Bile Acids in Neurodegenerative Disorders

Abstract

Bile acids, a structurally related group of molecules derived from cholesterol, have a long history as therapeutic agents in medicine, from treatment for primarily ocular diseases in ancient Chinese medicine to modern day use as approved drugs for certain liver diseases. Despite evidence supporting a neuroprotective role in a diverse spectrum of age-related neurodegenerative disorders, including several small pilot clinical trials, little is known about their molecular mechanisms or their physiological roles in the nervous system. We review the data reported for their use as treatments for neurodegenerative diseases and their underlying molecular basis. While data from cellular and animal models and clinical trials support potential efficacy to treat a variety of neurodegenerative disorders, the relevant bile acids, their origin, and the precise molecular mechanism(s) by which they confer neuroprotection are not known delaying translation to the clinical setting.

Keywords: bile acids; neurodegeneration; neuroprotection.

Figure 1

Despite documented neuroprotective roles in models of neurodegenerative disorders, the primary signaling pathways (TGR5 and FXR) and the potential role of endogenous bile acids have not yet been studied.

Figure 2

Molecular pathways implicated in the neuroprotective effects of bile acids in neurodegenerative disease models. Despite the relatively large structurally related group of bile acids, relatively few have been studied in neurodegenerative disorders. A major focus has been on apoptotic pathways and the PI3 kinase and AKT signaling pathway. Surprisingly, the primary signaling pathways through which bile acids act, TGR5, FXR, and FXR/RXR have received essentially no attention (designated by “?”), despite that retinoic acid is known to be a potent neurotrophic molecule.