The co-author of that paper is actually a friend of mine (now I know why he has been so busy since he went to Zürich 
). I'm going to meet him soon and of course, I will discuss that paper with him. If you have questions regarding the paper, maybe I can ask for you.
I have a question for the professor. C
ould direct supplementation with 1-methyl-nicotinamide have health or life extension benefits in humans? (Pro: bypass/obviate the need to bump up sirtuin levels? Con: maybe it could produce an excess of ROS?)
It seems that until recently 1-methylnicotinamide has been thought of as an inactive metabolite of niacin. But there is at least some research indicating it might have promise as a supplement:
http://www.ncbi.nlm....les/PMC1978255/
1-Methylnicotinamide (MNA), a primary metabolite of nicotinamide, exerts anti-thrombotic activity mediated by a cyclooxygenase-2/prostacyclin pathway
S Chlopicki,1,* J Swies,1 A Mogielnicki,2 W Buczko,2 M Bartus,1 M Lomnicka,1 J Adamus,3 and J Gebicki3,*
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Abstract
Background and purpose:
1-methylnicotinamide (MNA) has been considered to be an inactive metabolite of nicotinamide. Here we assessed the anti-thrombotic activity of MNA in vivo.
Experimental approach:
Antithrombotic action of MNA was studied in normotensive rats with extracorporeal thrombus formation (thrombolysis), in renovascular hypertensive rats with intraarterial thrombus formation (arterial thrombosis) and in a venous thrombosis model in rats (venous thrombosis).
Key results:
MNA (3-100 mg kg−1) induced a dose-dependent and sustained thrombolytic response, associated with a rise in 6-keto-PGF1α in blood. Various compounds structurally related to MNA were either inactive or weaker thrombolytics. Rofecoxib (0.01-1 mg kg−1), dose-dependently inhibited the thrombolytic response of MNA, indomethacin (5 mg kg−1) abolished it, while L-NAME (5 mg kg−1) were without effect. MNA (3–30 mg kg−1) also reduced arterial thrombosis and this effect was abrogated by indomethacin (2.5 mg kg−1) as well as by rofecoxib (1
mg kg−1). MNA, however, did not affect venous thrombosis. In vitro MNA did not modify platelet aggregation nor induce vasodilation.
Conclusions and implications:
MNA displayed a profile of anti-thrombotic activity in vivo that surpasses that of closely related compounds. MNA inhibited platelet-dependent thrombosis by a mechanism involving cyclooxygenase-2 and prostacyclin. Our findings suggest that endogenous MNA, produced in the liver by nicotinamide N-methyltransferase, could be an endogenous activator of prostacyclin production and thus may regulate thrombotic as well as inflammatory processes in the cardiovascular system.
Keywords: 1-methylnicotinamide, thrombolysis, thrombosis, PGI2, COX-2, platelets
From the discussion section of the above paper:
... it was quite surprising that, among the various structurally modified MNA analogues, we have not found a compound with better thrombolytic activity than MNA itself. Only the replacement of the amide group at the three-position of the pyridine ring by an acetyl group, as in the case of MAP, resulted in the retention of sustained dose-dependent thrombolysis (3–30mgkg−1) with a concomitant rise in 6-keto-PGF1α in blood. Other tested compounds were inactive or much weaker thrombolytic agents. For example, 6-amino nicotinamide—an inhibitor of pentose phosphate pathway (PPP) (Gupte et al., 2003) and 1-ribosylnicotinamide—a newly discovered precursor of NAD+ (Bieganowski and Brenner, 2004)—were virtually inactive as thrombolytics. Thus the mechanism of MNA-induced thrombolysis would seem independent of PPP activity or of intracellular NAD+. Nicotinic acid and trigonelline were also ineffective thrombolytically, even though nicotinic acid, at very high doses, has previously been shown to induce a remarkable thrombolytic response in cats that was attributed to the release of PGI2 (Swies and Dabrowski, 1984). In turn, the nicotinamide-induced response was substantially weaker than that of MNA. The observed weak anti-thrombotic activity of nicotinamide may be explained by the fact that only a minor part of nicotinamide is transformed to MNA by liver nicotinamide-N-methyltransferase upon direct intravascular administration, while the different magnitude of the response to nicotinic acid in cats vs rats may underline species differences known to mark the selective biological response to nicotinic acid (Declercq et al., 2005).
