Tauroursodeoxycholic acid: more than just a neuroprotective bile conjugate

Neurological diseases and the neuroin fl ammatory response: Neurological diseases are usually accompanied by dramatic changes in the tissue homeostasis, inducing a neuroinflam‐matory environment that leads to the progressive activation of central nervous system (CNS) resident cells, and in certain cases, to the in fi ltration of leukocytes into the CNS. If this neu‐roinflammatory response persists, it is toxic for CNS resident cells, especially for neurons, and consequently is detrimental for the progression and outcome of neurological diseases.e blood‐brain barrier (BBB) is a physical and functional barrier that facilitates the maintenance of homeostasis restricting the tra ffi c of substances and cells from the blood to the CNS paren‐chyma. CNS resident cells (mainly glial cells) actively monitor and detect any alteration in tissue homeostasis. Any unbalance (such as infections, trauma, stroke, and neurodegeneration) leads to the activation of CNS glial cells (mainly astrocytes and microglia), to counterbalance the alteration and bring back ho‐meostasis (Tian et al., 2012). Upon activation, microglial cells and astrocytes undergo severe morphological and structural changes, ranging from a resting to a reactive state. Reactive gli‐al cells show enhanced release of pro‐ and anti‐inflammatory mediators, phagocytic capacity and increased migration to the insult site. If this glial response cannot restore proper physio‐logical condition, the in fl ammatory status is maintained by the secretion of pro‐in fl ammatory mediators, resulting in chronic neuroin fl ammation and the loss of white and gray matter dis‐ tinctive of CNS pathologies (Popovich et al., 2002). Moreover, pro‐in fl ammatory cytokines and chemokines alter the BBB per‐meability, allowing the activation and recruitment of leukocytes to the CNS parenchyma (Weiss et al., 2009; Tian et al., 2012) that help to maintain the chronic neuroin fl ammation as a feed‐back mechanism with detrimental effects on the progression and outcome of neurological diseases.

Figure 1 Proposed model for the e ff ect of tauroursodeoxycholic acid (UDCA) in the neuroin fl ammatory process.

Additional anti-inflammatory effect ofUDCA inducingGF-β pathway: Recently, we found that TUDCA has an addi‐tional anti‐in fl ammatory e ff ect in neuroin fl ammation through the regulation of the transforming growth factor β (TGF‐β) pathway (Yanguas‐Casás et al., 2016; Figure 1). TGF‐β is a pleiotropic cytokine involved in a wide variety of physiological and pathological conditions that actively modulate the in fl am‐matory process by a direct e ff ect on immune and CNS resident cells under physiological and neuropathological conditions (Blobe et al., 2000). TGF‐β inhibits the activation of pro‐in‐flammatory pathways, reducing the production and release of pro‐in fl ammatory mediators. Besides, TGF‐β drives microglial cells towards an anti‐in fl ammatory phenotype, contributing to homeostasis restoration. In a mouse model of acute neuroin‐fl ammation by intracerebraventricular injection of LPS, TUD‐ CA increases the transcription of TGF‐β2 and TGF‐β3 in the hippocampus of LPS treated mice, compared to those treated with LPS alone. We found that TGF‐β3 protein expression was increased in the brains of those mice. Interestingly, TGF‐β3 expression was limited to certain cell types, such as microglia, endothelial cells and some neurons, but was absent in astro‐cytes (Yanguas‐Casás et al., 2016). The inhibition of TGF‐β receptor (ALK5) in mice treated with TUDCA reduced TGF‐β3 expression and restored microglia activation to the same levels as mice treated with LPS alone.is result suggests that TUD‐CA‐induced TGF‐β3 expression might be regulated by TGF‐β pathway as a positive feed‐back. Moreover, TGF‐β pathway ac‐tivation is required for TUDCA‐induced inhibition of microglia activation in mice treated with LPS (Yanguas‐Casás et al., 2016). We cannot exclude that the increasing expression of TGF‐β3 in endothelial cells might participate in the e ff ects of TUDCA on VCAM‐1 expression and leukocyte in fi ltration into the CNS.

Conclusions: Although the neuroprotective e ff ects of TUDCA have been widely described, little is known about the e ff ect of TUDCA on glial cells. In addition to its direct neuroprotec‐tive e ff ect on di ff erent animal models of neurological diseases, TUDCA might have an indirect neuroprotective e ff ect through the inhibition of glia and endothelium activation under pro‐in‐flammatory conditions. TUDCA treatment inhibits NF‐κB pathway and increases further TGF‐β pathway favoring the res‐olution of the in fl ammatory process.e anti‐in fl ammatory en‐vironment promoted by glial cells might lead to an increase of neuronal survival and a faster restoration of neural function in the CNS. Our results have therapeutical implications for those neuropathologies that course with neuroin fl ammation.

Lorenzo Romero-Ramírez＊, Manuel Nieto-Sampedro, Natalia Yanguas-Casás

Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain (Romero‐Ramírez L, Nieto‐Sampedro M, Yanguas‐Casás N) Instituto Cajal, CSIC, Madrid, Spain (Nieto‐Sampedro M, Yanguas‐Casás N)

＊Correspondence to: Lorenzo Romero-Ramírez, Ph.D., lromeroramirez@sescam.jccm.es.

Accepted:2017-01-14

orcid: 0000-0002-8974-6698 (Lorenzo Romero-Ramírez)

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10.4103/1673-5374.198979

How to cite this article:Romero-Ramírez L, Nieto-Sampedro M, Yanguas-Casás N (2017) Tauroursodeoxycholic acid: more than just a neuroprotective bile conjugate. Neural Regen Res 12(1):62-63.

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