European Union was successfully completed by PHARMENA SA. In 2017, the European Food Safety Authority (EFSA) confirmed the safety of 1-MNA chloride in food supplements, leading to its authorization in 2018 under EU Regulation 2018/1123.[24]

1-MNA chloride is currently used in dietary supplements.[25] Other chemical forms of 1-MNA are not currently allowed on the market as food.

Safety

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The safety of 1-MNA chloride has been thoroughly evaluated by EFSA, confirming its safe use. It must meet quality parameters defined in EU Regulation 2018/1123.[24][26]

References

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  1. ^ Sokol, P. P.; Holohan, P. D.; Ross, C. R. (1986). "Essential disulfide and sulfhydryl groups for organic cation transport in renal brush-border membranes". Journal of Biological Chemistry. 261 (7): 3282–3287. doi:10.1016/S0021-9258(17)35779-4. PMID 2936734. Retrieved 5 March 2021.
  2. ^ a b Li, Jing-Jing; Sun, Wei-Dong; Zhu, Xiao-Juan; Mei, Ya-Zhong; Li, Wen-Song; Li, Jiang-Hua (2024-06-19). "Nicotinamide N-Methyltransferase (NNMT): A New Hope for Treating Aging and Age-Related Conditions". Metabolites. 14 (6): 343. doi:10.3390/metabo14060343. ISSN 2218-1989. PMC 11205546. PMID 38921477.
  3. ^ Taguchi, H.; Sakaguchi, M.; Shimabayashi, Y. (1986). 各種食品中のキノリン酸,トリゴネリンおよびN1-メチルニコチンアミドの含量ならびに加熱によるそれらのニコチン酸,ニコチンアミドへの変換 [Contents of quinolinic acid, trigonelline and N1-methylnicotinamide in various foods and thermal conversion of these compounds into nicotinic acid and nicotinamide]. ビタミン ビタミン [Vitamins] (in Japanese). 60 (11): 537–546. doi:10.20632/vso.60.11_537.
  4. ^ "GTEx Portal". www.gtexportal.org. Retrieved 2024-12-06.
  5. ^ Mangan, Mary (2010-12-07). "Tip of the Week: BioGPS for expression data and more". SciVee. doi:10.4016/26142.01 (inactive 6 December 2024). Retrieved 2024-12-06.{{cite web}}: CS1 maint: DOI inactive as of December 2024 (link)
  6. ^ Aksoy S, Brandriff BF, Ward A, Little PF, Weinshilboum RM (Mar 1996). "Human nicotinamide N-methyltransferase gene: molecular cloning, structural characterization and chromosomal localization". Genomics. 29 (3): 555–561. doi:10.1006/geno.1995.9966. PMID 8575745.
  7. ^ a b c Pissios P (2017). "Nicotinamide N-Methyltransferase: More Than a Vitamin B3 Clearance Enzyme". Trends in Endocrinology and Metabolism. 28 (5): 340–353. doi:10.1016/j.tem.2017.02.004. PMC 5446048. PMID 28291578.
  8. ^ a b c d e Bartuś, M.; Łomnicka, M.; Kostogrys, R. B.; Kaźmierczak, P.; Watała, C.; Słominska, E. M.; Smoleński, R. T.; Pisulewski, P. M.; Adamus, J.; Gębicki, J.; Chlopicki, S. (2008). "1-Methylnicotinamide (MNA) prevents endothelial dysfunction in hypertriglyceridemic and diabetic rats" (PDF). Pharmacological Reports. 60 (1): 127–138. PMID 18276994.
  9. ^ a b c d e Domagala, T. B.; Szeffler, A.; Dobrucki, L. W.; Dropinski, J.; Polanski, S.; Leszczynska-Wiloch, M.; Kotula-Horowitz, K.; Wojciechowski, J.; Wojnowski, L.; Szczeklik, A.; Kalinowski, L. (2012). "Nitric oxide production and endothelium-dependent vasorelaxation ameliorated by N1-methylnicotinamide in human blood vessels". Hypertension. 59 (4): 825–832. doi:10.1161/HYPERTENSIONAHA.111.183210. PMID 22353616. S2CID 302943.
  10. ^ a b 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". British Journal of Pharmacology. 152 (2): 230–239. doi:10.1038/sj.bjp.0707383. PMC 1978255. PMID 17641676.
  11. ^ a b Mateuszuk, L.; Jasztal, A.; Maslak, E.; Gasior-Glogowska, M.; Baranska, M.; Sitek, B.; Kostogrys, R.; Zakrzewska, A.; Kij, A.; Walczak, M.; Chlopicki, S. (2016-01-22). "Antiatherosclerotic Effects of 1-Methylnicotinamide in Apolipoprotein E/Low-Density Lipoprotein Receptor-Deficient Mice: A Comparison with Nicotinic Acid". Journal of Pharmacology and Experimental Therapeutics. 356 (2): 514–524. doi:10.1124/jpet.115.228643. ISSN 1521-0103. PMC 6047228. PMID 26631491.
  12. ^ a b Jakubowski, Andrzej; Sternak, Magdalena; Jablonski, Konrad; Ciszek-Lenda, Marta; Marcinkiewicz, Janusz; Chlopicki, Stefan (2016). "1-Methylnicotinamide protects against liver injury induced by concanavalin A via a prostacyclin-dependent mechanism: A possible involvement of IL-4 and TNF-α". International Immunopharmacology. 31: 98–104. doi:10.1016/j.intimp.2015.11.032. PMID 26709075.
