타우린 인체에 가장 많은 유리 아미노산 뇌신경, 시신경 보호 기전 탐구!!!

[문형철]

문형철 치유연구소에서 선정한 필수 비타민, 미네랄, 영양소 중 하나가

타우린이다.

https://kr.iherb.com/search?kw=%ED%83%80%EC%9A%B0%EB%A6%B0

REVIEW article

Front. Mol. Neurosci., 05 July 2022

Sec. Molecular Signalling and Pathways

Volume 15 - 2022 | https://doi.org/10.3389/fnmol.2022.937789

This article is part of the Research TopicAstrocytic Synaptic Plasticity in Epilepsy: From Synapses to CircuitsView all 10 articles

Taurine and Astrocytes: A Homeostatic and Neuroprotective Relationship

• 1Grupo de Investigación en Neurociencias (NeURos), Centro de Neurociencias Neurovitae-UR, Instituto de Medicina Traslacional (IMT), Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá, Colombia
• 2Grupo de Investigación en Ciencias Biomédicas GRINCIBIO, Facultad de Medicina, Universidad Antonio Nariño, Bogotá, Colombia

Taurine is considered the most abundant free amino acid in the brain. Even though there are endogenous mechanisms for taurine production in neural cells, an exogenous supply of taurine is required to meet physiological needs. Taurine is required for optimal postnatal brain development; however, its brain concentration decreases with age. Synthesis of taurine in the central nervous system (CNS) occurs predominantly in astrocytes. A metabolic coupling between astrocytes and neurons has been reported, in which astrocytes provide neurons with hypotaurine as a substrate for taurine production. Taurine has antioxidative, osmoregulatory, and anti-inflammatory functions, among other cytoprotective properties. Astrocytes release taurine as a gliotransmitter, promoting both extracellular and intracellular effects in neurons. The extracellular effects include binding to neuronal GABAA and glycine receptors, with subsequent cellular hyperpolarization, and attenuation of N-methyl-D-aspartic acid (NMDA)-mediated glutamate excitotoxicity. Taurine intracellular effects are directed toward calcium homeostatic pathway, reducing calcium overload and thus preventing excitotoxicity, mitochondrial stress, and apoptosis. However, several physiological aspects of taurine remain unclear, such as the existence or not of a specific taurine receptor. Therefore, further research is needed not only in astrocytes and neurons, but also in other glial cells in order to fully comprehend taurine metabolism and function in the brain. Nonetheless, astrocyte’s role in taurine-induced neuroprotective functions should be considered as a promising therapeutic target of several neuroinflammatory, neurodegenerative and psychiatric diseases in the near future. This review provides an overview of the significant relationship between taurine and astrocytes, as well as its homeostatic and neuroprotective role in the nervous system.

타우린은

뇌에 가장 풍부한 유리 아미노산으로 간주됩니다.

신경 세포에서

타우린이 생성되는 내인성 메커니즘이 있지만,

생리적 요구를 충족하려면

타우린의 외인성 공급이 필요합니다.

타우린은

출생 후 최적의 뇌 발달을 위해 필요하지만

나이가 들면서 뇌 농도가 감소합니다.

중추신경계(CNS)에서

타우린의 합성은

주로 성상교세포에서 일어납니다.

성상 세포와 뉴런 사이의 대사 결합이 보고되었는데,

성상 세포는 타우린 생성을 위해

뉴런에 저타우린을 기질로 제공합니다.

타우린은

다른 세포 보호 특성 중에서도

항산화, 산화질소 조절 및 항염증 기능을 가지고 있습니다.

