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N-Acetyl Serotonin Derivatives As Potent Neuroprotectants for Retinas

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N-Acetyl Serotonin Derivatives As Potent Neuroprotectants for Retinas N-acetyl serotonin derivatives as potent neuroprotectants for retinas Jianying Shena, Kanika Ghaib, Pradoldej Sompola, Xia Liua, Xuebing Caob,1, P. Michael Iuvonec, and Keqiang Yea,1 Departments of aPathology and Laboratory Medicine and cOphthalmology and Pharmacology, Emory University School of Medicine; Atlanta, GA 30322; and bDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved January 24, 2012 (received for review November 22, 2011) N-acetylserotonin (NAS) is synthesized from serotonin by arylalkyl- (13, 14). Intraocular injection of NGF, BDNF, and NT-4/5 res- amine N-acetyltransferase (AANAT), which is predominantly ex- cues RGCs after axotomy (15–18). NT-4/5, in combination with pressed in the pineal gland and retina. NAS activates TrkB in a other trophic factors, is involved in the postnatal survival of circadian manner and exhibits antidepressant effects in a TrkB-de- retinal neurons during both development and degeneration (19). pendent manner. It also enhances neurogenesis in hippocampus in Despite the fact that BDNF is not required for RGC survival sleep-deprived mice. Here we report the identification of NAS deriv- during development (20), it promotes survival of RGCs in a va- atives that possess much more robust neurotrophic effects with riety of experimental lesion models both in vitro and in vivo (15, improved pharmacokinetic profiles. The compound N-[2-(5-hydroxy- 21–24). This is consistent with the findings that RGCs express 1H-indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide (HIOC) selectively the BDNF receptor TrkB (20, 25, 26). Furthermore, BDNF is activates TrkB receptor with greater potency than NAS. It potently a potent stimulator of neurite growth in RGCs (27). TrkB protects retinas from light-induced retinal degeneration (LIRD), which receptors are also known to be expressed on a variety of other is tightly coupled with pronounced TrkB activation in retinas. Pharma- retinal cell types including Müller glia, horizontal cells, amacrine cokinetic studies demonstrate that this compound is stable in serum cells, and the retinal pigment epithelial cells (28), and BDNF has and liver microsomes. It can pass the blood–brain barrier and blood– been shown to protect photoreceptors from light-induced retinal retinal barrier. Hence, HIOC is a good lead compound for further drug degeneration (LIRD) (29, 30). development for treating retinal degenerative diseases. In the present study, we have identified and characterized a NAS derivative that possesses much stronger stimulatory effect circadian rhythm | melatonin | small molecule | neurotrophins on TrkB receptor than NAS. It specifically activates TrkB but not TrkA receptor in mouse brain and retina upon i.p. administration. rylalkylamine N-acetyltransferase (AANAT) acetylates N- It exerts neuroprotective actions in a TrkB-dependent manner. Aacetylserotonin (NAS) from the neurotransmitter serotonin Moreover, the compound strongly protects retinal photo- in the pineal gland and retina. NAS is subsequently methylated receptors in a LIRD animal model, and this action is associated and converted into melatonin by hydroxyindole-O-methyl- with potent TrkB receptor activation in retinas. We also show that transferase (HIOMT). The three components of the melatonin this compound is quite stable in serum and liver microsomes, and synthetic pathway, namely 5-HT, NAS, and melatonin, all display it can pass the blood–brain barrier (BBB) and blood–retinal dramatic circadian rhythms (1). It has long been thought that barrier (BRB), and exhibits half-lives of ∼4 h and 1 h in brain and NAS only acts as a precursor of melatonin in the process of retinas, respectively. melatonin biosynthesis. Recently, we demonstrated that NAS activates the TrkB receptor and exerts antidepressant effects in Results a TrkB-dependent manner (2). Moreover, we reported that NAS NAS Derivatives Trigger TrkB Signal Cascades in Primary Neurons. but not melatonin stimulates neurogenesis in the hippocampus Recently, we showed that NAS but not melatonin or serotonin of sleep-deprived mice via activating TrkB receptor in dentate selectively activates TrkB but not other Trk receptors (2, 3). gyrus (3). In addition to these findings, NAS has been shown to Nonetheless, NAS is labile, and its half-life in the circulatory system facilitate memory (4), regulate hypothermic body temperature is relatively short (31). To identify more stable and robust com- (5), induce analgesia in central nervous system (6), and exert pounds that provoke TrkB activation, we tested numerous NAS antioxidative actions (7). derivatives (Fig. 1A). Among these compounds, -[2-(5-hydroxy-1H- Brain-derived neurotrophic factor (BDNF), a member of the indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide (HIOC) elicited