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.
N-Acetylserotonin是褪黑素生物合成中的一个化学中间体，以昼夜节律的方式激活酪氨酸激酶受体B（TrkB）。TrkB是一种主要的神经营养因子受体，参与细胞存活、分化和突触可塑性[1-2]。N-Acetylserotonin主要在松果体中合成，随后通过羟基色胺-O-甲基转移酶甲基化合成褪黑素[3]。N-Acetylserotonin具有神经保护特性，可以通过抑制氧化应激、抗凋亡、调节自噬功能障碍和抗炎来发挥神经保护作用[1]。
在体外，用N-Acetylserotonin（0.01nM-100μM; 2h）孵育原代大脑皮层神经元（PCNs）可显著抑制氧糖剥夺（OGD）介导的PCN细胞死亡，且使PCNs暴露于H₂O₂（1000μmol/L）并添加N-Acetylserotonin，可更好地呈剂量依赖性抑制细胞死亡[4]。预先用N-Acetylserotonin（0、20、50、100、200和400μM; 6h）孵育神经祖细胞（NPCs），不仅能改善H₂O₂诱导的细胞活性降低、乳酸脱氢酶（LDH）释放以及增殖和迁移能力受损，还能以剂量依赖性方式抵消H₂O₂触发的一氧化氮（NO）、活性氧（ROS）、丙二醛（MDA）和8-羟基-脱氧鸟苷（8-OHdG）的产生[5]。
在体内，对脑源性神经营养因子（BDNF）前脑条件性敲除小鼠给予N-Acetylserotonin（20mg/kg；腹腔注射），海马和视网膜的TrkB磷酸化在给药后0.5小时开始出现，并在1小时达到峰值[3]。在由6-羟基多巴胺诱导的大鼠纹状体损伤模型中，用N-Acetylserotonin（2、5、10 mg/kg·天；腹腔注射）治疗，使阿扑吗啡诱导的旋转次数减少，多巴胺水平增加，3,4-二羟基苯乙酸和高香草酸水平降低[6]。在创伤性脑损伤小鼠中，用N-Acetylserotonin（10mg/kg；腹腔注射）处理后，观察到基质金属蛋白酶-9（MMP-9）减少，而Claudin-5和Bcl-2增加[7]。