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: Hiroshi Katsuki, Emi Kurimoto, Sachiko Takemori, Yuki Kurauchi, Akinori Hisatsune, Yoichiro Isohama, Yasuhiko Izumi, Toshiaki Kume, Koichi Shudo, Akinori Akaike
• Journal: Journal of neurochemistry (J Neurochem) Vol. 110 Issue 2 Pg. 707-18 (Jul 2009) ISSN: 1471-4159 [Electronic] England
• PMID: 19457078 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzoates
• Brain-Derived Neurotrophic Factor
• Inflammation Mediators
• Receptors, Retinoic Acid
• Retinoids
• Tetrahydronaphthalenes
• tamibarotene
• Dopamine

Topics

• Animals
• Benzoates (chemical synthesis, pharmacology)
• Brain-Derived Neurotrophic Factor (physiology)
• Dopamine (physiology)
• Humans
• Inflammation Mediators (metabolism, physiology)
• Male
• Mesencephalon (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Nerve Degeneration (metabolism, prevention & control)
• Neurons (drug effects, metabolism)
• Organ Culture Techniques
• Rats
• Rats, Wistar
• Receptors, Retinoic Acid (agonists, metabolism, physiology)
• Retinoids (agonists, chemical synthesis, metabolism)
• Signal Transduction (drug effects, physiology)
• Tetrahydronaphthalenes (chemical synthesis, pharmacology)