만성 신경 퇴행성 질환인 알츠하이머병(AD)은 치매의 주요 원인입니다. 과도하게 활성화된 미세아교세포는 아밀로이드 베타(Aβ) 및 인산화 타우(포스포타우) 축적이 AD 뇌에 축적되는 것과 관련이 있습니다. 타우린은 항염증 효과를 포함한 다양한 생리학적 기능을 가진 아미노산으로, 알츠하이머병에서 신경 보호 효과가 있는 것으로 보고되었습니다. 그러나 미세아교세포 매개성 AD에서 타우린의 역할은 아직 명확하지 않습니다. 여기에서는 1% 타우린 물을 투여한 쥐와 증류수(DW)를 투여한 쥐를 비교하여 타우린이 노화 촉진 마우스(SAMP8) 쥐의 뇌에 미치는 영향을 조사했습니다. 타우린을 처리한 마우스의 뇌에서 대조군 마우스에 비해 타우린과 타우린 수송체(TAUT)의 수치가 증가하는 것을 관찰했습니다. 면역조직화학 및 웨스턴 블롯 분석 결과 타우린이 해마와 피질에서 활성화된 미세아교세포의 수, 포스포타우 및 Aβ 침착 수준을 현저히 감소시키는 것으로 나타났습니다. 골수성 세포-2(TREM2)에서 발현되는 트리거 수용체는 알츠하이머병 발병을 예방하는 것으로 알려져 있습니다. 타우린은 해마와 피질에서 TREM2 발현을 상향 조절합니다. 결론적으로, 본 연구는 타우린 치료가 포스포타우와 Aβ의 축적을 감소시킴으로써 미세아교세포의 과활성화를 방지하기 위해 TREM2를 상향 조절할 수 있음을 시사하며, 새로운 AD 예방 전략에 대한 통찰력을 제공합니다.

성상교세포는

타우린을 신경교 전달 물질로 방출하여

신경세포의 세포 외 및 세포 내 효과를 모두 촉진합니다.

세포 외 효과에는

신경세포의 GABAA 및 글리신 수용체와의 결합과

그에 따른 세포 과분극, N-메틸-D-아스파르트산(NMDA) 매개

글루타메이트 흥분 독성 약화 등이 있습니다.

타우린의 세포 내 효과는

칼슘 항상성 경로를 통해 칼슘 과부하를 줄여

흥분성 독성, 미토콘드리아 스트레스 및 세포 사멸을 예방합니다.

그러나

특정 타우린 수용체의 존재 여부와 같이

타우린의 여러 생리학적 측면은 아직 명확하지 않습니다.

따라서

뇌에서 타우린 대사와 기능을 완전히 이해하기 위해서는

성상 세포와 뉴런뿐만 아니라 다

른 신경교 세포에 대한 추가 연구가 필요합니다.

그럼에도 불구하고

타우린에 의한 신경 보호 기능에서 성상교세포의 역할은

가까운 미래에 여러 신경염증, 신경 퇴행성 및 정신 질환의

유망한 치료 표적으로 고려되어야 합니다.

이 리뷰에서는

타우린과 성상세포 사이의 중요한 관계와 신경계에서

타우린의 항상성 및 신경 보호 역할에 대한 개요를 제공합니다.

Introduction

More than 900 natural amino acids are currently known, although only around 2% of them are encoded in the genetic code of eukaryotes and used to synthesize proteins, thereby called “proteinogenic amino acids” (Yamane et al., 2010). The other 98% correspond to “non-proteinogenic” or “non-coded” amino acids, such as taurine, which are not coded into the DNA and are therefore not involved in protein synthesis, but have important physiological functions (Popova and Koksharova, 2016; Fichtner et al., 2017). Taurine is considered the most abundant free amino acid present in the brain, retina, and muscle (Ripps and Shen, 2012). For example, human levels of taurine can range from 1 to 20 μmol/g in the brain, 30 to 40 μmol/g in the retina, and around 50 to 100 μmol/L in plasma (Wójcik et al., 2010).

The word taurine comes from the Latin taurus, meaning bull, the species from which it was first isolated (Caspi et al., 2018). Taurine (2-aminoethanesulfonic acid) is a beta-amino acid, with a molecular weight of 125.15 g/mol and a wide distribution in animal tissues (Caspi et al., 2018). It differs from other amino acids, due to the position of its amino group on the beta-carbon and the presence of a sulfonic acid group with a low pKa instead of the conventional carboxylic acid group (Hayes and Sturman, 1981). Taurine is endogenously synthesized in mammalian tissues, especially in the brain, heart, retina, and liver cells as part of the L-cysteine and L-methionine metabolic pathway (Huxtable, 1992). This process requires vitamin B6 as an enzyme cofactor; therefore, its dietary deficiency can lead to taurine depletion (Park and Linkswiler, 1970; Spinneker et al., 2007). Even though there are endogenous mechanisms for taurine production, an exogenous supply of taurine is required to meet physiological needs, especially in infants, in which taurine is a conditionally essential amino acid (Papet et al., 2019; Wu, 2020). Moreover, taurine is highly enriched in meat, seafood, fish, and milk (Froger et al., 2014), and a major component of energy drinks, along with caffeine and B-group vitamins (Piccioni et al., 2021). Taurine uptake by tissues is predominantly mediated by the chloride sodium-dependent taurine transporter (TauT) encoded by the SLC6A6 gene (Baliou et al., 2020). However, taurine and hypotaurine transport has also been described through the GABA transporter 2 (GAT-2) in the blood-brain barrier (BBB) (Nishimura et al., 2018). Although TauT transporter predominates in the plasma membrane, studies with mouse fibroblasts models have identified its presence in the nucleus (Voss et al., 2004), whereas other models with HeLa cells propose its existence within the mitochondria (Suzuki et al., 2002).

