title: HU0622: a small molecule promoting GAP-43 activation and neurotrophic effects.
abstract: During the course of neuronal development or regeneration, the axonal growth cone protein growth-associated protein 43 (GAP-43) is expressed in a great majority of differentiating neurons, suggesting that the regulation of this gene is tied to important differentiation signals common to many neurons. In order to discover non-peptide molecules capable of mimicking the effects of NGF, we developed a reporter gene assay system based on measurement of light production in PC12 cells stably transfected with the luciferase reporter gene, the expression of which depends on the transcriptional activation of GAP-43. High throughput screening of the proprietary compound collection using this system revealed (E,E)-1-[5-(3,4-dihydroxyphenyl)-1-oxo-2,4-pentadienyl]piperidine (HU0622), a piperine derivative, to be an activator of GAP-43 transcription. HU0622 strongly induced neurite outgrowth and extension in PC12 and sensory neuronal cultures of chick dorsal root ganglia. The compound induced sustained extracellular signal-regulated kinase (ERK) activation that is crucial for neurite outgrowth activity without activating NGF receptor, TrkA. Furthermore, HU0622 as well as NGF promoted PC12 survival under serum-free conditions and activated Akt/protein kinase B downstream from phosphatidylinositol 3-kinase (PI3K). HU0622 also promoted survival of rat dorsal root ganglion neurons deprived of NGF. HU0622, a small non-peptidyl molecule, may be a novel promising lead compound for the stimulation of nerve regeneration.
authors.affiliation: Discovery Research Laboratories, Shionogi & Co., Ltd., 12-4, Sagisu 5-chome, Fukushima-ku, Osaka 553-0002, Japan. ken-ichiro.uwabe@shionogi.co.jp
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Uwabe
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Iwakawa
authors.forename: Mitsunobu
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Koji
authors.initials: K
authors.lastname: Talkahashi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Nagata
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D052117:Benzodioxoles; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D019922:GAP-43 Protein / Q000235:genetics / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000166:cytology; D007150:Immunohistochemistry / Q000379:methods; D008156:Luciferases / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides; D051381:Rats; D014162:Transfection / Q000379:methods; D014404:Tubulin / Q000378:metabolism
chemical_list: C514507:(E,E)-1-(5-(3,4-dihydroxyphenyl)-1-oxo-2,4-pentadienyl)piperidine; D000470:Alkaloids; D052117:Benzodioxoles; D004791:Enzyme Inhibitors; D005419:Flavonoids; D019922:GAP-43 Protein; D009414:Nerve Growth Factors; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D014404:Tubulin; D008156:Luciferases; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C008922:piperine