Abstract
BackgroundBile acids are steroid acids found predominantly in the bile of mammals. The bile acid conjugate tauroursodeoxycholic acid (TUDCA) is a neuroprotective agent in different animal models of stroke and neurological diseases. However, the anti-inflammatory properties of TUDCA in the central nervous system (CNS) remain unknown.MethodsThe acute neuroinflammation model of intracerebroventricular (icv) injection with bacterial lipopolysaccharide (LPS) in C57BL/6 adult mice was used herein. Immunoreactivity against Iba-1, GFAP, and VCAM-1 was measured in coronal sections in the mice hippocampus. Primary cultures of microglial cells and astrocytes were obtained from neonatal Wistar rats. Glial cells were treated with proinflammatory stimuli to determine the effect of TUDCA on nitrite production and activation of inducible enzyme nitric oxide synthase (iNOS) and NFκB luciferase reporters. We studied the effect of TUDCA on transcriptional induction of iNOS and monocyte chemotactic protein-1 (MCP-1) mRNA as well as induction of protein expression and phosphorylation of different proteins from the NFκB pathway.ResultsTUDCA specifically reduces microglial reactivity in the hippocampus of mice treated by icv injection of LPS. TUDCA treatment reduced the production of nitrites by microglial cells and astrocytes induced by proinflammatory stimuli that led to transcriptional and translational diminution of the iNOS. This effect might be due to inhibition of the NFκB pathway, activated by proinflammatory stimuli. TUDCA decreased in vitro microglial migration induced by both IFN-γ and astrocytes treated with LPS plus IFN-γ. TUDCA inhibition of MCP-1 expression induced by proinflammatory stimuli could be in part responsible for this effect. VCAM-1 inmunoreactivity in the hippocampus of animals treated by icv LPS was reduced by TUDCA treatment, compared to animals treated with LPS alone.ConclusionsWe show a triple anti-inflammatory effect of TUDCA on glial cells: i) reduced glial cell activation, ii) reduced microglial cell migratory capacity, and iii) reduced expression of chemoattractants (e.g., MCP-1) and vascular adhesion proteins (e.g., VCAM-1) required for microglial migration and blood monocyte invasion to the CNS inflammation site. Our results present a novel TUDCA anti-inflammatory mechanism, with therapeutic implications for inflammatory CNS diseases.
Highlights
Bile acids are steroid acids found predominantly in the bile of mammals
Glial fibrillary acidic protein (GFAP) and Ionized calcium-binding adapter molecule 1 (Iba-1) immunoreactivity were used to determine the glial reactivity in coronal sections from mice hippocampus
INOS mRNA transcription induced by LPS or LPS plus IFN-γ, was reduced in tauroursodeoxycholic acid (TUDCA) treated cells, compared to control cells (Figure 2E and F). These results demonstrate that the inhibitory effect of TUDCA on nitrite production induced by LPS or LPS plus IFN-γ was mostly dependent on transcriptional regulation of inducible enzyme nitric oxide synthase (iNOS)
Summary
Bile acids are steroid acids found predominantly in the bile of mammals. The bile acid conjugate tauroursodeoxycholic acid (TUDCA) is a neuroprotective agent in different animal models of stroke and neurological diseases. The response is resolved once the threat has been eliminated and homeostasis is restored This acute neuroinflammatory response includes the activation of astrocytes [1] and the resident immune cells (microglia) [2]. If the glial cells cannot restore the homeostasis, the inflammatory response is maintained long after the initial insult. This chronic neuroinflammation causes the loss of white and grey matter that leads to functional deficits [6,7] that characterize the pathology of neurodegenerative diseases [8,9], stroke [10], and traumatic brain injuries [11]. Reactive glial cells release a wide number of mediators, including proinflammatory and anti-inflammatory cytokines, and chemokines that increase BBB permeability and induce the activation and recruitment of blood monocytes, lymphocytes, and neutrophils to the inflammation site inside the CNS parenchyma [12,13]
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