소개

현재 900개 이상의 천연 아미노산이 알려져 있지만,

그중 약 2%만이 진핵생물의 유전 암호에 암호화되어

단백질 합성에 사용되므로

“단백질 생성 아미노산”이라고 불립니다(Yamane et al., 2010).

나머지 98%는 타우린과 같이 DNA에 코딩되어 있지 않아

단백질 합성에 관여하지 않지만

중요한 생리적 기능을 하는 “비단백질성” 또는 “비코딩” 아미노산에 해당합니다(Popova and Koksharova, 2016; Fichtner et al., 2017).

타우린은

뇌, 망막, 근육에 존재하는

가장 풍부한 유리 아미노산으로 간주됩니다(Ripps and Shen, 2012).

예를 들어,

인간의 타우린 수치는

뇌에서 1~20μmol/g,

망막에서 30~40μmol/g,

혈장에서 약 50~100μmol/L입니다(Wójcik et al., 2010).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941169/

망막 장애는 실명의 주요 원인이며 활성산소와 항산화제(항산화제 선호) 간의 불균형 또는 산화 환원 신호 전달 및 제어 장애로 인해 발생합니다. 실제로 산화 스트레스가 망막 퇴행성 질환의 주요 원인 중 하나라는 것은 잘 알려져 있습니다. 건강기능식품을 사용한 다양한 접근 방식은 이러한 질환을 보호하는 효과를 가져왔습니다. 이 리뷰에서는 망막 신경 퇴행성 질환에서 산화 스트레스의 영향과 망막 조직의 산화 손상을 피하거나 대응하기 위한 잠재적 전략에 대해 타우린에 초점을 맞추어 논의합니다. 타우린이 퇴행성 망막 질환의 진행을 늦추는 데 효과적일 수 있다는 데이터가 증가함에 따라 타우린이 이러한 질환의 예방 또는 보조 치료제로서 유망한 후보가 될 수 있음을 시사하고 있습니다. 타우린 보충제가 작용하는 메커니즘은 주로 산화 스트레스 감소와 관련이 있습니다. 특히 망막 환원 글루타치온, 말론다이알데히드, 슈퍼옥사이드 디스뮤타제 및 카탈라아제 활성을 개선하는 것으로 입증되었습니다. 항아포토시스 효과도 관여하지만, 타우린이 망막 손상에 대해 발휘하는 보호 메커니즘은 아직 더 연구해야 할 부분이 많습니다.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10142897/

보고에 따르면 적절한 용량의 타우린을 보충하면 시각적 피로를 줄이는 데 도움이 될 수 있다고 합니다. 현재 눈 건강과 타우린에 관한 연구는 어느 정도 진전을 이루었지만, 체계적인 요약이 부족하여 시각 피로 완화에 타우린을 적용하는 데는 소홀히 다루어지고 있습니다. 따라서 이 논문에서는 내인성 대사 경로와 외인성 식이 경로를 포함하여 타우린의 공급원에 대한 체계적인 검토와 외인성 타우린의 분포 및 생성에 대한 자세한 검토를 제공합니다. 시각피로 생성의 기초가 되는 생리적 기전을 요약하고, 타우린의 섭취 안전성 및 시각피로 완화 작용 기전 등 시각피로 완화에 대한 연구 성과를 검토하여 시각피로 완화 기능성 식품에 타우린을 개발 및 적용하는 데 참고할 수 있는 근거와 영감을 제공하고자 합니다.

