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Ursodeoxycholic acid indications , also known as 3a, 7 β - dihydroxy-5 β - cholestan-24-acid, is an organic compound. Molecular formula C24H40O4, CAS 128-13-2, White powder, odorless, bitter taste. Soluble in ethanol, insoluble in chloroform; Easily soluble in glacial acetic acid and soluble in sodium hydroxide solution. Medically, it is used to increase the secretion of bile acids and change the composition of bile, reducing cholesterol and cholesterol lipids in bile, which is beneficial for the gradual dissolution of cholesterol in gallstones. The clinical product of this substance is suitable for gallbladder cholesterol stones, which must be stones that can be penetrated by X-rays, and the gallbladder contraction function must be normal; Cholestasis related liver disease (such as primary biliary cirrhosis); Bile reflux gastritis.
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Chemical Formula |
C24H40O4 |
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Exact Mass |
392 |
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Molecular Weight |
393 |
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m/z |
392 (100.0%), 393 (26.0%), 394 (2.7%) |
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Elemental Analysis |
C, 73.43; H, 10.27; O, 16.30 |
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Pharmacology and Toxicology
Relaxing the Oddi sphincter muscle has a choleretic effect.
Reduce liver fat, increase the activity of liver peroxidase, promote the accumulation of liver glycogen, and improve the liver's ability to resist and detoxify.
It can reduce the concentration of triglycerides in the liver and serum.
Inhibit the secretion of digestive enzymes and digestive juices.
Foreign studies have also shown that ursodeoxycholic acid has immunomodulatory effects in chronic liver diseases, significantly reducing the expression of HLA class I antigens in liver cells and decreasing the number of activated T cells. Ursodeoxycholic acid is more effective in dissolving cholesterol stones in the body than chenodeoxycholic acid (CDCA).
Liver disease treatment
Ursodeoxycholic acid indications (3 α, 7 β - dihydroxy-5 β - cholic acid, UDCA) is a dihydroxycholic acid that accounts for 3% of total human bile. It was first named after Shoda from Okayama University in Japan, who isolated it from Chinese bear bile. In 1985, Leuschner et al. found a decrease in serum transaminase levels when using it to treat gallstones with hepatitis. Subsequently, numerous clinical studies have confirmed that UDCA has a definite therapeutic effect on some liver diseases. The mechanism of action and therapeutic effect are briefly introduced as follows:
1. Mechanism of action
Cholestasis induced liver disease is associated with the accumulation of chenodeoxycholic acid, deoxycholic acid, and lithocholic acid, which cause liver cell damage due to their descaling effect. UDCA is a non-toxic hydrophilic bile acid that competitively inhibits the absorption of toxic endogenous bile acids in the ileum. By activating the signal network composed of calcium ions and protein kinase C, and by activating the mitotic active protein kinase, the secretion ability of bile stasis liver cells is enhanced, reducing the concentration of endogenous hydrophobic bile acids in the blood and liver cells, achieving the effect of anti bile stasis. UDCA can competitively replace toxic bile acid molecules on cell membranes and organelles, preventing liver cells and bile duct cells from being damaged by more toxic bile acids.
The above effects are specifically manifested in:
(1) Cellular protective effect.
UDCA complexes can significantly alleviate cell lysis induced by hydrophobic bile acids in liver cells and reduce apoptosis induced by toxic bile acids in cultured mouse and human liver cells.
(2) Membrane stabilization effect.
UDCA can prevent changes in mitochondrial membrane permeability induced by bile acids, which means that it can prevent damage to mitochondrial membranes, basement membranes, and small bile duct membranes induced by toxic bile acids through membrane stabilization.
(3) Antioxidant effect.
UDCA can inhibit the activation of Kupffer cells caused by toxic bile acids, increase the levels of glutathione and thiol containing proteins in liver cells, and prevent oxidative damage to liver cells.
(4) Immune regulatory effect.
UDCA indirectly inhibits the stimulating effect of hydrophobic bile acids and directly suppresses the expression of histocompatibility complex (MHC) class I and II genes by activating glucocorticoid receptors.
2. Clinical application
Primary biliary cirrhosis (PBC). PBC is a chronic progressive cholestatic liver disease that mainly occurs in middle-aged women and may be related to immune factors. Pares et al. conducted an experiment with an average interval of 4.5 years between biopsies. Ursodeoxycholic acid indications was found that UDCA can indeed prevent the progression of histological staging in PBC. In 1999, Angulo et al. reported that in a long-term treatment trial (average 6.6 years) of UDCA for non cirrhotic PBC patients, the onset of cirrhosis was delayed in the treatment group compared to the group receiving ineffective treatment. In most UDCA treatment trials, the dosage used is 13-15 milligrams per kilogram per day. Two recent studies aimed at exploring the appropriate dosage of UDCA have found that doses of 13-15 mg/kg and 20-25 mg/kg per day are more effective than doses of 10-15 mg/kg or less per day. The efficacy of combining UDCA with methotrexate or colchicine in the treatment of PBC is not superior to using UDCA alone; But when combined with prednisone or prednisone plus azathioprine, its efficacy in improving inflammation is significantly better than using UDCA alone.
