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Tauroursodeoxycholic Acid Enhances Mitochondrial Biogenesis, Neural Stem Cell Pool, and Early Neurogenesis in Adult Rats

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Abstract

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.

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Acknowledgements

The authors wish to thank M.Sc. Ana Moreira and Rui Rodrigues as well as Dr. Rita Aroeira (Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal) for their assistance in neurosphere cultures and immunohistochemistry. We would also like to thank all members of the iMed.ULisboa and iMM laboratories for insightful discussions. This work was supported by grant UID/DTP/04138/2013 from Fundação para a Ciência e Tecnologia, Lisbon, Portugal.

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  1. Cecília M. P. Rodrigues and Susana Solá contributed equally.

Authors and Affiliations

  1. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisbon, Portugal

    Rita Soares, Tânia Genebra, Maria F. Ribeiro, Cecília M. P. Rodrigues & Susana Solá

  2. Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

    Rita Soares, Filipa F. Ribeiro, Sara Xapelli & Ana M. Sebastião

  3. Instituto de Medicina Molecular (iMM), Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

    Rita Soares, Filipa F. Ribeiro, Sara Xapelli & Ana M. Sebastião

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  1. Rita Soares
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Human and Animal Rights

Sprague-Dawley rats were acquired from Charles River (France). All experimental procedures were in accordance with current Portuguese laws on Animal Care and with the European Union Directive (86/609/EEC; 2010/63/EU; 2012/707/EU), on the protection of animals used for experimental and other scientific purposes. All efforts were made to minimize animal suffering and reduce numbers.

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Soares, R., Ribeiro, F.F., Xapelli, S. et al. Tauroursodeoxycholic Acid Enhances Mitochondrial Biogenesis, Neural Stem Cell Pool, and Early Neurogenesis in Adult Rats. Mol Neurobiol 55, 3725–3738 (2018). https://doi.org/10.1007/s12035-017-0592-5

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