title: Retinoic acid receptor stimulation protects midbrain dopaminergic neurons from inflammatory degeneration via BDNF-mediated signaling.
abstract: Functions of retinoic acid receptors (RARs) in adult CNS have been poorly characterized. Here we investigated potential neuroprotective action of tamibarotene (Am80), an RARalpha/beta agonist available for the treatment of acute promyelocytic leukemia, on midbrain dopaminergic neurons. Am80 protected dopaminergic neurons in rat midbrain slice culture from injury mediated by lipopolysaccharide-activated microglia, without affecting production of nitric oxide, a key mediator of cell injury. The effect of Am80 was mimicked by another RAR agonist, TAC-101, but not by a retinoid X receptor agonist, HX630, and HX630 did not synergize with Am80. We observed neuronal expression of RARalpha and RARbeta in midbrain slice culture and also found that Am80 increased tissue level of brain-derived neurotrophic factor (BDNF) mRNA. Exogenous BDNF prevented dopaminergic neurodegeneration, and the neuroprotective effect of Am80 was suppressed by a TrkB inhibitor, K252a, or by anti-BDNF neutralizing antibody. These results reveal a novel action of RARs mediated by enhancement of BDNF expression. Finally, oral administration of Am80 prevented dopaminergic cell loss in the substantia nigra induced by local injection of lipopolysaccharide in mice, indicating that RARs are a promising target of therapeutics for neurodegenerative disorders.
authors.affiliation: Department of Chemico-Pharmacological Sciences, Kumamoto University, Japan. hkatsuki@gpo.kumamoto-u.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katsuki
authors.forename: Emi
authors.initials: E
authors.lastname: Kurimoto
authors.forename: Sachiko
authors.initials: S
authors.lastname: Takemori
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kurauchi
authors.forename: Akinori
authors.initials: A
authors.lastname: Hisatsune
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Isohama
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Izumi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kume
authors.forename: Koichi
authors.initials: K
authors.lastname: Shudo
authors.forename: Akinori
authors.initials: A
authors.lastname: Akaike
mesh_terms: D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D004298:Dopamine / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000378:metabolism / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000378:metabolism* / Q000502:physiology; D012176:Retinoids / Q000819:agonists / Q000138:chemical synthesis / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D001565:Benzoates; D019208:Brain-Derived Neurotrophic Factor; D018836:Inflammation Mediators; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D013764:Tetrahydronaphthalenes; C061133:tamibarotene; D004298:Dopamine