Taurine: a promising nutraceutic in the prevention of retinal degeneration

Abstract

Taurine is considered a non-essential amino acid because it is synthesized by most mammals. However, dietary intake of taurine may be necessary to achieve the physiological levels required for the development, maintenance, and function of certain tissues. Taurine may be especially important for the retina. The concentration of taurine in the retina is higher than that in any other tissue in the body and taurine deficiency causes retinal oxidative stress, apoptosis, and degeneration of photoreceptors and retinal ganglion cells. Low plasma taurine levels may also underlie retinal degeneration in humans and therefore, taurine administration could exert retinal neuroprotective effects. Taurine has antioxidant, anti-apoptotic, immunomodulatory, and calcium homeostasis-regulatory properties. This review summarizes the role of taurine in retinal health and disease, where it appears that taurine may be a promising nutraceutical.

Introduction

Taurine (2-amino-ethane sulfonic acid) was isolated from the bile of an ox in 1827 and named after this animal (Froger et al., 2014). It is one of the most abundant amino acids in the central nervous system (CNS) and is considered a putative neurotransmitter (Kilb, 2017). The molecular structure of taurine is similar to that of gamma-aminobutyric acid (GABA; Figure 1), the main inhibitory neurotransmitter in the CNS (Froger et al., 2014).

Figure 1.

Chemical structure of taurine, β-alanine, guanidoethane sulfonate, vigabatrin and gamma-aminobutyric acid.

Created with https://molview.org/.

Taurine is present in mammalian milk (Agostoni et al., 2000). For decades, taurine has been considered as a key nutritional molecule in the development and regeneration of the CNS (Suárez et al., 2016; Mersman et al., 2020). Indeed, taurine intake during development may influence organ development and general health in adulthood (Tochitani, 2022). Several studies have demonstrated the necessity of taurine for retinal development and health, particularly for retinal neuronal survival (Ament et al., 1986; Neuringer and Sturman, 1987; Froger et al., 2014; Hadj-Saïd et al., 2016; García-Ayuso et al., 2018b, 2019a; Di Pierdomenico et al., 2023). Additionally, its concentration increases during retinal development (Pasantes-Morales, 1986). Taurine intake during development may also be crucial for brain, visual, and immune system development; osmotic regulation; reproduction; membrane stabilization; stem cell proliferation; synapse development; heart muscle regulation; and inflammation (Jakaria et al., 2019; Mersman et al., 2020).

Taurine might be a potential candidate for the treatment of retinal degenerative diseases. These diseases, in their different forms (e.g., inherited photoreceptor degeneration, age-related macular degeneration (AMD), diabetic retinopathy (DR) or glaucoma), are one of the main causes of irreversible blindness worldwide ( GBD 2019 Blindness and Vision Impairment Collaborators; Vision Loss Expert Group of the Global Burden of Disease Study, 2021a). AMD is the most common cause of photoreceptor degeneration (Wong et al., 2014; GBD 2019 Blindness and Vision Impairment Collaborators; Vision Loss Expert Group of the Global Burden of Disease Study 2021a) and with increasing life expectancy has become a major public health problem (Wong et al., 2014; Bourne et al., 2021a). Retinitis pigmentosa (RP) is the most common cause of inherited photoreceptor degeneration (Schneider et al., 2021). All these diseases represent a major economic burden for health care systems and society. In 2020, glaucoma, DR and AMD were estimated to be responsible for more than 19 million cases of moderate or severe visual impairment in adults aged over 50 years (GBD 2019 Blindness and Vision Impairment Collaborators; Vision Loss Expert Group of the Global Burden of Disease Study, 2021b). Therefore, there is an urgent need to develop strategies to prevent and/or slow disease progression and minimize their health impact.

In the first part of this review, we provide an overview of taurine structure and main properties and its role in the retina and central nervous system. In the second part, we explore the role of taurine as a potential neuroprotective agent for the treatment of retinal degeneration.

Search Strategy and Selection Criteria

We conducted a MEDLINE/PubMed search for articles published between 1975 and 2023, using the following search terms: taurine AND retina OR retinal degeneration OR photoreceptor OR development. The results were further screened by scrutinizing the titles, abstracts and full texts. Articles on unrelated topics were excluded from this review. Other exclusion criteria were non-indexed articles and articles not in English. No restrictions were imposed on human or animal studies.