타우린이라는 단어는

타우린이 처음 분리된 종인 황소를 의미하는

라틴어 황소자리에서 유래했습니다(Caspi et al., 2018).

타우린(2- 아미노에탄설폰산)은

베타 아미노산으로 분자량이 125.15 g/mol이고

동물 조직에 광범위하게 분포합니다(Caspi et al., 2018).

그것은 베타 탄소에서

아미노기의 위치와 기존의 카르복실산 그룹 대신

낮은 pKa를 가진 술폰산 그룹의 존재로 인해

다른 아미노산과 다릅니다 (Hayes and Sturman, 1981).

타우린은

포유류 조직,

특히 뇌, 심장, 망막, 간세포에서 L-시스테인 및 L-메티오닌 대사 경로의 일부로서

내인성적으로 합성됩니다(Huxtable, 1992).

분석 대상에는 25개의 RCT에 참여한 1024명이 포함되었습니다. 연구에 사용된 타우린의 일일 복용량은 0.5g/일에서 6g/일 사이였으며, 추적 관찰 기간은 5일에서 365일 사이였습니다. 타우린 보충제는 대조군에 비해 SBP(가중평균차[WMD] = -3.999 mmHg, 95% 신뢰구간[CI] = -7.293 ~ -0.706, p= 0.017), DBP(WMD = -1.509 mmHg, 95% CI = -2. 479에서 -0.539, p= 0.002), FBG(WMD: -5.882 mg/dL, 95% CI: -10.747에서 -1.018, p= 0.018), TG(WMD: -18.315 mg/dL, 95% CI: -25.628에서 -11.002, p<0.001)에서 유의한 차이가 있었지만 HDL-C(WMD: 0.644 mg/dl, 95% CI: -0.244에서 1.532, p= 0.155), 그렇지 않은 것으로 밝혀졌습니다. 메타 회귀 분석 결과, 용량에 따라 DBP(계수 = -0.0108 mmHg/g/g, p= 0.0297)와 FBG(계수 = -0.0445 mg/dL/g/g, p= 0.0273)가 감소한 것으로 나타났습니다. 대조군에 비해 유의미한 부작용은 관찰되지 않았습니다. 결론 타우린 보충제는 여러 MetS 관련 요인에 긍정적인 영향을 미치므로 MetS의 위험이 있거나 이미 경험하고 있는 사람이 식단에 추가할 수 있는 잠재적인 보충제가 될 수 있습니다. 향후 연구에서는 타우린의 용량 최적화 전략과 MetS 관리를 위한 타우린의 잠재적인 장기적 이점을 탐구할 수 있습니다.

이 과정에는

효소 보조 인자로서 비타민 B6가 필요하므로

식이 결핍은

타우린 고갈로 이어질 수 있습니다(박과 링크스윌러, 1970; 스피네커 등, 2007).

타우린 생산에는

내인성 메커니즘이 있지만,

타우린이 조건부 필수 아미노산인 유아의 경우

생리적 요구를 충족하려면

타우린의 외인성 공급이 필요합니다(Papet et al., 2019; Wu, 2020).

또한

타우린은

육류, 해산물, 생선, 우유에 풍부하며(Froger et al., 2014),

카페인 및 비타민 B군과 함께

에너지 음료의 주요 성분이기도 합니다(Piccioni et al., 2021).

조직에 의한 타우린 흡수는

주로 SLC6A6 유전자에 의해 코딩된

염화물 나트륨 의존 타우린 수송체(TauT)에 의해

매개됩니다(발리우 외., 2020).

그러나

타우린과 저타우린 수송은

혈액뇌장벽(BBB)의 GABA 수송체 2(GAT-2)를 통해서도

설명되었습니다(Nishimura et al., 2018).

