N-Acetylserotonin

N-Acetylserotonin, a chemical intermediate in melatonin biosynthesis, activates tyrosine kinase receptor B (TrkB) in a circadian rhythm manner. TrkB is a major neurotrophic factor receptor involved in cell survival, differentiation, and synaptic plasticity^[1-2]. N-Acetylserotonin is mainly synthesized in the pineal gland and is subsequently methylated by hydroxyindole-O-methyltransferase to synthesize melatonin^[3]. N-Acetylserotonin has neuroprotective properties and can exert neuroprotective effects by inhibiting oxidative stress, anti-apoptosis, regulating autophagy dysfunction, and anti-inflammation^[1].

In vitro, incubation of primary cerebrocortical neurons (PCNs) with N-Acetylserotonin (0.01nM-100μM; 2h) resulted in statistically significant inhibition of oxygen-glucose deprivation (OGD)-mediated PCN cell death, and exposing PCNs to H₂O₂ (1000μmol/L) with N-Acetylserotonin resulted in better dose-dependent inhibition of cell death^[4]. Pre-incubation neural progenitor cells (NPCs) with N-Acetylserotonin (0, 20, 50, 100, 200, and 400μM; 6h) not only ameliorates H₂O₂-induced cell viability loss, lactate dehydrogenase (LDH) release, and proliferative and migratory capacity impairments, but counteracts H₂O₂-triggered production of nitric oxide (NO), reactive oxygen species (ROS), malondialdehyde (MDA), and 8-hydroxy-deoxyguanosine (8-OHdG) in a dose-dependent manner^[5].

In vivo, the Brain-derived neurotrophic factor (BDNF) forebrain conditional knockout mice treated with N-Acetylserotonin (20mg/kg; i.p.), both hippocampal and retinal TrkB phosphorylation became evident after 0.5h and peaked 1h following N-Acetylserotonin administration^[3]. In the rat striatal injury model induced by 6-hydroxydopamine, treatment with N-Acetylserotonin (2, 5, 10mg/kg·d; i.p.) resulted in a decrease in the number of apomorphine-induced rotations, an increase in dopamine levels, and a decrease in both 3,4-dihydroxyphenylacetic acid and homovanillic acid levels^[6]. After treating the traumatic brain injury mouse with N-Acetylserotonin (10mg/kg; i.p.), a decrease in matrix metalloproteinase-9 (MMP-9) and increases in Claudin-5 and Bcl-2 were observed^[7].

References:
[1] Kang JH, Guo XD, Wang YD, Kang XW. Neuroprotective Effects of N-acetylserotonin and Its Derivative. Neuroscience. 2023;517:18-25.
[2] Boulle F, Kenis G, Cazorla M, et al. TrkB inhibition as a therapeutic target for CNS-related disorders. Prog Neurobiol. 2012;98(2):197-206.
[3] Jang SW, Liu X, Pradoldej S, et al. N-acetylserotonin activates TrkB receptor in a circadian rhythm. Proc Natl Acad Sci U S A. 2010;107(8):3876-3881.
[4] Zhou H, Wang J, Jiang J, et al. N-acetyl-serotonin offers neuroprotection through inhibiting mitochondrial death pathways and autophagic activation in experimental models of ischemic injury. J Neurosci. 2014;34(8):2967-2978.
[5] Li Q, Wang P, Huang C, et al. N-Acetyl Serotonin Protects Neural Progenitor Cells Against Oxidative Stress-Induced Apoptosis and Improves Neurogenesis in Adult Mouse Hippocampus Following Traumatic Brain Injury. J Mol Neurosci. 2019;67(4):574-588.
[6] Aguiar LM, Macedo DS, de Freitas RM, et al. Protective effects of N-acetylserotonin against 6-hydroxydopamine-induced neurotoxicity. Life Sci. 2005;76(19):2193-2202.
[7] Rui T, Wang Z, Li Q, et al. A TrkB receptor agonist N-acetyl serotonin provides cerebral protection after traumatic brain injury by mitigating apoptotic activation and autophagic dysfunction. Neurochem Int. 2020;132:104606.