Taurine

The structure of the amino acid taurine differs from that of other amino acids because it contains a sulfonic acid instead of a carboxyl group (Jakaria et al., 2019; Castelli et al., 2021; Figure 1). Taurine is ubiquitously present in most cells and tissues of the mammalian body, including the brain, retina, heart, placenta, leukocytes and muscles (Jakaria et al., 2019). Taurine can be synthesized endogenously in the liver and kidney of most mammals through catabolism of the amino acid cysteine. However, endogenous taurine is insufficient to meet the requirements of mammals and should thus be included in the diet. A diet that contains animal products (meat and fish) should contain sufficient taurine to meet physiological needs. However, the exact daily requirement of taurine remains unknown. Taurine is rapidly absorbed into the gastrointestinal tract. This molecule is absorbed by enterocytes via carrier-mediated active transport by two transmembrane transporters: H⁺-coupled PAT1 (SLC36A1) and Na⁺- and Cl^–-dependent taurine transporter (Tau-T) (SLC6A6). From the intestinal brush border membrane (Anderson et al., 2009), taurine is transported through the portal vein to the liver, where it is released into general circulation (Surai et al., 2021). Taurine is excreted from the body via two main routes (Rafiee et al., 2022): i) glomerular filtration in the kidney and ii) conjugation with bile acids in the liver. Renal excretion is the predominant excretion route, as approximately 95% of taurine is excreted in urine (Sturman et al., 1975). The rates of reabsorption and excretion of taurine in the kidney vary depending on taurine intake, with higher reabsorption when dietary intake is restricted and higher excretion when intake is high (Sturman et al., 1975). Thus, the kidney serves to equilibrate the body pools of taurine.

Taurine also differs from other amino acids because it is not incorporated into proteins and, as a result, its concentration is abundant in several body tissues. The function of this non-proteinogenic amino acid in tissues remains unclear. However, several studies have shown that it plays a crucial role in several biological processes (see below).

Taurine structure is similar to that of β-alanine (Figure 1), another non-proteinogenic amino acid that is a component of vitamin B5, and to a synthetic compound called guanidoethane sulfonate (GES) (Figure 1). Both compounds may compete with taurine for receptors in the gastrointestinal tract. Thus, they act as inhibitors of taurine absorption. Taurine depletion may be achieved by administration of these compounds to provide insight into the biological effects of taurine (Hadj-Saïd et al., 2016; García-Ayuso et al., 2018b, 2019a; Martínez-Vacas et al., 2021; Di Pierdomenico et al., 2023). As noted previously, there are two types of taurine transporters in the gastrointestinal tract, Tau-T and PAT1. Tau-T (SLC6A6 gene) is a high-affinity, low-capacity, ion (sodium and chloride) dependent transporter of taurine and is considered the main transporter. The PAT1 transporter (SLC36A1) is a proton-coupled/pH-dependent transporter and a high-capacity, low-affinity transporter for taurine (Baliou et al., 2020).

Taurine in the retina

Taurine is found in high concentrations in the mammalian retina. It is one of the most abundant amino acids in the retina, both during development and adulthood (Schaffer and Kim, 2018). Taurine concentration in the retina is higher than that in any other ocular structure or in the brain (Froger et al., 2014; Schaffer and Kim, 2018), reaching up to 50 µmol/g tissue in rats or 40 µmol/g in mice (Huxtable, 1989; Froger et al., 2014). The outer retina, where photoreceptors are located, and more specifically, the outer nuclear layer, contains more than 60% of the taurine present in the retina (Huxtable, 1989; Froger et al., 2014). Despite the high concentrations of taurine in the retina, its role in this tissue remains unclear (Froger et al., 2014; Castelli et al., 2021). Taurine may be essential for retinal and photoreceptor development, for the maintenance of synaptic connections or antioxidant protection (Martínez-Vacas et al., 2021, 2022). Taurine also plays a role in retinal pigment epithelium (RPE) phagocytosis (Ogino et al., 1983; Martínez-Vacas et al., 2021, 2022). Decreased levels of taurine in the retina have been also linked to photoreceptor degeneration in animal models of retinal degeneration (Okada et al., 2000).

Functions of taurine in different tissues

Taurine plays a vital role in regulating calcium (Ca²⁺) homeostasis, a crucial physiological process in cells. Under normal and pathological conditions like neurological diseases, Ca²⁺ homeostasis regulation can reduce endoplasmic reticulum stress (Jakaria et al., 2019). In the CNS, taurine protects neurons from glutamate-induced apoptosis by modulating Ca²⁺ homeostasis (Leon et al., 2009). It also regulates endoplasmic reticulum stress, ensures normal mitochondrial functions (Jong et al., 2021) and downregulates the expression of pro-apoptotic Bcl-2-associated protein (Bax) and caspase-3 in rodent models (Jeong et al., 2009). Taurine may therefore reduce the risk of apoptosis and premature cell death in neuronal diseases (Ma et al., 2021).

