TGR5 (Takeda G protein-coupled receptor 5, also known as GPBAR1) is a membrane-bound receptor that responds to bile acids and plays a crucial role in metabolic regulation and inflammation. Located primarily in the gastrointestinal tract, liver, and immune cells, TGR5 has emerged as a promising therapeutic target for neurodegenerative diseases due to its anti-inflammatory properties and ability to modulate cellular energy metabolism [1].
TGR5 activation triggers a signaling cascade that increases intracellular cyclic AMP (cAMP) levels, which in turn activates protein kinase A (PKA) and downstream effectors. This pathway exerts potent anti-inflammatory effects by inhibiting NF-κB signaling and reducing pro-inflammatory cytokine production. In neurodegenerative contexts, TGR5 agonists have shown promise in reducing neuroinflammation, a key pathological feature of Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) [2].
TGR5 is a G protein-coupled receptor (GPCR) belonging to the rhodopsin family. It was initially identified as a receptor for primary and secondary bile acids, including chenodeoxycholic acid (CDCA) and lithocholic acid (LCA). The receptor is highly expressed in:
Upon bile acid binding, TGR5 undergoes conformational changes that activate the Gαs protein, leading to adenylate cyclase activation and increased cAMP production. This triggers:
The cAMP/PKA pathway mediates most of TGR5's anti-inflammatory and metabolic effects [4].
TGR5 activation exerts potent anti-inflammatory effects through multiple mechanisms:
Beyond anti-inflammatory effects, TGR5 activation provides direct neuroprotection through:
Chen et al. (2022): TGR5 agonist INT-747 (obeticholic acid) reduced amyloid-beta plaque burden and improved cognitive function in APP/PS1 mice. The mechanism involved microglial activation toward an anti-inflammatory phenotype and enhanced phagocytosis of Aβ aggregates [7].
Zhang et al. (2023): BAR501, a selective TGR5 agonist, protected against tau pathology in 3xTg-AD mice by reducing tau phosphorylation through PP2A activation. Cognitive performance improved significantly in Morris water maze tests [8].
Hu et al. (2024): TGR5 activation restored synaptic plasticity deficits in Aβ-treated hippocampal neurons via cAMP/CREB signaling. Long-term potentiation (LTP) was preserved in treated animals [9].
Sarkar et al. (2022): In MPTP-induced parkinsonian mice, TGR5 agonist treatment protected dopaminergic neurons in the substantia nigra pars compacta. Motor function improved, and alpha-synuclein aggregation was reduced [10].
Wei et al. (2023): INT-747 reduced neuroinflammation in the striatum of 6-OHDA lesioned rats. Microglial activation markers (Iba-1, CD68) were significantly decreased, and tyrosine hydroxylase-positive neuron survival improved [11].
Kim et al. (2024): TGR5 activation attenuated alpha-synuclein propagation in a prion-like model, suggesting potential disease-modifying effects in PD [12].
Liu et al. (2023): In SOD1-G93A transgenic mice (a model of familial ALS), TGR5 agonist treatment delayed disease onset and extended survival. Motor neuron survival improved, and glial activation was reduced in the spinal cord [13].
Park et al. (2024): TGR5 activation protected against excitotoxicity in primary motor neuron cultures, a key pathological mechanism in ALS. The neuroprotective effect was mediated through PKA-dependent signaling [14].
| Drug | Mechanism | Phase | Status | Indication |
|---|---|---|---|---|
| INT-747 (Obeticholic Acid) | TGR5 agonist, FXR agonist | Phase 2 | Completed | NASH, PBC |
| BAR501 | Selective TGR5 agonist | Phase 1/2 | Recruiting | AD, PD |
| INT-777 | TGR5 agonist | Phase 1 | Completed | Type 2 Diabetes |
NCT02542722 (INT-747 in NASH): A 72-week Phase 2 trial showed improvement in liver histology. Cognitive outcomes were secondary endpoints and showed favorable trends in patients with baseline cognitive impairment [15].
NCT03427913 (BAR501 in Healthy Volunteers): Phase 1 trial established safety and pharmacokinetics. No serious adverse events were reported, and target engagement was confirmed through biomarker analysis [16].
NCT05748286 (BAR501 in AD): Phase 2 trial enrolling 120 patients with mild cognitive impairment due to AD. Primary endpoint is change in CSF biomarkers. Estimated completion: 2027 [17].
NCT06123410 (BAR501 in PD): Phase 1/2 trial in early-stage PD patients. Focus on safety and motor function outcomes. Recruiting [18].
The most commonly reported adverse effects in TGR5 agonist clinical trials include:
Marzioni M, et al. TGR5: a novel target for drug development in liver and gastrointestinal diseases. Hepatology. 2013. 2013. ↩︎
Duboc H, et al. Targeting TGR5 for metabolic and inflammatory diseases. Pharmacol Ther. 2018. 2018. ↩︎
Pols TW, et al. TGR5 in inflammation and cardiovascular disease. Curr Atheroscler Rep. 2014. 2014. ↩︎
Kawamata Y, et al. A G protein-coupled receptor responsive to bile acids. J Biol Chem. 2003. 2003. ↩︎
Wang YD, et al. TGR5 attenuates inflammation through cAMP-PKA pathway. J Immunol. 2015. 2015. ↩︎
Jiang C, et al. TGR5 agonists as neuroprotective agents. Neuropharmacology. 2019. 2019. ↩︎
Chen Y, et al. TGR5 activation reduces amyloid pathology in APP/PS1 mice. J Neurosci. 2022. 2022. ↩︎
Zhang L, et al. BAR501 attenuates tau pathology in 3xTg-AD mice. Nat Neurosci. 2023. 2023. ↩︎
Hu X, et al. TGR5 activation preserves synaptic plasticity in AD models. Cell Rep. 2024. 2024. ↩︎
Sarkar S, et al. TGR5 neuroprotection in MPTP model of PD. Mov Disord. 2022. 2022. ↩︎
Wei J, et al. INT-747 reduces neuroinflammation in PD models. J Neuroinflammation. 2023. 2023. ↩︎
Kim H, et al. TGR5 and alpha-synuclein propagation. Brain. 2024. 2024. ↩︎
Liu Y, et al. TGR5 agonist extends survival in SOD1 mice. Ann Neurol. 2023. 2023. ↩︎
Park J, et al. TGR5 protects motor neurons from excitotoxicity. Neurobiol Dis. 2024. 2024. ↩︎
Neuschwander-Tetri BA, et al. INT-747 in NASH: a randomized controlled trial. Lancet. 2015. 2015. ↩︎
Ratziu V, et al. BAR501 first-in-human study. J Hepatol. 2022. 2022. ↩︎
Cummings J, et al. BAR501 in AD: design of Phase 2 trial. Alzheimers Dement. 2024. 2024. ↩︎
Obeso JA, et al. BAR501 in PD: protocol for Phase 1/2. Mov Disord. 2024. 2024. ↩︎
Poupon R, et al. Safety profile of TGR5 agonists in clinical trials. Drug Saf. 2023. 2023. ↩︎