뇌 모세혈관에 존재하는 혈액-뇌 장벽(BBB)은 뇌의 정상적인 기능과 발달에 필수적인 장벽 메커니즘을 구성합니다. 인접한 내피 세포 사이에 단단한 접합부가 존재하면 세포 외액과 혈장 사이의 투과성과 분자의 이동이 제한됩니다. 세포와 세포의 부착을 조절하는 단백질 복합체도 세포막을 내강(혈액을 향한 쪽)과 외강(뇌를 향한 쪽)으로 나눌 수 있도록 양극화하여 뇌에 들어오고 나가는 각 용질은 두 막을 모두 통과해야 합니다. BBB의 양쪽에 서로 다른 분포를 가진 여러 아미노산(AA) 수송 시스템이 설명되어 있습니다. 넓은 의미에서 최소 5가지 이상의 촉진 수송체 시스템이 있으며, 이들 모두는 내강 막에서 발견됩니다. 이러한 수송체 중 일부는 소수의 기질 그룹에 매우 특이적이며 BBB의 내강 쪽에만 위치합니다. 그러나 두 가지 주요 촉진 운반체인 시스템 L과 시스템 y+는 비대칭적으로 양쪽 막에 모두 위치합니다. 이러한 Na+ 독립적 수송체의 위치는 뇌에서 AA의 가용성과 내피 세포를 통한 양방향 수송을 보장합니다. 반면에 Na+ 이온의 이동과 함께 농도 구배에 따라 AA를 운반하는 여러 Na+ 의존적 수송 시스템이 있습니다. 이러한 활성 수송체의 대부분은 복막에만 존재하며 뇌에서 내피 세포로의 AA 유출을 담당합니다. 이들은 Na+와 결합되어 있기 때문에 나트륨 펌프 Na+/K+-ATPase도 BBB의 이 복부 쪽에서 많이 발현됩니다. 세포 내부로 들어가면 내강막에 위치한 촉진 수송체가 내피 세포에서 혈액으로 배출되는 것을 매개합니다. 요약하면, 내강막과 외강막 사이의 이러한 수송 시스템의 양극화된 분포와 하나 이상의 수송체가 동일한 기질을 운반할 수 있다는 사실은 뇌 안팎으로 AA의 공급과 배출을 보장하여 뇌의 항상성과 적절한 기능을 제어합니다.

AAs Facilitative Na + -independent transporters in the BBB. Amino acids are transported by systems L and y +  from blood to ECs and then into the brain. These two systems are located at both sides of the cell membrane. However other systems will also be present but exclusively at the luminal side of the BBB. The location of these transporters and their main substrates is depicted in the figure. AAs BBB의 촉진성 Na+-독립 수송체. 아미노산은 시스템 L과 y+에 의해 혈액에서 EC로 운반된 다음 뇌로 운반됩니다. 이 두 시스템은 세포막의 양쪽에 위치합니다. 그러나 다른 시스템도 존재하지만 BBB의 내강 쪽에만 존재합니다. 이러한 수송체와 주요 기질의 위치는 그림에 표시되어 있습니다.

TauT 수송체는

혈장막에 우세하지만,

마우스 섬유아세포 모델을 사용한 연구에서는

핵에 존재하는 것으로 확인된 반면(Voss et al., 2004),

HeLa 세포를 사용한 다른 모델에서는

미토콘드리아 내에 존재하는 것으로 제안되었습니다(Suzuki et al., 2002).

Taurine has diverse functions in the cells, particularly cytoprotective actions through its antioxidative and anti-inflammatory effects (Schaffer and Kim, 2018). This amino acid neutralizes hypochlorous acid through the formation of taurine chloramine, a more stable molecule, and thus, diminishes the generation of reactive oxygen species (ROS) (Weiss et al., 1982). Similarly, taurine conjugates with a tRNA to enhance the expression‎ of the nicotinamide adenine dinucleotide (NAD)-ubiquinone oxidoreductase chain 6, a subunit of the respiratory chain complex I, associated with the reduction of oxidative stress (Jong et al., 2012; Schaffer et al., 2014). Furthermore, taurine deficiency in heart tissue reduces glucose oxidation due to a decrease in pyruvate followed by an increase in lactate (Schaffer et al., 2016). Such a rise in lactate levels increases the NADH/NAD+ ratio and decreases pyruvate dehydrogenase activity, inducing a reduction in total ATP production. Moreover, taurine deficiency leads to reduced fatty acid metabolism, downregulating the expression‎ of peroxisome proliferator-activated receptor alpha (PPARα), an important nuclear receptor protein that promotes the fatty acid β-oxidation (Wen et al., 2019). These results highlight the essential role of taurine in the effective maintenance of cellular energy processes.

