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Retinoic acid receptor stimulation protects midbrain dopaminergic neurons from inflammatory degeneration via BDNF‐mediated signaling
Author(s) -
Katsuki Hiroshi,
Kurimoto Emi,
Takemori Sachiko,
Kurauchi Yuki,
Hisatsune Akinori,
Isohama Yoichiro,
Izumi Yasuhiko,
Kume Toshiaki,
Shudo Koichi,
Akaike Akinori
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06171.x
Subject(s) - dopaminergic , agonist , neuroprotection , endocrinology , substantia nigra , neurotrophic factors , medicine , neurodegeneration , microglia , retinoic acid receptor , chemistry , biology , pharmacology , neuroscience , dopamine , receptor , retinoic acid , inflammation , biochemistry , disease , gene
Functions of retinoic acid receptors (RARs) in adult CNS have been poorly characterized. Here we investigated potential neuroprotective action of tamibarotene (Am80), an RARα/β 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 RARα and RARβ 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.