N-Acetylserotonin: the grand child of 5-hydroxytryptophan and parent to melatonin.
N-Acetylserotonin is a melatonin precursor and downstream metabolite of 5-HTP. Melatonin, also known as N-acetyl-5-methoxy tryptamine, is a hormone produced in the pineal gland of animals which is involved in the regulation of circadian rhythms and also acts as an anti-oxidant. 5-Hydroxytryptophan, AKA Oxitripan AKA 5-HTP, is a naturally occurring precursor to serotonin. 5-HTP is produced by the enzyme tryptophan hydroxylase acting upon the amino acid tryptophan, 5-HTP is then decarboxylated to the neuro transmitter serotonin by the enzyme aromatic L-amino acid decarboxylase. The compound of interest N-acetylserotonin (NAS)is also referred to as Normelatonin; the illustration shows that NAS has structural similarities to both Melatonin and 5-HTP. It is an agonist of melatonin receptors MT1, MT2, and MT3. NAS shares some of melatonin's anti-oxidant effects but excels with greater anti-oxidant capacity, possible cognition enhancement, anti-aging, neuroprotective, antidepressant, and BDNF effects. (2)
N-Acetylserotonin is a naturally occurring chemical which is a precursor to melatonin in the pineal gland and retina. N-acetylserotonin is also present in the hippocampus, olfactory bulb, spinal cord and cerebellum. NAS is biosynthesized from serotonin by the enzyme arylalkylamine N-acetyltransferase. N-Acetylserotonin is not solely a precursor to melatonin, it exhibits bioactive properties independently and even targets areas of the brain that serotonin and melatonin do not.(4)(5) NAS was shown to perform better than melatonin in scavenging reactive oxygen species and far surpassed melatonin in protecting against radical-induced cell death.(1)(2) This tells us that NAS is a better antioxidant than melatonin.
N-Acetylserotonin serotonin levels were shown to increase in female Fisher 344N rats with the administration of the drug deprenyl at .25mg/kg. Deprenyl has been shown to increase life span and it has been suggested that NAS is the mechanism for life extension. NAS was administered to mice at 2.5mg/kg of bodyweight starting at four weeks of age, this extended the life of male C3H mice by more than 20%. This data suggests there may be anti-aging or life extension benefits from the exogenous administration or indirect increase of NAS due to NAS modulating drug administration. (11)
N-acetylserotonin has been shown to be an agonist of TrkB which is the same receptor brain-derived neurotrophic factor (BDNF) activates. (3)(9) It has also been suggested that NAS protects against B-amyloid toxicity which is associated with Alzheimer’s disease. It is also protective against MPP+ which is a drug with the ability to induce Parkinson’s disease. Additionally, NAS stimulates neuroprogenitor cells and prevents negative effects of sleep deprivation. (5)(8) N-Acetylserotonin levels have been shown to increase up to 5-fold with administration clorgyline, an irreversible and selective MAO-A inhibitor with antidepressive effects.(4)(10) As previously mentioned NAS activates TrkB, this is a trait that is shared with SSRIs, SNRIs, and clorgyline. Exogenous administration of NAS in mice shows a decrease of immobility in mouse tail suspension test. (4) These findings suggest that NAS has antidepressant properties, it has been postulated that increased levels of NAS induced by anti-depressant compounds may be responsible for the positive effects of these drugs. These findings may show that NAS is neuroprotective, cognition enhancing, and antidepressant. (5)(8)(9)
NAS exhibits a more diverse and potentially greater beneficial effects than both 5-HTP and Melatonin. NAS’s similarity in structure to 5-HTP and melatonin along with its biological roll as a precursor to melatonin make it a viable compound for a new dietary ingredient in OTC nutritional supplements.
1. N-acetylserotonin is a better extra- and intracellular antioxidant than melatonin; Albert Wölfler-1999
2.Antioxidant and Antiaging Activity of N-Acetylserotonin and Melatonin in the in Vivo Models; G. OXENKRUG-2001
3.N-acetylserotonin activates TrkB receptor in a circadian rhythml; Sung-Wuk Jang-2010
4.The effect of nifedipine, Ca2+ antagonist, on activity of MAO inhibitors, N-acetylserotonin and melatonin in the mouse tail suspension test; Irine V. Prakhie
5.N-Acetylserotonin Neuroprotection, Neurogenesis, and the Sleepy Brain; Gianluca Tosini
6. N-Acetylserotonin in the central nervous system; Gregory M.Brown
7. The serotonin-N-acetylserotonin–melatonin pathway as a biomarker for autism spectrum disorders; C Pagan
8. N-acetylserotonin promotes hippocampal neuroprogenitor cell proliferation in sleep-deprived mice; Pradoldej Sompol, Xia Liu- 2011
9. N-Acetylserotonin: Circadian Activation of the BDNF Receptor and Neuroprotection in the Retina and Brain; P. Michael- 2014
10. The effect of MAO-A inhibition and cold-immobilization stress on N-acetylserotonin and melatonin in SHR and WKY rats; G. F. Oxenkrug
11. N-Acetylserotonin and Aging-Associated Cognitive Impairment and Depression; Gregory Oxenkrug-2012