Taurine scavenges free radicals by inhibiting reactive oxygen species (ROS)-producing enzymatic activities (Qu et al., 2022), including xanthine oxidase (XO) and NADPH oxidase (Surai et al., 2021), both significant sources of ROS. Several studies have demonstrated that dietary taurine supplementation is associated with a decrease in oxidative stress and inflammation in plasma markers (hs-C-reactive protein and the lipid peroxidation marker thiobarbituric acid-reactive substances) in obese women (Rosa et al., 2014) and patients with type 2 diabetes (Maleki et al., 2020). Interestingly, retinal taurine levels decrease with age (Militante and Lombardini, 2004). The homeostasis-regulating and protein-folding-promoting properties of taurine may mitigate the effects of aging on various tissues, including the heart, skeletal muscle, liver and skin, according to several preclinical and clinical studies (Bhat et al., 2020). Taurine has an antioxidant effect in women aged 55–70 years, preventing the decrease in plasma levels of the antioxidant enzyme superoxide dismutase (SOD) (Abud et al., 2022). The anti-aging properties of taurine may be mediated by the control of oxidative stress during aging (Abud et al., 2022). Aging results in a decrease in ionotropic GABA receptors in the enzyme glutamate decarboxylase (GAD; the enzyme that catalyzes the decarboxylation of glutamate to GABA and carbon dioxide (CO₂)) and in somatostatinergic subpopulations of GABAergic neurons in the brain (Govoni et al., 1980). Taurine increases the levels of the GABA neurotransmitter, glutamate, and the expression of GAD and the neuropeptide somatostatin in the brain, relieving the age-dependent decline in spatial memory acquisition and retention in aged mice (El Idrissi et al., 2013).

Taurine also exhibits anti-inflammatory properties. It reduces the levels of different cytokines (interleukin (IL)-1α, IL-1β, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, and IL-17) and tumor necrosis factor (TNF-α) during disease or injury, as shown in preclinical and clinical studies (Su et al., 2014; Jakaria et al., 2019; Ma et al., 2021). The anti-inflammatory effects of taurine may also be related to microglial and macroglial activation (Schaffer et al., 2016; Che et al., 2018). Taurine provides neuroprotection by inactivating microglia-dependent inflammatory responses in the CNS (Che et al., 2018). Taurine also increases macroglial cellular energy metabolism by activating complex I and nicotinamide adenine dinucleotide hydrate (NADH)-sensitive enzymes by reducing the NADH/NAD⁺ ratio during macroglial glycolysis (Schaffer et al., 2016).

A link between inflammation and mitochondrial dysfunction has been documented in some neurological diseases. Inflammatory mediators produced by the activation of microglial cells and infiltrating monocytes induce intracellular signalling cascades that cause mitochondrial membrane permeabilization and damage mitochondrial metabolism, potentially leading to cell death (van Horssen et al., 2019). Damaged mitochondria may then release their contents into the extracellular milieu, amplifying the inflammatory response. A way to prevent the amplification of the inflammatory process could be to ensure normal mitochondrial functions by reducing oxidative stress, regulating intracellular Ca²⁺ homeostasis, and inhibiting mitochondrial-mediated apoptosis, all of which are properties of taurine (Jong et al., 2021).

Taurine requirements for retinal health

Dietary taurine may be necessary for normal retinal function. This was first suggested in cats fed a taurine-free diet that developed photoreceptor degeneration (Hayes et al., 1975). Other histological and functional analyses have also shown in cats that a taurine-free diet causes photoreceptor degeneration (reviewed in Froger et al., 2014). Furthermore, vision impairment has been documented in taurine-deprived infant primates (Neuringer and Sturman, 1987). Finally, impaired electroretinographic responses and reduced taurine plasma levels (Ament et al., 1986) have been detected in humans aged 3 months to 18 years (mean age of 5.2 years) receiving long-term parenteral nutrition without including taurine for periods varying from 2 to 29 months (mean duration of 24 months).

