title: Neuritogenic activity of a genipin derivative in retinal ganglion cells is mediated by retinoic acid receptor β expression through nitric oxide/S-nitrosylation signaling.
abstract: Genipin, a herbal iridoid, is known to have both neuroprotective and neuritogenic activity in neuronal cell lines. As it is structurally similar to tetrahydrobiopterin, its activity is believed to be nitric oxide (NO)-dependent. We previously proposed a novel neuroprotective activity of a genipin derivative, (1R)-isoPropyloxygenipin (IPRG001), whereby it reduces oxidative stress in RGC-5, a neuronal precursor cell line of retinal origin through protein S-nitrosylation. In the present study, we investigated another neuritogenic property of IPRG001 in RGC-5 cells and retinal explant culture where in we focused on the NO-cGMP-dependent and protein S-nitrosylation pathways. IPRG001 stimulated neurite outgrowth in RGC-5 cells and retinal explant culture through NO-dependent signaling, but not NO-dependent cGMP signaling. Neurite outgrowth with IPRG001 requires retinoic acid receptor β (RARβ) expression, which is suppressed by an RAR blocking agent and siRNA inhibition. Thereby, we hypothesized that RARβ expression is mediated by protein S-nitrosylation. S-nitrosylation of histone deacetylase 2 is a key mechanism in chromatin remodeling leading to transcriptional gene activation. We found a parallelism between S-nitrosylation of histone diacetylase 2 and the induction of RARβ expression with IPRG001 treatment. The both neuroprotective and neuritogenic activities of genipin could be a new target for the regeneration of retinal ganglion cells after glaucomatous conditions.
authors: Department of Molecular Neurobiology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan. koriyama@med.kanazawa-u.ac.jp
authors: Yoshiki
authors: Y
authors: Koriyama
authors: Yusuke
authors: Y
authors: Takagi
authors: Kenzo
authors: K
authors: Chiba
authors: Matsumi
authors: M
authors: Yamazaki
authors: Kunizo
authors: K
authors: Arai
authors: Toru
authors: T
authors: Matsukawa
authors: Hirokazu
authors: H
authors: Suzuki
authors: Kayo
authors: K
authors: Sugitani
authors: Hiroyuki
authors: H
authors: Kagechika
authors: Satoru
authors: S
authors: Kato
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002461:Cell Line, Transformed; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006801:Humans; D057889:Iridoid Glycosides / Q000494:pharmacology*; D039823:Iridoids / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009924:Organ Culture Techniques; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000166:cytology*; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: C569486:1-isopropyloxygenipin; D004791:Enzyme Inhibitors; D057889:Iridoid Glycosides; D039823:Iridoids; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D009569:Nitric Oxide; C007834:genipin; D019001:Nitric Oxide Synthase; D017869:Cyclic GMP-Dependent Protein Kinases; C533426:Hdac2 protein, rat; D056464:Histone Deacetylase 2; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester