Retinoic acid receptor stimulation protects midbrain dopaminergic neurons from inflammatory degeneration via BDNF-mediated signaling
Retinoic acid receptor stimulation protects midbrain dopaminergic neurons from inflammatory degeneration via BDNF-mediated signaling
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DOI：
10.1111/j.1471-4159.2009.06171.x
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发表时间：
2009-07-01
影响因子：
4.7
通讯作者：
Akaike, Akinori
中科院分区：
文献类型：
--
作者：
Katsuki, Hiroshi;Kurimoto, Emi;Akaike, Akinori
成人中枢神经系统中视黄酸受体（RARs）的功能特征尚不清楚。在这里，我们研究了他米巴罗汀（Am 80），一种RAR α/β激动剂，可用于治疗急性早幼粒细胞白血病，对中脑多巴胺能神经元的潜在神经保护作用。AM 80保护大鼠中脑切片培养的多巴胺能神经元免受脂多糖激活的小胶质细胞介导的损伤，而不影响细胞损伤的关键介质一氧化氮的产生。Am 80的作用被另一种RAR激动剂TAC-101模拟，但不被类维生素A X受体激动剂HX 630模拟，并且HX 630不与Am 80协同。我们在中脑切片培养中观察了RAR α和RAR β的神经元表达，还发现Am 80增加了脑源性神经营养因子（BDNF）mRNA的组织水平。外源性BDNF阻止多巴胺能神经变性，Am 80的神经保护作用被TrkB抑制剂K252 a或抗BDNF中和抗体抑制。这些结果揭示了RAR通过增强BDNF表达介导的新作用。最后，Am 80的口服给药防止了小鼠中由局部注射脂多糖诱导的黑质中的多巴胺能细胞损失，表明RAR是神经退行性疾病的有希望的治疗靶点。
Functions of retinoic acid receptors (RARs) in adult CNS have been poorly characterized. Here we investigated potential neuroprotective action of tamibarotene (Am80), an RAR alpha/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 RAR alpha and RAR beta 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.