The need for taurine for retinal health has also been studied using animal models of induced taurine depletion (Di Pierdomenico et al., 2023). These models use the above-mentioned pharmacological agents to block Tau-T activity, β-alanine and GES. In this regard, the use of β-alanine deserves special attention, as it is a dietary supplement commonly used by athletes (Saunders et al., 2017; Dolan et al., 2019) because of its performance-enhancing effects (Saunders et al., 2017). However, high doses of β-alanine may induce taurine depletion and have harmful effects (Dolan et al., 2019), particularly in the retina (Martínez-Vacas et al., 2021). GES-induced taurine depletion in rodents causes also photoreceptor and retinal ganglion cell (RGC) degeneration (Lake and Malik, 1987; Gaucher et al., 2012; Hadj-Saïd et al., 2016; Martínez-Vacas et al., 2021; Di Pierdomenico et al., 2023) and RPE function impairment (Lake and Malik, 1987; Martínez-Vacas et al., 2021). A recent study using a mouse model of GES-induced taurine depletion showed that S-cones were most affected, followed by L-cones and RGCs (Hadj-Saïd et al., 2016). The effect of taurine depletion induced by β-alanine treatment has also been studied in cats (Lu et al., 1996; Sturman et al., 1996) and rats (Pasantes-Morales et al., 1983; García-Ayuso et al., 2018b, 2019a). Recent studies conducted in rats have shown that the administration of 3% β-alanine in drinking water significantly decreases plasma taurine levels (García-Ayuso et al., 2018b, 2019a; Martínez-Vacas et al., 2021; Di Pierdomenico et al., 2023). These studies showed RGC and S- and L-cones loss secondary to taurine depletion (García-Ayuso et al., 2018b). This cell loss occurs along with activation of retinal glial cells and oxidative stress in the rat retina (Martínez-Vacas et al., 2021). Besides, these studies showed impaired axonal transport in the retinal nerve fiber layer (García-Ayuso et al., 2019a), as well as impaired RPE function (Martínez-Vacas et al., 2021). There is limited information on the differential effects of taurine depletion on rods and cones. However, some studies have suggested that taurine depletion causes earlier cone loss and minimal rod loss (Hadj-Saïd et al., 2016; García-Ayuso et al., 2018b).

To study the effects of permanent taurine depletion, a mutant knockout mouse model was raised by disrupting the Tau-T gene (the Tau-t^–/–) (Heller-Stilb et al., 2002). This animal showed plasma hypotaurinemia (Heller-Stilb et al., 2002; Froger et al., 2014) and decreased retinal taurine levels (80–90%). The knockout mice also showed early onset, rapid and progressive retinal degeneration (Heller-Stilb et al., 2002). This is similar to pharmacologically induced taurine depletion (Hadj-Saïd et al., 2016) (see above).

Vigabatrin is a GABA analog used as an antiepileptic drug and for the treatment of infantile spasms (Froger et al., 2014). Daily vigabatrin treatment in rats and mice results in reduced taurine plasma levels and retinal toxicity (Duboc et al., 2004; Jammoul et al., 2009, 2010; Rasmussen et al., 2014; Tao et al., 2016; Chan et al., 2020). In humans, vigabatrin treatment causes visual field defects, cone damage, electroretinographic impairments, RPE dysfunction, and decreased retinal nerve fiber layer thickness (Biswas et al., 2020; Strong et al., 2021). Interestingly, taurine supplementation prevents vigabatrin-induced retinal toxicity in rodents (Jammoul et al., 2009, 2010) and humans (Jammoul et al., 2009; Horvath et al., 2016). However, taurine supplementation is not recommended currently in vigabatrin-treated patients.

Recent studies have shown that individuals carrying a homozygous missense mutation in the human SLC6A6 gene, which deactivates the Tau-T transmembrane transmitter, show decreased taurine plasma levels and early and progressive loss of photoreceptors, as well as tritanopia, suggesting preferential damage to S-cones (Preising et al., 2019). It would be interesting to conduct studies with animal models using genetic or biochemical manipulations of SLC6A6 to better understand its role in the observed retinal disease. Interestingly, visual field, color vision and blue color vision defects (tritanopia) have also been reported as side effects in epileptic vigabatrin-treated patients (Nousiainen et al., 2000). Decreased taurine plasma levels have also been reported in other types of human retinal degeneration such as Leber hereditary optic neuropathy (Bocca et al., 2021) and central serous chorioretinopathy (Xu et al., 2021). Therefore, taurine plasma levels have been proposed as biomarkers for these diseases, and detecting blood taurine levels in neonates has been proposed to identify children with taurine deficiency and, therefore, at risk of retinal degeneration (Antonarakis, 2020).