On the other hand, taurine works as a gene and transcription factor regulator in different models, including human hepatoma cells HepG2 (Park et al., 2006) and rodent heart (Schaffer et al., 2016). Genes regulated by taurine are involved in amino acid metabolism and protein synthesis. For instance, taurine depletion can provoke abnormal protein folding, thereby affecting longevity and cellular senescence (Ito et al., 2014). Cell injury and mitochondrial oxidative stress causes an imbalance between degradation and biosynthesis/folding of proteins, leading to the accumulation of unfolded or misfolded proteins, activating the unfolded protein response pathway (UPR) (Gharibani et al., 2015; Jong et al., 2015). By suppressing the UPR, taurine diminishes protein degradation, activation of chaperones, autophagy, and apoptosis that attenuates endoplasmic reticulum (ER) stress (Gharibani et al., 2013; Ito et al., 2015). This depicts taurine’s role in the protein quality control systems of the cells and its anti-senescence function.

After its uptake, hypotaurine is oxidized into taurine by the hypotaurine dehydrogenase (Vitvitsky et al., 2011). Extracellular taurine binds to GABAA and glycine receptors augmenting its inhibitory effect (Jia et al., 2008). On the other hand, intracellular taurine concentrations are higher than extracellular levels, making it an organic osmolyte that contributes to the osmotic stress regulation in the cell (Oja and Saransaari, 2017). Moreover, taurine inhibits calcium release from internal stores, such as mitochondria, enhancing intracellular calcium modulation (Wu et al., 2005; Ramila et al., 2015). Other mechanisms described for taurine regulation of calcium influx include actions directed toward calbindin, calreticulin, and the Na+/Ca2+ exchanger in the outer cell membrane (Schaffer et al., 2002; Junyent et al., 2010).

Thus, due to its multiple physiological functions in cells, taurine has been proposed as a novel therapeutic agent for many human diseases including stroke, epilepsy, neurodegenerative diseases like Alzheimer’s disease (AD), retinal degeneration, heart failure, and mitochondrial diseases, such as mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), among others (Schaffer and Kim, 2018). Despite previous research regarding taurine’s effect in different tissues, its role in the nervous system, particularly the functional relationship with astrocytes, remains to be further elucidated. This aspect is important, as astrocytes are considered the main producers of taurine in the central nervous system (CNS) (Vitvitsky et al., 2011). Astrocytes also release taurine as a gliotransmitter, acting on other cells, mainly in neurons. Hence, a deeper understanding of taurine’s effect in astrocytes can contribute to a better insight of its physiological effects, which could potentially be used to ameliorate the course of several nervous system pathologies. This review, therefore, will provide an overview of the significant relationship between taurine and astrocytes, as well as its homeostatic and neuroprotective role in the pathologies of the nervous system.

타우린은

세포에서 다양한 기능을 하며,

특히 항산화 및 항염증 효과를 통해

세포를 보호하는 작용을 합니다(Schaffer and Kim, 2018).

이 아미노산은 보다 안정적인 분자인

타우린 클로라민 taurine chloramine 을 형성하여

차아염소산 hypochlorous acid 을 중화시켜

활성산소 종(ROS)의 생성을 감소시킵니다(Weiss et al., 1982).

This amino acid neutralizes hypochlorous acid through the formation of taurine chloramine, a more stable molecule, and thus, diminishes the generation of reactive oxygen species (ROS) 

https://www.spandidos-publications.com/10.3892/mmr.2021.12242

Taurine is a fundamental mediator of homeostasis that exerts multiple roles to confer protection against oxidant stress. The development of hypertension, muscle/neuro‑​associated disorders, hepatic cirrhosis, cardiac dysfunction and ischemia/reperfusion are examples of some injuries that are linked with oxidative stress. The present review gives a comprehensive description of all the underlying mechanisms of taurine, with the aim to explain its anti‑oxidant actions. Taurine is regarded as a cytoprotective molecule due to its ability to sustain normal electron transport chain, maintain glutathione stores, upregulate anti‑oxidant responses, increase membrane stability, eliminate inflammation and prevent calcium accumulation. In parallel, the synergistic effect of taurine with other potential therapeutic modalities in multiple disorders are highlighted. Apart from the results derived from research findings, the current review bridges the gap between bench and bedside, providing mechanistic insights into the biological activity of taurine that supports its potential therapeutic efficacy in clinic. In the future, further clinical studies are required to support the ameliorative effect of taurine against oxidative stress.

마찬가지로

타우린은 호흡기 사슬 복합체 I의 하위 단위인

니코틴아미드 아데닌 디뉴클레오티드(NAD)-유비퀴논 산화환원효소 사슬 6의 발현을 향상시키는

tRNA와 결합하여

산화 스트레스 감소와 관련이 있습니다(Jong et al., 2012; Schaffer et al., 2014).

Similarly, taurine conjugates with a tRNA to enhance the expression‎ of the nicotinamide adenine dinucleotide (NAD)-ubiquinone oxidoreductase chain 6, a subunit of the respiratory chain complex I, associated with the reduction of oxidative stress (

또한

심장 조직에서 타우린이 결핍되면

피루브산염이 감소하고

젖산염이 증가하여 포도당 산화가 감소합니다(Schaffer et al., 2016).

https://www.nature.com/articles/s41598-023-37978-1

전신 결핍이 없는 반려견의 울혈성 심부전(CHF) 치료에서 타우린의 역할은 아직 밝혀지지 않았습니다. 타우린은 결핍 대체 외에도 심장 건강에 유익한 효과가 있을 수 있습니다. 우리는 자연적으로 발생하는 CHF를 가진 개에게 경구용 타우린 보충제를 투여하면 레닌-안지오텐신 알도스테론 시스템(RAAS)이 억제될 것이라는 가설을 세웠습니다. 안정된 CHF를 가진 14마리의 개에게 경구 타우린을 투여했습니다. CHF에 대한 배경 푸로세미드 및 피모벤단 치료에 타우린 보충제를 추가하기 전과 2주 후에 혈청 생화학 변수, 혈중 타우린 농도, RAAS 변수에 대한 종합적인 분석을 비교했습니다. 전혈 타우린 농도는 보충제 투여 후 증가했습니다(전 중앙값 408 nMol/mL, 범위 248-608, 후 중앙값 493 nMol/mL, 범위 396-690; P = .006). 알도스테론 대 안지오텐신 II 비율(AA2)은 타우린 보충 후 유의하게 감소했지만(중앙값 1.00, 범위 0.03-7.05 이전과 중앙값 0.65, 범위 0.01-3.63 이후; P = .009), 다른 RAAS 성분은 시점 간에 유의한 차이가 없었습니다. 일부 개는 타우린을 섭취한 후 RAAS 대사산물이 현저하게 감소했으며, 이러한 개는 고전적인 RAAS 대사산물이 현저하게 감소하지 않은 개보다 최근에 CHF 치료를 위해 입원했을 가능성이 더 높았습니다. 전반적으로 타우린은 이 개 그룹에서 AA2만 낮추었지만, 일부 개는 RAAS가 억제된 것으로 나타나는 등 반응의 이질성이 나타났습니다.

이러한

젖산염 수치의 상승은

NADH/NAD+ 비율을 증가시키고

피루브산 탈수소효소 활성을 감소시켜

총 ATP 생산량 감소를 유도합니다.

https://www.nature.com/articles/s42255-023-00761-7

세포 대사의 전반적인 변화가 인간의 신장 질환에 어떻게 기여하는지에 대한 우리의 이해는 아직 불완전하게 이해되고 있습니다. 여기에서는 니코틴아마이드 아데닌 디뉴클레오티드( NAD+ ) 결핍이 미토콘드리아 기능 장애를 일으켜 염증과 신장 질환 발병을 유발한다는 사실을 보여줍니다. 건강한 사람과 질병에 걸린 사람의 신장에서 편견 없는 글로벌 대사체학을 사용하여 NAD+ 결핍을 질병의 징후로 식별합니다. 또한 수컷 생쥐의 시스플라틴 또는 허혈 재관류 유도 신장 손상 모델을 사용하여 NAD+ 고갈을 관찰했습니다. 니코틴아마이드 리보사이드 또는 니코틴아마이드 모노뉴클레오타이드를 보충하면 NAD+ 수준이 회복되고 신장 기능이 개선되는 것을 확인했습니다. 시스플라틴 노출은 미토콘드리아 RNA(mtRNA)의 세포질 누출과 세포질 패턴 인식 수용체 레티노산 유도 유전자 I(RIG-I)의 활성화를 유발하며, 이 두 가지 모두 NAD+ 회복을 통해 개선될 수 있다는 사실을 발견했습니다. RIG-I 녹아웃(KO) 수컷 마우스는 시스플라틴으로 유발된 신장 질환으로부터 보호됩니다. 요약하면, 우리는 mtRNA의 세포질 방출과 RIG-I 활성화가 신장 질환에 기여하는 NAD+ 민감성 메커니즘임을 입증했습니다.