Primary sclerosing cholangitis (PSC). PSC is a rare cholestatic disease characterized by stenosis and dilation of intrahepatic and extrahepatic bile ducts. A recent prospective randomized placebo-controlled trial consisting of 105 patients with an average treatment duration of 2.2 years (UDCA daily 13-15 mg/kg) showed significant improvement in biochemical indicators, with no significant changes in clinical symptoms and liver histology. But for obvious bile duct stenosis, adding UDCA to endoscopic treatment can improve the prognosis of patients.
Intrahepatic cholestasis of pregnancy (ICP). ICP often occurs in late pregnancy, with the main symptoms being itching and jaundice, which can lead to complications such as premature birth, stillbirth, and stillbirth. It is believed to be related to the increase of estrogen in the body on the basis of genetics. A randomized double-blind placebo-controlled trial of UDCA treatment for IPC included 15 patients. The treatment group showed improvement in itching and liver biochemical indicators, and 8 pregnant women (receiving UDCA 1.0 g/day) gave birth at or near their due date; Among the 7 pregnant women treated with placebo, 5 gave birth at 36 weeks of gestation, including 1 stillbirth. No maternal or infant side effects were observed during the treatment period. Therefore, UDCA treatment for ICP seems to be effective and safe.
Gallbladder fibrotic liver disease (CF). Colom Bo et al. compared UDCA treatment (15 mg/kg daily) with a placebo group after 1 year in a follow-up double-blind placebo-controlled trial involving 55 patients. As a result, it was found that the treatment group showed significant improvements in symptoms, nutritional status, biochemical indicators, etc. VanderMeeberg and SulliVan reported that higher doses of UDCA (20 mg/kg daily) were more effective than lower doses (5-15 mg/kg daily).
Chronic hepatitis C. In 2001, several randomized placebo-controlled trials of UDCA combined with alpha interferon for the treatment of chronic hepatitis C were reported. Biochemical indicators improved after treatment, but the clearance of hepatitis C virus (HCV) - RNA was ineffective, and there was no change in liver histological characteristics.
Other. Studies have shown that UDCA combined with cyclosporine A and methotrexate can prevent venous occlusion and acute graft-versus-host disease in the treatment of heterotypic bone marrow transplantation. A daily dose of 15 mg/kg UDCA can improve the symptoms and biochemical indicators of progressive familial intrahepatic cholestasis, biliary atresia, and total parenteral nutrition related liver diseases. Research on the use of UDCA for the treatment of other liver diseases has also been conducted, such as alcoholic liver disease, non-alcoholic fatty liver disease, benign recurrent intrahepatic cholestasis, congenital intrahepatic bile duct cystic dilation, autoimmune hepatitis, and acute hepatitis. Ursodeoxycholic acid indications efficacy needs further evaluation.
Neuroprotection and Anti-Aging
Ursodeoxycholic Acid Indications, as a traditional drug for treating liver and gallbladder diseases, has gradually entered the forefront of neuroscience and anti-aging research in recent years due to its unique molecular characteristics (hydrophilic bile acid, low cytotoxicity) and extensive biological effects. From regulating mitochondrial function to inhibiting neuroinflammation, from eliminating senescent cells to improving metabolic homeostasis, UDCA is transforming from a "drug specific to liver diseases" to a "multi-system protector". In the following, from the two major directions of neuroprotection and anti-aging, we will analyze its potential mechanisms and preclinical evidence.
Neuroprotection: Mechanisms from Liver to Brain Extension
The neuroprotective effect of UDCA stems from its regulation of the bile acid signaling pathway, mitochondrial function, and neuroinflammation. These mechanisms are in line with the core roles in liver disease treatment, but the targeted tissues have expanded from the liver to the central nervous system.
Mitochondrial protection: Fighting the energy crisis of neurons
Neurons highly rely on mitochondria for energy supply, and mitochondrial dysfunction is a core pathological feature of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). UDCA improves mitochondrial function through the following pathways:
Stabilizing membrane potential: UDCA can insert into the mitochondrial membrane, reducing the increase in membrane permeability caused by hydrophobic bile acids (such as deoxycholic acid), thereby maintaining stable membrane potential and preventing the release of cytochrome c and the apoptotic cascade.
Promoting ATP synthesis: In AD models, UDCA (50-100 μM) can restore the activity of mitochondrial complex I, increase ATP production by 30%, and improve neuronal energy supply.
Inhibiting oxidative stress: UDCA upregulates the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx), reducing mitochondrial reactive oxygen species (ROS) levels and minimizing DNA oxidative damage.
Inhibiting neuroinflammation: Breaking the chronic inflammatory cycle
Neuroinflammation is a key driver of neurodegenerative diseases, characterized by excessive activation of microglia and the release of pro-inflammatory factors (such as IL-1β, TNF-α). UDCA exerts anti-inflammatory effects through the following mechanisms:
Regulating microglial cell phenotype: In PD models, UDCA (25 mg/kg/d, orally administered) can promote the transformation of microglia from the pro-inflammatory M1 type to the anti-inflammatory M2 type, reducing the level of IL-6 in cerebrospinal fluid by 40%.
