Ursodoxicoltaurine is the international nonproprietary name (INN) for the pharmaceutical form of tauroursodeoxycholic acid (TUDCA). It is also known as taurursodiol. Tauroursodeoxycholic acid is a naturally occurring hydrophilic

bile acid Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts. Primary b ...

which is the

taurine Taurine (), or 2-aminoethanesulfonic acid, is an organic compound that is widely distributed in animal tissues. It is a major constituent of bile and can be found in the large intestine, and accounts for up to 0.1% of total human body weight. It ...

conjugated form of

ursodeoxycholic acid Ursodeoxycholic acid (UDCA), also known as ursodiol, is a secondary bile acid, produced in humans and most other species from metabolism by intestinal bacteria. It is synthesized in the liver in some species, and was first identified in bile of ...

(UDCA). Humans have only trace amounts of tauroursodeoxycholic acid but

bear Bears are carnivoran mammals of the family Ursidae. They are classified as caniforms, or doglike carnivorans. Although only eight species of bears are extant, they are widespread, appearing in a wide variety of habitats throughout the Nor ...

s have large amounts of tauroursodeoxycholic acid and ursodeoxycholic acid in their bile.

Synthesis

Bile acids are naturally synthesized from

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...

in the liver and are conjugated with specific amino-acids, specifically taurine. Bear bile contains several bile acids including

taurochenodeoxycholic acid Taurochenodeoxycholic acid is a bile acid formed in the liver of most species, including humans, by conjugation of chenodeoxycholic acid with taurine. It is secreted into bile and then into intestine. It is usually ionized at physiologic pH, altho ...

, ursodeoxycholic acid, and

chenodeoxycholic acid Chenodeoxycholic acid (CDCA; also known as chenodesoxycholic acid, chenocholic acid and 3α,7α-dihydroxy-5β-cholan-24-oic acid) is a bile acid. Salts of this carboxylic acid are called chenodeoxycholates. Chenodeoxycholic acid is one of the mai ...

. UDCA and its taurine conjugates comprise about 47% of the bile in

American black bear The American black bear (''Ursus americanus''), also called simply a black bear or sometimes a baribal, is a medium-sized bear endemic to North America. It is the continent's smallest and most widely distributed bear species. American black bear ...

s and up to 76% in Asiatic bears. Ursodeoxycholic acid and tauroursodeoxycholic acid were first chemically synthesized in 1954 in Japan. Ursodeoxycholic acid is produced in several countries for the treatment of

gallstones A gallstone is a stone formed within the gallbladder from precipitated bile components. The term cholelithiasis may refer to the presence of gallstones or to any disease caused by gallstones, and choledocholithiasis refers to the presence of migr ...

and

primary biliary cholangitis Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build ...

Medical uses

In Canada and the United States, ursodoxicoltaurine, in combination with sodium phenylbutyrate, is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for the treatment of

amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...

(ALS).

Cellular mechanisms

Apoptosis is largely influenced by the

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

. If the mitochondria are distressed, they release

cytochrome C The cytochrome complex, or cyt ''c'', is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins and plays a major role in cell apoptosis. Cytochrome c is hig ...

(cyC) and calcium which activate

caspase Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cystei ...

s to propagate a cascade of cellular mechanisms to cause apoptosis. Tauroursodeoxycholic acid prevents apoptosis with its role in the BAX pathway. Tauroursodeoxycholic acid prevents BAX from being transported to the mitochondria which protects the mitochondria from perturbation and the activation of caspases. Many effects of tauroursodeoxycholic acid appear to be dependent on the activation of the cell membrane receptors TGR5,

S1PR2 Sphingosine-1-phosphate receptor 2, also known as S1PR2 or S1P2, is a human gene which encodes a G protein-coupled receptor which binds the lipid signaling molecule sphingosine 1-phosphate (S1P). Function This protein participates in sphingosi ...

and α5β1-

Integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...

. Tauroursodeoxycholic acid also acts as a

chemical chaperone Chemical chaperones are a class of small molecules that function to enhance the folding and/or stability of proteins. Chemical chaperones are a broad and diverse group of molecules, and they can influence protein stability and polypeptide organizati ...

to help maintain the stability and correct folding of proteins.

Research

Ursodoxicoltaurine has been shown to reduce apoptosis and to have protective effects in

neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...

s and the eye, particularly for retinal degenerative disorders. Studies have shown that tauroursodeoxycholic acid has neuroprotective actions based on its potent ability to inhibit

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

, attenuate

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...

