Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisbon, Portugal.
Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
Mol Neurobiol. 2018 May;55(5):3725-3738. doi: 10.1007/s12035-017-0592-5. Epub 2017 May 22.
Although neurogenesis occurs in restricted regions of the adult mammalian brain, neural stem cells (NSCs) produce very few neurons during ageing or after injury. We have recently discovered that the endogenous bile acid tauroursodeoxycholic acid (TUDCA), a strong inhibitor of mitochondrial apoptosis and a neuroprotective in animal models of neurodegenerative disorders, also enhances NSC proliferation, self-renewal, and neuronal conversion by improving mitochondrial integrity and function of NSCs. In the present study, we explore the effect of TUDCA on regulation of NSC fate in neurogenic niches, the subventricular zone (SVZ) of the lateral ventricles and the hippocampal dentate gyrus (DG), using rat postnatal neurospheres and adult rats exposed to the bile acid. TUDCA significantly induced NSC proliferation, self-renewal, and neural differentiation in the SVZ, without affecting DG-derived NSCs. More importantly, expression levels of mitochondrial biogenesis-related proteins and mitochondrial antioxidant responses were significantly increased by TUDCA in SVZ-derived NSCs. Finally, intracerebroventricular administration of TUDCA in adult rats markedly enhanced both NSC proliferation and early differentiation in SVZ regions, corroborating in vitro data. Collectively, our results highlight a potential novel role for TUDCA in neurologic disorders associated with SVZ niche deterioration and impaired neurogenesis.
尽管神经发生发生在成年哺乳动物大脑的特定区域，但神经干细胞（NSC）在衰老或受伤后很少产生神经元。我们最近发现，内源性胆酸牛磺熊脱氧胆酸（TUDCA）是一种强烈的线粒体凋亡抑制剂，也是神经退行性疾病动物模型中的一种神经保护剂，它还通过改善 NSC 的线粒体完整性和功能来增强 NSC 的增殖、自我更新和神经元转化。在本研究中，我们使用大鼠出生后神经球和暴露于胆汁酸的成年大鼠，探讨了 TUDCA 在神经发生龛（侧脑室的室下区 (SVZ) 和海马齿状回 (DG) ）中调节 NSC 命运的作用。TUDCA 显著诱导 SVZ 中的 NSC 增殖、自我更新和神经分化，而不影响 DG 来源的 NSCs。更重要的是，TUDCA 显著增加了 SVZ 来源的 NSCs 中线粒体生物发生相关蛋白和线粒体抗氧化反应的表达水平。最后，TUDCA 在成年大鼠的侧脑室给药显著增强了 SVZ 区域的 NSC 增殖和早期分化，与体外数据相符。总之，我们的研究结果强调了 TUDCA 在与 SVZ 龛位恶化和神经发生受损相关的神经疾病中的潜在新作用。
