Amyotrophic lateral sclerosis
The loss of motor neurons in Amyotrophic lateral sclerosis (ALS) has prompted therapeutic strategies aimed at preventing neuronal cell death and promoting regeneration (Carvalho et al., 2015). NSC-34 cells, created by fusion of cultured neuroblastoma cells and motor neurons from mouse spinal cord, can be treated with retinoic acid to induce neurite outgrowth and functional characteristics of motor neurons and are considered a highly stable and widely used murine motor neuron cell line model (Maier et al., 2013; Veyrat-Durebex et al., 2014). NSC-34 cells modified to carry the human form of SOD1 with the G93A mutation (hSOD1G93A) have thus been used as a model for ALS. GUDCA was reported to reduce cell death in the NSC-34 hSOD1G93A cell model and to block caspase-9 activation (Vaz et al., 2015).
Bile acids also appear to have physiological roles in the central nervous system. CA, a bile acid present in the adult brain, was identified by LC/MS as a ligand of liver X receptor (LXR), activating LXR but not FXR in ventral midbrain dopaminergic neurons (Theofilopoulos et al., 2013). 6α-hydroxylated bile acids and the synthetic bile acid ligand GW3965 were also highly potent activators of LXR. Male LXR knockout mice develop an adult-onset motor neuron degeneration that is associated with impairment of motor coordination, axonal atrophy, astrogliosis, accumulation of lipid and loss of motor neurons in the spinal cord, findings similar to the neuropathology of ALS (Andersson et al., 2005). Additionally, FXR has been shown to contribute to normal motor function in mice (Huang et al., 2015).
Several clinical trials of bile acids have been conducted in ALS patients in which evidence for safety and potential efficacy was observed (Parry et al., 2010; Min et al., 2012; Elia et al., 2016). In an ALS clinical trial with orally administered UDCA, the bile acid was found to be well tolerated and crossed into the cerebrospinal fluid in a dose-dependent manner (Parry et al., 2010). In a separate clinical trial to test the efficacy of UDCA for treating ALS patients, oral solubilized administration for 3 months was shown to be well tolerated and there was a slight decrease in the progression of ALS in the treatment group as compared to the placebo group (Min et al., 2012). However, due to the small size of the study and the high rate of patient dropout, the efficacy of the treatment was inconclusive. TUDCA administered orally twice per day for over 1 year resulted in a higher percentage of subjects achieving at least a 15% improvement in the ALS Functional Rating Scale Revised (ALSFRS-R) slope (Elia et al., 2016).
Genetic data also implicates bile acid metabolism in ALS. Gene expression profiles obtained from the peripheral blood cells of sporadic ALS patients and normal controls were analyzed in the context of genome-wide SNP genotype data to identify expression quantitative trait loci (eQTLs). A cluster of transcript-SNP pairs with the highest level of statistical significance and meeting correction for multiple testing was associated with CYP27A1 expression in ALS (Diekstra et al., 2012). CYP27A1 is a key enzyme in the alternative bile acid synthesis pathway, and mutations in this enzyme can cause cerebrotendinous xanthomatosis as described below.