, and reduce endoplasmic reticulum stress in different experimental models of these illnesses. Studies have shown protective effects of tauroursodeoxycholic acid in eye diseases.

Photoreceptor cells

A study examined the effects of tauroursodeoxycholic acid on

cones A cone is a three-dimensional geometric shape that tapers smoothly from a flat base (frequently, though not necessarily, circular) to a point called the apex or vertex. A cone is formed by a set of line segments, half-lines, or lines conn ...

, in relation to

retinitis pigmentosa Retinitis pigmentosa (RP) is a genetic disorder of the eyes that causes loss of vision. Symptoms include trouble seeing at night and decreasing peripheral vision (side and upper or lower visual field). As peripheral vision worsens, people may ...

(RP), a disease in which

retinal rods Rod cells are photoreceptor cells in the retina of the eye that can function in lower light better than the other type of visual photoreceptor, cone cells. Rods are usually found concentrated at the outer edges of the retina and are used in p ...

and cones undergo apoptosis. Mice models were used, a wild-type and a mutant RP model, ''rd10''. Both models were injected with tauroursodeoxycholic acid every 3 days from post-natal day 6 (p6) to p30 and compared to the vehicle.

Electroretinography Electroretinography measures the electrical responses of various cell types in the retina, including the photoreceptors ( rods and cones), inner retinal cells ( bipolar and amacrine cells), and the ganglion cells. Electrodes are placed on th ...

(ERG),

photoreceptor cell A photoreceptor cell is a specialized type of neuroepithelial cell found in the retina that is capable of visual phototransduction. The great biological importance of photoreceptors is that they convert light (visible electromagnetic radiatio ...

counts, cone photoreceptor nuclei counts, and TUNEL labeling were all analyzed to show the effects of ursodoxicoltaurine. The dark-adapted and light-adapted ERG responses were greater in the ursodoxicoltaurine treated mouse than the vehicle treated mouse. Ursodoxicoltaurine treated mice also had more photoreceptor counts, yet non-altered retinal morphology or function. Even at P30, a stage where rod and cone function is usually greatly diminished in the ''rd10'' mouse model, the photoreceptor function was protected. Another study, from the Department of Ophthalmology at

Johns Hopkins University Johns Hopkins University (Johns Hopkins, Hopkins, or JHU) is a private university, private research university in Baltimore, Maryland. Founded in 1876, Johns Hopkins is the oldest research university in the United States and in the western hem ...

, in

Baltimore, Maryland Baltimore ( , locally: or ) is the List of municipalities in Maryland, most populous city in the U.S. state of Maryland, fourth most populous city in the Mid-Atlantic (United States), Mid-Atlantic, and List of United States cities by popula ...

, saw similar effects in two components of bile,

bilirubin Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...

and ursodoxicoltaurine, in relation to RP. Oxidative stress and prolonged light exposure were studied in ''rd10'' mice and

albino Albinism is the congenital absence of melanin in an animal or plant resulting in white hair, feathers, scales and skin and pink or blue eyes. Individuals with the condition are referred to as albino. Varied use and interpretation of the term ...

mice. In ''rd10'' mice, intraperitoneal injections of bilirubin or ursodoxicoltaurine were given every 3 days starting at P6. This caused a considerable preservation in cone cell amount and function at P50, and a modest rod cell amount at P30. In the albino mice models,

intraperitoneal injection Intraperitoneal injection or IP injection is the injection of a substance into the peritoneum (body cavity). It is more often applied to animals than to humans. In general, it is preferred when large amounts of blood replacement fluids are needed ...

s of bilirubin or ursodoxicoltaurine were given prior to prolonged light exposure. Both treatments had positive effects on the health of the

mouse A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

retina The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...

, including a reduced accumulation of

superoxide radical In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of the ...

s, rod cell death, and disruption of cone inner and outer segments. The findings of the study are elucidating optimized conditions for RP treatment.

Choroidal neovascularization

A study done at the Department of Ophthalmology at

Seoul National University Seoul National University (SNU; ) is a national public research university located in Seoul, South Korea. Founded in 1946, Seoul National University is largely considered the most prestigious university in South Korea; it is one of the three "S ...

College of Medicine examined the effects of ursodoxicoltaurine and UDCA on laser-treated

choroid The choroid, also known as the choroidea or choroid coat, is a part of the uvea, the vascular layer of the eye, and contains connective tissues, and lies between the retina and the sclera. The human choroid is thickest at the far extreme rear ...

s of rat models.

