title: N-acetylserotonin: circadian activation of the BDNF receptor and neuroprotection in the retina and brain.
abstract: TrkB is the cognate receptor for brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family involved in neuronal survival, neurogenesis and synaptic plasticity. BDNF has been shown to protect photoreceptors from light-induced retinal degeneration (LIRD) and to improve ganglion cell survival following optic nerve damage. However, the utility of BDNF as a retinal neuroprotectant is limited by its short half-life, inability to cross the blood-brain and blood-retinal barriers, and activation of the proapoptotic p75 neurotrophin receptor. N-Acetylserotonin (NAS) is a naturally occurring chemical intermediate in the melatonin biosynthetic pathway in the pineal gland and retina. Its synthesis occurs in a circadian fashion with high levels at night and is suppressed by light exposure. Until recently, NAS was thought to function primarily as a melatonin precursor with little or no biological function of its own. We have now shown that TrkB activation in the retina and hippocampus is circadian in C3H/f(+/+) mice, which synthesize NAS, but not in C57BL/6 mice, which have a mutation in the gene encoding the enzyme that converts serotonin to NAS. In addition, treatment of mice exogenous NAS, but not with serotonin or melatonin, activates TrkB during the daytime in a BDNF-independent manner. NAS appears to have neuroprotective properties and its administration reduces caspase 3 activation in the brain in response to kainic acid, a neurotoxic glutamate analog. We have developed structural analogs of NAS that activate TrkB. One of these derivatives, N- [2-(-indol-3-yl)ethyl]-2-oxopiperideine-3-carboximide (HIOC), selectively activates TrkB with greater potency than NAS and has a significantly 5-hydroxy-1Hlonger biological half-life than NAS after systemic administration. HIOC administration results in long-lasting activation of TrkB and downstream signaling kinases. The compound can pass the blood-brain and blood-retinal barriers when administered systemically and reduces kainic acid-induced neuronal cell death in a TrkB-dependent manner. Systemic administration of HIOC mitigates LIRD, assessed electrophysiologically and morphometrically. Hence, NAS may function as an endogenous circadian neurotrophin-like compound and HIOC is a good lead compound for further drug development for treatment of retinal degenerative diseases.
authors.affiliation: Department of Ophthalmology, Emory University School of Medicine, 30322, Atlanta, GA, USA, miuvone@emory.edu.
authors.forename: P Michael
authors.initials: PM
authors.lastname: Iuvone
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Boatright
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tosini
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology*; D008027:Light; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D020813:Receptor, trkB / Q000819:agonists* / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012701:Serotonin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D012701:Serotonin; D020813:Receptor, trkB; C006389:N-acetylserotonin