  13. ^ a b 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". European Journal of Pharmacology. 578 (2–3): 332–338. doi:10.1016/j.ejphar.2007.09.011. PMID 17935712.
  14. ^ a b Biedron, Rafal; Ciszek, Marta; Tokarczyk, Marianna; Bobek, Malgorzata; Kurnyta, Maria; Slominska, Ewa M.; Smolenski, Ryszard T.; Marcinkiewicz, Janusz (2008). "1-Methylnicotinamide and nicotinamide: two related anti-inflammatory agents that differentially affect the functions of activated macrophages". Archivum Immunologiae et Therapiae Experimentalis. 56 (2): 127–134. doi:10.1007/s00005-008-0009-2. ISSN 0004-069X. PMC 2766500. PMID 18373238.
  15. ^ a b Fu, Lili; Liu, Caihong; Chen, Liang; Lv, Yangge; Meng, Guoliang; Hu, Mei; Long, Yan; Hong, Hao; Tang, Susu (2019). "Protective Effects of 1-Methylnicotinamide on Aβ1–42-Induced Cognitive Deficits, Neuroinflammation and Apoptosis in Mice". Journal of Neuroimmune Pharmacology. 14 (3): 401–412. doi:10.1007/s11481-018-09830-1. ISSN 1557-1890. PMID 30635816.
  16. ^ a b Chudzik, Michał; Burzyńska, Monika; Kapusta, Joanna (2022-07-22). "Use of 1-MNA to Improve Exercise Tolerance and Fatigue in Patients after COVID-19". Nutrients. 14 (15): 3004. doi:10.3390/nu14153004. ISSN 2072-6643. PMC 9331270. PMID 35893858.
  17. ^ Hong, Shangyu; Moreno-Navarrete, Jose M; Wei, Xiaojing; Kikukawa, Yusuke; Tzameli, Iphigenia; Prasad, Deepthi; Lee, Yoonjin; Asara, John M; Fernandez-Real, Jose Manuel; Maratos-Flier, Eleftheria; Pissios, Pavlos (2015). "Nicotinamide N-methyltransferase regulates hepatic nutrient metabolism through Sirt1 protein stabilization". Nature Medicine. 21 (8): 887–894. doi:10.1038/nm.3882. ISSN 1078-8956. PMC 4529375. PMID 26168293.
  18. ^ Schmeisser, K.; Mansfeld, J.; Kuhlow, D.; Weimer, S.; et al. (2013). "Role of sirtuins in lifespan regulation is linked to methylation of nicotinamide". Nature Chemical Biology. 9 (11): 693–700. doi:10.1038/nchembio.1352. PMC 4076143. PMID 24077178.
  19. ^ Kuchmerovska, T.; Shymanskyy, I.; Chlopicki, S.; Klimenko, A. (2010). "1-Methylnicotinamide (MNA) in prevention of diabetes-associated brain disorders". Neurochemistry International. 56 (2): 221–228. doi:10.1016/j.neuint.2009.10.004. PMID 19837120. S2CID 21785102.
  20. ^ Zhao, Jie; Zhang, Yin; Liu, Yue; Tang, Wen-Qian; Ji, Chun-Hui; Gu, Jiang-Hong; Jiang, Bo (2021). "Antidepressant-like effects of 1-methylnicotinamide in a chronic unpredictable mild stress model of depression". Neuroscience Letters. 742: 135535. doi:10.1016/j.neulet.2020.135535. PMID 33248165.
  21. ^ Milani, Zeinab H.; Ramsden, David B.; Parsons, Richard B. (2013). "Neuroprotective Effects of Nicotinamide N -Methyltransferase and its Metabolite 1-Methylnicotinamide". Journal of Biochemical and Molecular Toxicology. 27 (9): 451–456. doi:10.1002/jbt.21508. ISSN 1095-6670. PMID 23868305.
  22. ^ Nejabati, Hamid Reza; Ghaffari-Novin, Mahsa; Fathi-Maroufi, Nazila; Faridvand, Yousef; Holmberg, Hans-Christer; Hansson, Ola; Nikanfar, Saba; Nouri, Mohammad (2022). "N1-Methylnicotinamide: Is it Time to Consider it as a Dietary Supplement for Athletes?". Current Pharmaceutical Design. 28 (10): 800–805. doi:10.2174/1381612828666220211151204. PMID 35152860.
  23. ^ Przyborowski, Kamil; Wojewoda, Marta; Sitek, Barbara; Zakrzewska, Agnieszka; Kij, Agnieszka; Wandzel, Krystyna; Zoladz, Jerzy Andrzej; Chlopicki, Stefan (2015). Menezes, Gustavo Batista (ed.). "Effects of 1-Methylnicotinamide (MNA) on Exercise Capacity and Endothelial Response in Diabetic Mice". PLOS ONE. 10 (6): e0130908. doi:10.1371/journal.pone.0130908. ISSN 1932-6203. PMC 4482656. PMID 26115505.
  24. ^ a b "Implementing regulation - 2018/1123 - EN - EUR-Lex". eur-lex.europa.eu. Retrieved 2024-12-09.
  25. ^ "Endotelio – Molekuła przyszłości". Endotelio. Retrieved 2024-12-09.
  26. ^ EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA); Turck, Dominique; Bresson, Jean-Louis; Burlingame, Barbara; Dean, Tara; Fairweather-Tait, Susan; Heinonen, Marina; Hirsch-Ernst, Karen Ildico; Mangelsdorf, Inge; McArdle, Harry J; Naska, Androniki; Neuhäuser-Berthold, Monika; Nowicka, Grażyna; Pentieva, Kristina; Sanz, Yolanda (2017). "Safety of 1-methylnicotinamide chloride (1-MNA) as a novel food pursuant to Regulation (EC) No 258/97". EFSA Journal. 15 (10). doi:10.2903/j.efsa.2017.5001. PMC 7010160. PMID 32625296.
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