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Kurauchi Y.,Kumamoto University | Hisatsune A.,Kumamoto University | Isohama Y.,Kumamoto University | Sawa T.,Kumamoto University | And 3 more authors.
Journal of Neurochemistry | Year: 2011

Stimulation of retinoic acid receptors (RARs) protects midbrain dopaminergic neurons, presumably via up-regulation of brain-derived neurotrophic factor (BDNF) expression. The present study was focused on unexplored signaling mechanisms linking RAR stimulation to BDNF expression. Rat midbrain slice cultures treated with an RAR agonist Am80 showed increased tissue levels of BDNF mRNA and protein as compared to cultures without treatment. Am80-induced increase in BDNF expression was observed in dopaminergic neurons, which was blocked by inhibition of extracellular signal-regulated kinase (ERK) activation. We also found that Am80 increased neuronal nitric oxide synthase expression in dopaminergic neurons even during ERK inhibition, and this increase was accompanied by 8-nitro-cyclic GMP formation. Notably, the effect of Am80 on BDNF expression was attenuated by inhibitors of nitric oxide synthase, soluble guanylyl cyclase and cyclic GMP-dependent protein kinase (PKG). Am80-induced ERK phosphorylation in dopaminergic neurons was also attenuated by inhibition of soluble guanylyl cyclase and PKG. Moreover, 8-Br-cyclic GMP induced ERK phosphorylation and BDNF expression in dopaminergic neurons. These results suggest that, by recruiting cyclic GMP and PKG, neuronal nitric oxide synthase-derived nitric oxide plays a novel and essential role in RAR signaling leading to ERK-dependent BDNF up-regulation in midbrain dopaminergic neurons. © 2010 The Authors. Journal of Neurochemistry © 2010 International Society for Neurochemistry.


Matsushita H.,Kumamoto University | Hijioka M.,Kumamoto University | Hisatsune A.,Kumamoto University | Isohama Y.,Kumamoto University | And 2 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2011

Am80 (tamibarotene) is a retinoic acid receptor (RAR) agonist clinically available for treatment of acute promyelocytic leukemia. As intracerebral hemorrhage (ICH) accompanies inflammatory reactions in the brain and also because retinoids may suppress activation of microglia, we investigated the effect of Am80 on collagenase-induced experimental model of ICH in adult mice. Daily oral administration of Am80 (5 mg/kg) starting from 1 day before or from up to 6 hours after intrastriatal injection of collagenase significantly inhibited the decrease in the number of striatal neurons at 3 days after the insult. Am80 showed no significant effect on the hematoma size and the extent of edema associated with hemorrhage. Prominent expression of RARα was observed in activated microglia/macrophages, and the number of activated microglia/macrophages in the perihematoma region was lower in Am80-treated mice than in vehicle-treated mice. Am80 treatment also reduced areas affected by hemorrhage-associated oxidative stress as indicated by nitrotyrosine immunoreactivity, and attenuated heme oxygenase-1 expression in activated microglia/macrophages. Moreover, Am80-treated mice exhibited better recovery from hemorrhage-induced neurologic deficits than vehicle-treated mice. These results suggest that RAR is a promising target of neuroprotective therapy for ICH. © 2011 ISCBFM All rights reserved.


Patent
Kemphys Ltd. and Research Foundation Itsuu Laboratory | Date: 2012-04-30

A medicament for promoting memory consolidation, which comprises, as an active ingredient, a non-natural retinoid, preferably a retinoid having a basic skeleton comprising an aromatic ring bound with an aromatic carboxylic acid or tropolone by means of a bridging group, more preferably 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid or 4-[(3,5-bis-trimethylsilylphenyl)-carboxamido]benzoic acid.


Patent
Research Foundation Itsuu Laboratory | Date: 2012-07-04

A compound corresponding to 3-[4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]phenyl]propionic acid in which a part or all of hydrogen atoms in the ethylene group constituting the propionic acid moiety are replaced with deuterium atoms, a salt thereof, or an ester thereof, and a prodrug for releasing Am80 as an active medicament after being absorbed into a living body, which comprises the aforementioned compound, a salt thereof, or an ester thereof as an active ingredient.


Patent
Kemphys Ltd. and Research Foundation Itsuu Laboratory | Date: 2012-04-19

A compound represented by the formula (I) [R

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