Rationale for the use of taurine treatment for retinal degeneration

It is now widely accepted that both inflammation (Di Pierdomenico et al., 2020; Martínez-Vacas et al., 2021) and oxidative stress (Nita and Grzybowski, 2016; Pinilla et al., 2022) play a role in retinal degeneration. Taurine supplementation has been proposed as a therapy for retinal degeneration because of its antioxidant and anti-inflammatory properties (Froger et al., 2014; Castelli et al., 2021).

Inflammation is a universal protective response of the immune system to a perceived threat that helps maintain normal physiological homeostasis. Within the retina, microglial cells mediate the inflammatory response and contribute to retinal homeostasis (Di Pierdomenico et al., 2017, 2020; Martínez-Vacas et al., 2021; Pinilla et al., 2022). Additionally, macroglial cells, Müller cells and astrocytes are pivotal for maintaining retinal health and homeostasis (Di Pierdomenico et al., 2020; Martínez-Vacas et al., 2021; Pinilla et al., 2022). Many retinal degenerative diseases have strong inflammatory components, mostly due to immunological responses (Xu and Rao, 2022). Photoreceptor degenerative diseases involve activation, migration and proliferation of microglial cells (Di Pierdomenico et al., 2017, 2020), as well as hypertrophy of Müller cells and increased expression of glial fibrillary acidic protein (GFAP) in Müller cells (Di Pierdomenico et al., 2020). These events may contribute to increased neurodegeneration (García-Ayuso et al., 2018a, 2019b; Di Pierdomenico et al., 2019, 2020; Pfeiffer et al., 2020).

Oxidative stress contributes to various retinal diseases such as AMD and inherited retinal degeneration. This may be due to the high metabolic activity and, thus, the high demand for oxygen and nutrients of the photoreceptors that determines the increased vulnerability of the outer retina to disease.

Taurine shows neuroprotective properties in the retina. A study documented that taurine supplementation enhanced RGC survival in two rodent models of glaucoma and in a rat model of inherited photoreceptor degeneration (Froger et al., 2012). Taurine also protects RGC against N-methyl-D-aspartate (NMDA) excitotoxicity, both in vivo (Jafri et al., 2019; Lambuk et al., 2019) and ex vivo (Froger et al., 2012). It has been postulated that the protective role of taurine in diseases involving RGC is presumably mediated by stimulation of GABA_B receptors (Hadj-Saïd et al., 2017).

The neuroprotective actions of taurine in photoreceptor degenerations may be a consequence of its antiapoptotic and antioxidant properties. A study using a mouse model of photoreceptor degeneration induced by intraperitoneal injection of N-methyl-N-nitrosourea (MNU) documented that taurine might relieve visual impairment and cone degeneration (Tao et al., 2019). In an animal model of Usher syndrome, taurine supplementation prevented retinal degeneration, augmented the electroretinographic response, increased photoreceptor survival, and reduced the inflammatory response (Trouillet et al., 2018). Recently, a study in an animal model of inherited photoreceptor degeneration, the RCS rat (García-Ayuso et al., 2014), demonstrated that taurine has anti-apoptotic, anti-inflammatory, and antioxidant effects, resulting in increased survival of functional photoreceptors, decreased glial cell activation, and improved RPE phagocytic function (Martínez-Vacas et al., 2022).

A relationship between lower taurine plasma levels and the development of retinal complications in diabetic patients has been documented (Inam-u-llah et al., 2018; Güngel et al., 2021). Indeed, increased plasma taurine levels can prevent vision loss in diabetic patients (Güngel et al., 2021). Studies using rodent models have shown that taurine exerts various beneficial effects in the retina of diabetic rats, including anti-gliotic activity (Zeng et al., 2009; Fan et al., 2020), improvement of synaptic connections, reduction of retinal cell apoptosis (Fan et al., 2020), and counteraction of biochemical retinal alterations (Di Leo et al., 2003). These effects were also dose-dependent (Di Leo et al., 2003).

Conclusions

Taurine is necessary for retinal health. Taurine depletion or deficiency results in glial activation, oxidative stress and retinal cell degeneration. Recent evidence has shown that taurine has neuroprotective effects in retinal degeneration, and it is believed to be the result of its antioxidant effects, the inhibition of mitochondrial dysfunction and apoptosis, or immunomodulatory effects. Therefore, taurine supplementation may be a promising agent for the treatment of retinal degenerative diseases, regardless of etiology. For this purpose, further research will be needed to understand the retinal neuroprotective effects of taurine at the molecular level.