Inhibiting the NF-κB pathway: UDCA blocks IκB degradation, reduces nuclear translocation of NF-κB, and thereby inhibits the expression of downstream pro-inflammatory genes. In AD mouse models, UDCA treatment reduces NF-κB activity in the hippocampus by 50% and reduces neuronal loss by 30%.
Regulating the gut-brain axis: UDCA can alter the composition of the gut microbiota (increasing the abundance of short-chain fatty acid-producing bacteria), reduce the entry of intestinal endotoxins (such as LPS) into the brain, and indirectly inhibit neuroinflammation.
Preclinical evidence: From animal models to potential human applications
AD model: In APP/PS1 transgenic mice, after 6 months of UDCA (100 mg/kg/d, intraperitoneal injection) treatment, the number of Aβ plaques in the brain decreased by 35%, and spatial memory ability significantly improved.
PD model: In MPTP-induced PD mice, UDCA (50 mg/kg/d, orally administered) can protect dopaminergic neurons in the substantia nigra and reduce motor impairment scores by 50%.
Stroke model: In rat stroke models, UDCA (200 mg/kg, single intraperitoneal injection) can reduce the infarct volume by 40% and improve neurological deficit scores.
Although UDCA has not yet been approved for use in neurological diseases, the University of Sheffield in the UK has initiated a Phase I clinical trial (NCT04571820) to assess the safety and tolerance of UDCA in patients with progressive supranuclear palsy (PSP), providing preliminary human data for neuroprotective applications.
Anti-aging: Targeting the clearance and metabolic reprogramming of senescent cells
The accumulation of senescent cells (Senescent cells) is the core mechanism of tissue functional decline, and the pro-inflammatory factors (SASP) secreted by them can drive systemic chronic inflammation and organ aging. UDCA exhibits anti-aging potential through selective induction of senescent cell apoptosis and improvement of metabolic homeostasis.
Selective elimination of senescent cells: Targeting the mitochondrial apoptotic pathway
UDCA can specifically induce apoptosis of senescent cells while having no significant effect on normal cells. The mechanism is related to the mitochondrial dysfunction in senescent cells:
Bax/Bak activation: UDCA (20-50 μM) can increase the expression of Bax/Bak proteins in senescent fibroblasts, promoting the permeabilization of the outer mitochondrial membrane (MOMP), releasing cytochrome c and activating caspase-3, ultimately inducing apoptosis.
ROS-dependent: Senescent cells are in an "oxidative stress pre-activated state" due to the increased production of mitochondrial ROS. UDCA further elevates the ROS level to the threshold, triggering the apoptotic signal, while normal cells can tolerate this dose due to their stronger antioxidant capacity.
Improving metabolic homeostasis: Counteracting aging-related metabolic disorders
Aging is closely related to metabolic syndrome (obesity, insulin resistance, lipid metabolism disorders). UDCA improves metabolism by regulating the bile acid-FXR/TGR5 signaling pathway:
Activating the TGR5 receptor: UDCA is a natural ligand of TGR5, and its activation can promote heat production in brown adipose tissue (BAT) and browning of white adipose tissue (WAT), increasing energy consumption. In aged mice, after 8 weeks of treatment with UDCA (0.5% w/w, dietary addition), the body fat percentage decreased by 20% and insulin sensitivity increased by 30%.
Inhibiting the FXR receptor: In the liver, UDCA moderately inhibits FXR activity, reduces triglyceride synthesis and promotes bile acid excretion, thereby lowering serum low-density lipoprotein (LDL) levels. In the non-alcoholic fatty liver disease (NAFLD) model, UDCA can reduce liver steatosis score by 40%.
Extending healthy lifespan: Preliminary validation in animal models
In the natural aging mouse model, after 12 months of treatment with UDCA (0.2% w/w, dietary addition), the median lifespan was extended by 15%, and the incidence of aging-related pathologies (such as cardiac fibrosis, glomerular sclerosis) decreased by 50%. The mechanism may be related to reducing the accumulation of senescent cells, inhibiting chronic inflammation, and improving metabolic function. Although human anti-aging research has not been conducted yet, the low toxicity (LD50 > 5000 mg/kg) and long-term safety data (clinical use for over 40 years) of UDCA provide important guarantees for its translational application.
Conclusion: Cross-border breakthrough from liver diseases to aging
The neuroprotective and anti-aging potential of UDCA stems from its unique molecular characteristics and multi-target action mechanism. From mitochondrial protection to inhibition of neuroinflammation, from elimination of senescent cells to metabolic reprogramming, UDCA is gradually breaking through the boundaries of traditional indications and becoming a candidate drug for the intervention of aging-related diseases. In the future, with the deepening of clinical research, UDCA is expected to move from "treatment of liver diseases" to "extension of healthy lifespan", providing new strategies for humans to combat neurodegenerative diseases and aging.
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