Tauroursodeoxycholic acid: a potential therapeutic tool in neurodegenerative diseases

Abstract

Most neurodegenerative disorders are diseases of protein homeostasis, with misfolded aggregates accumulating. The neurodegenerative process is mediated by numerous metabolic pathways, most of which lead to apoptosis. In recent years, hydrophilic bile acids, particularly tauroursodeoxycholic acid (TUDCA), have shown important anti-apoptotic and neuroprotective activities, with numerous experimental and clinical evidence suggesting their possible therapeutic use as disease-modifiers in neurodegenerative diseases. Experimental evidence on the mechanisms underlying TUDCA's neuroprotective action derives from animal models of Alzheimer's disease, Parkinson's disease, Huntington's diseases, amyotrophic lateral sclerosis (ALS) and cerebral ischemia. Preclinical studies indicate that TUDCA exerts its effects not only by regulating and inhibiting the apoptotic cascade, but also by reducing oxidative stress, protecting the mitochondria, producing an anti-neuroinflammatory action, and acting as a chemical chaperone to maintain the stability and correct folding of proteins. Furthermore, data from phase II clinical trials have shown TUDCA to be safe and a potential disease-modifier in ALS. ALS is the first neurodegenerative disease being treated with hydrophilic bile acids. While further clinical evidence is being accumulated for the other diseases, TUDCA stands as a promising treatment for neurodegenerative diseases.

Keywords: Alzheimer’s disease; Amyotrophic lateral sclerosis; Bile acids; Disease-modifying; Huntington’s disease; Neurodegeneration; Neuroprotection; Parkinson’s disease; Tauroursodeoxycholic acid; Ursodeoxycholic acid.

Fig. 1

Bile acids can be differentiated based on their polarity, as summarised by this figure. More hydrophobic bile acids are represented by their acronyms in the upper part, whereas more hydrophilic are in the bottom part. Abbreviations: CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; GCA, glycocholic acid; GCDCA, glycochenodeoxycholic acid; GDCA, glycodeoxycholic acid; LCA, lithocholic acid; TCA, taurocholic acid; TCDCA, taurochenodeoxycholic acid; TDCA, taurodeoxycholic acid; TUDCA, tauroursodeoxycholic acid; UDCA, ursodeoxycholic acid. Modified from [12]

Fig. 2

Schematic drawing of different possible neuroprotective mechanisms exerted by hydrophilic bile acids, with specific reference to the anti-apoptotic effects of TUDCA on different intracellular pathways. Factors and pathways inhibited by TUDCA are shown in red; pathways blocked by TUDCA are shown by a red cross; genes downregulated by TUDCA are shown by a red downward arrow. Proposed mechanisms of action of TUDCA include: inhibition of the intrinsic mitochondrial apoptotic pathway, through reduction of ROS and inactivation of BAX, in turn decreasing cytochrome c release; inhibition of the death receptor in the extrinsic apoptotic pathway, with further block of caspase 3; reduction of ER-mediated stress by decreasing caspase 12 activity and Ca²⁺ efflux decrease from the ER. TUDCA also inhibits the apoptotic induced pathways MAPK, JNK, PI3K, NF-кB, ERK and p38 [–29]. Furthermore, TUDCA is supposed to reduce the expression of genes involved in cell cycle regulation (Cyclin D1), the Apaf-1 apoptotic pathway, and the E2F/p53/BAX, and AP-1 pathways [30, 31]. Abbreviations: AKT, protein kinase B; AP1, activating Protein-1; Apaf-1, apoptotic protease activating factor-1; ATF2, activating transcription factor 2; BAK, Bcl-2 homologous antagonist killer; BAX, Bcl2-associated X protein; Bcl-2, B-cell lymphoma 2 family of regulator proteins; BID, BH3 interacting-domain death agonist C, cytochrome C; CDC42, cell division control protein 42; E2F-1, E2 promoter binding factor 1; ERK, extracellular signal-regulated kinase; IKK-α, nuclear factor kappa-B kinase subunit alpha; IKK-β, nuclear factor kappa-B kinase subunit beta; IKK-γ, nuclear factor kappa-B kinase subunit gamma; JNK, c-Jun N-terminal kinase; KRAS, Kirsten rat sarcoma viral oncogene; MAPKs, mitogen-activated protein kinase; MOM, mitochondrial outer membrane; mTOR, mammalian target of rapamycin; NF-ĸB, nuclear factor kappa B; P, phosphate; p53, cellular tumour antigen p53; PI3K, phosphoinositide 3-kinases; RAC, Rho family of GTPases; RAS, rat Sarcoma Virus; SRF, serum response factor; tBID, truncated BID; TCF, transcription factor; TLR, Toll-like Receptor; TUDCA, tauroursodeoxycholic acid

Fig. 3

ALSFRS-R functional decline reported by phase II studies on TUDCA in ALS. The mean reported decline is plotted for the study on TUDCA alone (blue) [89] and for TUDCA and NaPB study (red) [90]. Solid lines indicate the active groups; dashed lines represent the control groups. The table reports means (± SD) for baseline and end-of-study measures [89, 90]. Abbreviations: ALSFRS-R, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised; NaPB, sodium phenylbutyrate; TUDCA, tauroursodeoxycholic acid

Fig. 4

The potential neuroprotective effects of TUDCA are shown in context with deposition of protein aggregates and neuroinflammation. TUDCA regulates the expression of genes involved in cell cycle regulation and apoptotic pathways, thus promoting neuronal survival, as depicted in Fig. 2. TUDCA improves protein folding capacity through its chaperoning activity, in turn reducing protein aggregation and deposition (a). By preventing protein aggregation, TUDCA also reduces ROS production, ultimately leading to protection against mitochondrial dysfunction (b), and ameliorates ER stress (c). Finally, TUDCA inhibits the expression of pro-inflammatory cytokines, in turn exerting an anti-neuroinflammatory effect (d)