It is of note that in patients with peripheral artery disease the drugs with the nicotinic acid moiety such as β-pyridylcarbinol (Ronicol) or xanthinol nicotinate (Sadamin) exert their antiplatelet actions through the release of endothelial PGI2 (Dembinska-Kiec et al., 1983; Bieron et al., 1998), while nicotinic acid-induced flushing is mediated by a stimulation of the GPR109A receptor and the subsequent release of PGD2 and PGE2 from COX-1 (Benyo et al., 2005; Pike, 2005). It remains to be tested whether the MNA-induced release of PGI2 from COX-2 involves this vascular nicotinic acid-like receptor or other mechanisms.
There is overwhelming evidence that COX-2 derived PGI2 affords vasculoprotective, cardioprotective and anti-atherogenic activity (Gryglewski, 1980; Dowd et al., 2001; Grosser et al., 2006). The biological importance of the vascular COX-2/PGI2 pathway has recently been emphasized by the increased risk of myocardial infarction and stroke reported in patients treated with selective COX-2 inhibitors (Grosser et al., 2006). It is clear today that the long-term use of drugs known to inhibit COX and subsequently to depress PGI2 production proved to be harmful, while pharmacological stimulation of PGI2 in vivo with the use of MNA might be beneficial in vascular diseases. Indeed MNA, being a stable and non-toxic molecule, seems to be a good candidate for a drug to boost the endogenous COX-2/PGI2 pathway. So far, PGI2 or its stable analogues have been widely used in the treatment of pulmonary hypertension (Wise and Jones, 1996) and have been proven effective in cases of peripheral arterial disease (Gryglewski, 1980) or liver injury (Ohta et al., 2005). It will be important to test the therapeutic effectiveness of MNA.
It is important to note that in our experiments, MNA afforded anti-thrombotic action, not only in normotensive rats, but also in rats with renovascular hypertension (2K-1C hypertension). Hypertension is one of the most important risk factors of arterial thrombosis and its clinical consequences such as acute coronary syndrome or ischaemic stroke. Therefore studying thrombosis in hypertensive rats more closely resembles a clinically relevant situation. In various cardiovascular pathologies, including hypertension, endothelial dysfunction develops that is characterized by an impaired production of NO, an impairment of basal PGI2 production (Gryglewski, 1980; Frein et al., 2005) and a compensatory increase in PGI2 formation by COX-2 (FitzGerald et al., 2000). Our results suggest that in the setting of impaired NO-dependent function, the COX-2/PGI2 pathway is able to be stimulated pharmacologically with MNA. These findings have important therapeutic implications.
Finally, the demonstration of biological activity of MNA may bring a new understanding of the mechanism of the pharmacological activities of nicotinamide. Indeed, the anti-diabetic, neuroprotective (Satoh et al., 1999; Gosteli, 2005) as well as anti-inflammatory action of nicotinamide, at least in part, may be mediated by a MNA-COX-2/PGI2 pathway, as outlined here.
Summing up, we demonstrate here—to our knowledge for the first time—the novel biological activity of MNA in vivo that greatly surpasses that of closely related compounds. MNA appears as an anti-thrombotic agent that limits platelet-dependent experimental thrombosis by a mechanism dependent on the COX-2/PGI2 pathway. Although our study focused on exogenously applied MNA, our results could imply that endogenous MNA formed in the liver by nicotinamide N-methyltrasferase is an endogenous activator of the COX-2/PGI2 pathway and may play an important regulatory role in limiting thrombosis, as well as inflammatory processes in the cardiovascular system. Our findings of novel in vivo biological activity of MNA may have potentially important physiological, biochemical as well as therapeutic implications and warrant further studies.
Edited by blood, 01 November 2013 - 04:04 AM.