neurotrophin family that also includes nerve growth factor the strongest TrkB phosphorylation, which was followed by HIDD, (NGF), Neurotrophin-3 (NT-3), and NT-4/5, exerts its biological NAS, and ANAT. By contrast, GGS or melatonin did not elevate functions through two transmembrane receptors: the p75 neu- TrkB phosphorylation compared with vehicle control (Fig. 1B, Top rotrophin receptor (p75NTR) and TrkB receptor tyrosine ki- three). The downstream effector Akt was also robustly activated by HIOC as well (Fig. 1B, second from Bottom). The quantitative nase. BDNF binding to TrkB triggers its dimerization and fi autophosphorylation of tyrosine residues in its intracellular do- p-Akt ELISA with the neuronal cell lysates also con rmed that main, leading to activation of the three major downstream sig- HIOC strongly increased Akt activation (Fig. 1BBottom). Dosage naling cascades, including mitogen-activated protein kinase assay revealed that HIOC elicited prominent TrkB activation at (MAPK), phosphatidylinositol 3-kinase (PI3K), and phospholi- pase C-γ1 (PLC-γ1) (8, 9). Through these pathways, BDNF Author contributions: J.S., K.G., P.S., P.M.I., and K.Y. designed research; J.S., K.G., P.S., and mediates a variety of neuronal activities involved in neuronal X.L. performed research; X.C. contributed new reagents/analytic tools; J.S., K.G., P.S., X.C., survival, neurogenesis, and synaptic plasticity. Accumulating P.M.I., and K.Y. analyzed data; and J.S., K.G., P.M.I., and K.Y. wrote the paper. evidence demonstrates that neurotrophins play critical roles in The authors declare no conflict of interest. – the development of the retina and visual system (10 12). Lim- This article is a PNAS Direct Submission. iting amounts of neurotrophins in the target area of the superior 1To whom correspondence may be addressed. E-mail: [email protected] or caoxuebing@ colliculus may control the apoptosis of retinal ganglion cells 126.com. (RGCs) during early postnatal period. NT-4/5 or BDNF injected This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. into superior colliculus promotes the survival of neonatal RGCs 1073/pnas.1119201109/-/DCSupplemental. 3540–3545 | PNAS | February 28, 2012 | vol. 109 | no. 9 www.pnas.org/cgi/doi/10.1073/pnas.1119201109 Downloaded by guest on October 1, 2021 A B C NAS Control ANAT HIDD HIOC MW (kDa ) BDNF GGS melatonin 150 Fig. 1. HIOC reveals the most potent TrkB ac- 100 NAS melatonin HIDD ANAT HIOC GGS tivation activity in primarily cultured cortical anti-pTrkB (Y706) neurons. (A) Chemical structures of NAS and its 150 four derivatives (ANAT, HIDD, HIOC, and GGS). Conctrol BDNF 100 ng/ml 500 nM 100 nM 500 nM 500 nM 100 nM 500 nM 100 nM 500 nM 100 nM 500 nM 100 nM 100 MW (kDa ) 100 nM (B) TrkB activation and downstream signaling in 150 anti-pTrkB (Y816) primary cortical neurons treated with various 150 100 100 compounds. Primary rat cortical neurons from IB: anti-pTrkB706 E18 embryos (12 DIV) were treated with 500 nM anti-pTrkB (Y817) of the NAS derivatives for 30 min. As positive 150 controls, neurons were treated with 100 ng /mL 100 NEUROSCIENCE IB: anti-TrkB (Biovision) anti-TrkB (Biovision) BDNF for 10 min. The neuron cell lysates were 75 collected and resolved by 10% SDS/PAGE. Im- 50 munoblotting was conducted with various anti- anti-pAkt bodies (Upper). The neuronal lysates were also 75 D HIOC 50 ---------------------------- subjected to p-Akt ELISA analysis (Lower). (C) anti-Akt The dosage titration assay. The primary cultures were treated with 100 and 500 nM of various 0 min 15 min 1 hr 6 hr 24 hr * 12 hr BDNF 10 min compounds for 30 min. The cell lysates from the * neurons were analyzed by immunoblotting with p-TrkB antibody. HIOC activated TrkB much IB:anti-pTrkB(Y706) 190 stronger at 500 nM than at 100 nM. (D) Time 170 course assay of TrkB activation in primary corti- 150 cal neurons treated with HIOC. Primary rat cor- 130 IB: anti-TrkB tical neurons from E18 embryos (12 DIV) were 110 treated with 500 nM compound for indicated 90 time. As positive controls, neurons were treated pAkt ELISA ( % Control) pAkt ELISA 70 50 with 100 ng/mL BDNF for 10 min. The neuron cell lysates were collected and resolved by 10% SDS/PAGE. Immunoblotting was conducted with AS NAT N HIOC HIDD GGS Melatonin Control BDNF A various antibodies. 500 nM, which was comparable to BDNF. By contrast, the other Quantitative analysis of TrkB and TrkA phosphorylation signals compounds including NAS exhibited much lower effect than showed that TrkB but not TrkA was selectively phosphorylated HIOC. At 100 nM, the TrkB stimulatory activities by these com- in the brain in a dose-dependent manner. Maximal TrkB acti- pounds were marginal (Fig. 1C). We also examined HIOC’skinetic vation was observed with 5–20 mg/kg of HIOC (Fig. 2A). Hence, profiles in primary neuronal cultures. HIOC activated TrkB re- HIOC specifically activates TrkB receptor in mouse brain. Ki- ceptor and its downstream Erk1/2 in a time-dependent manner.
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