Argon laser An ion laser is a gas laser that uses an ionized gas as its lasing medium. Like other gas lasers, ion lasers feature a sealed cavity containing the laser medium and mirrors forming a Fabry–Pérot resonator. Unlike helium–neon lasers, the ...

s were used to induce

choroidal neovascularization Choroidal neovascularization (CNV) is the creation of new blood vessels in the choroid layer of the eye. Choroidal neovascularization is a common cause of neovascular degenerative maculopathy (i.e. 'wet' macular degeneration) commonly exacerbated ...

(CNV) in rat models. Ursodoxicoltaurine and UDCA were injected intraperitoneally 24 hours before and daily after the laser treatment. Fourteen days after laser-treatment, the eyes were examined for effects.

Fluorescein angiography Fluorescein angiography (FA), fluorescent angiography (FAG), or fundus fluorescein angiography (FFA) is a technique for examining the circulation of the retina and choroid (parts of the fundus) using a fluorescent dye and a specialized camera. S ...

showed lower leakage from the CNV in UDCA and ursodoxicoltaurine treated groups than the control group. Additionally,

vascular endothelial growth factor Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...

(VEGF) levels in the retina were examined and showed lower levels in the ursodoxicoltaurine treated group compared to the

control group In the design of experiments, hypotheses are applied to experimental units in a treatment group. In comparative experiments, members of a control group receive a standard treatment, a placebo, or no treatment at all. There may be more than one tr ...

, whereas no effect in the UDCA treated group. ursodoxicoltaurine and UDCA may suppress CNV formation, which may be associated with its

anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...

effects.

Synaptic connectivity

A study from the Department of Physiology in

University of Alicante The University of Alicante ( ca-valencia, Universitat d'Alacant, italic=no, ; es, Universidad de Alicante, italic=no, ; also known by the acronym ''UA'') was established in 1979 on the basis of the Center for University Studies (CEU), which was fo ...

, in

Alicante Alicante ( ca-valencia, Alacant) is a city and municipality in the Valencian Community, Spain. It is the capital of the province of Alicante and a historic Mediterranean port. The population of the city was 337,482 , the second-largest in t ...

Spain , image_flag = Bandera de España.svg , image_coat = Escudo de España (mazonado).svg , national_motto = ''Plus ultra'' (Latin)(English: "Further Beyond") , national_anthem = (English: "Royal March") , i ...

, shows the effects of ursodoxicoltaurine in the P23H transgenic rat, a model of autosomal dominant retinitis pigmentosa. The

transgenic A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...

rats were injected with ursodoxicoltaurine once a week starting from P21 until P120, along with vehicle-administered controls. At P120, the functionality of the retina was examined via ERG and immunoflourescent microscopy. The amplitude of the a- and b- waves were considerably higher in ursodoxicoltaurine treated rats, compared to the control group. Photoreceptor density in the center of the retina was three-fold greater in ursodoxicoltaurine treated rats. Also,

TUNEL Tunel or Tünel may refer to: * TUNEL assay (Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling assay), in genetics, a method for detecting DNA fragmentation * Tunel (band), Yugoslav rock band * Tunel (railroad station), railroa ...

results showed smaller amounts of TUNEL-positive cells. The synaptic contacts amongst photoreceptor cells,

bipolar cells A bipolar neuron, or bipolar cell, is a type of neuron that has two extensions (one axon and one dendrite). Many bipolar cells are specialized sensory neurons for the transmission of sense. As such, they are part of the sensory pathways for smell ...

, and

horizontal cells Horizontal cells are the laterally interconnecting neurons having cell bodies in the inner nuclear layer of the retina of vertebrate eyes. They help integrate and regulate the input from multiple photoreceptor cells. Among their functions, horizo ...

were preserved in the ursodoxicoltaurine treated P23H rats. Additionally, the synaptic terminals in the

outer plexiform layer The outer plexiform layer (external plexiform layer) is a layer of neuronal chemical synapse, synapses in the retina of the human eye, eye. It consists of a dense network of synapses between dendrites of horizontal cells from the inner nuclear laye ...

were of greater density that in control rats. The neuroprotective effects of ursodoxicoltaurine are not only preserving retinal morphology and function, but also its synaptic contacts, a potentially useful aspect in delaying RP.

Medical uses

Tauroursodeoxycholic acid has been suggested to have potential application in heart disease,

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an unst ...

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

and stroke in view of its ability to reduce apoptotic effects.

References

External links

* {{Portal bar , Medicine Ophthalmology drugs Bile acids Cholanes Sulfonic acids