https://www.nature.com/articles/s41598-019-39419-4

리 증후군은 신경 장애, 대사 이상, 조기 사망을 특징으로 하는 미토콘드리아 질환입니다. 리 증후군은 아직 치료법이 없어 새로운 치료 표적이 절실히 필요합니다. 리 증후군의 마우스 모델인 Ndufs4-KO 마우스에서 복합체 I 결핍이 NAD+ 수치의 감소와 NAD+ 산화 환원 불균형을 초래한다는 사실을 발견했습니다. 우리는 NAD+ 수치를 높이면 Ndufs4-KO 마우스에 도움이 될 것이라는 가설을 테스트했습니다. NAD+ 전구체인 니코틴아미드 모노뉴클레오티드(NMN)를 투여한 결과 Ndufs4-KO 마우스의 수명이 연장되고 젖산증이 약화되었습니다. NMN은 뇌에는 영향을 미치지 않으면서 NAD+ 산화 환원 불균형을 정상화하고 Ndufs4-KO 골격근의 HIF1a 축적을 낮춤으로써 수명을 늘렸습니다. NMN은 HIF1a 분해에 필수적인 대사 산물인 알파-케토글루타레이트(KG) 수치를 Ndufs4-KO 근육에서 상향 조절했습니다. KG의 보충이 Ndufs4-KO 마우스를 치료할 수 있는지 테스트하기 위해 세포 투과성 KG인 디메틸 케토글루타레이트(DMKG)를 투여했습니다. DMKG는 Ndufs4-KO 마우스의 수명을 연장하고 신경학적 표현형의 발병을 지연시켰습니다. 이 연구는 리 증후군을 치료하기 위해 약리학적으로 표적화할 수 있는 치료 메커니즘을 확인했습니다.

또한

타우린 결핍은

지방산 대사를 감소시켜

지방산 β 산화를 촉진하는 중요한 핵 수용체 단백질인

퍼옥시좀 증식 활성화 수용체 알파(PPARα)의 발현을

하향 조절합니다(Wen et al., 2019).

이러한 결과는

세포 에너지 과정을 효과적으로 유지하는 데

타우린이 필수적인 역할을 한다는 것을 강조합니다.

타우린은 다양한 세포 보호 활성을 가진 풍부한 β-아미노산입니다. 일부 종에서는 타우린이 필수 영양소이지만 사람에게는 준필수 영양소로 간주되지만 타우린이 부족한 세포는 주요 병리를 보입니다. 이러한 발견은 타우린의 치료제로서의 잠재적 사용에 대한 관심을 불러일으켰습니다. 타우린이 울혈성 심부전에 효과적인 치료법이라는 사실이 밝혀지면서 타우린을 다른 질병에 대한 치료제로 연구하게 되었습니다. 오늘날 타우린은 일본에서 울혈성 심부전 치료제로 승인되었으며 다른 여러 질병의 치료에도 가능성을 보이고 있습니다. 이 리뷰에서는 근육, 중추신경계 및 심혈관계 질환 치료에서 타우린의 역할을 뒷받침하는 연구를 요약하여 소개합니다. 또한 타우린은 미토콘드리아 질환, 미토콘드리아 뇌병증, 젖산증, 뇌졸중 유사 에피소드(MELAS) 치료에 매우 효과적이며 당뇨병과 같은 대사 질환과 관절염 같은 염증성 질환의 치료에 새로운 접근법을 제시합니다. 또한 이러한 치료 작용의 근간이 되는 타우린의 기능(항산화, 에너지 대사, 유전자 발현, ER 스트레스, 신경 조절, 품질 관리 및 칼슘 항상성 조절)에 대해서도 다룹니다.

한편,

타우린은

인간 간암 세포 HepG2(박 등, 2006)와 설치류 심장(샤퍼 등, 2016)을 포함한

다양한 모델에서 유전자 및 전사인자 조절자로서 작용합니다.

타우린에 의해 조절되는 유전자는

아미노산 대사와 단백질 합성에 관여합니다.

예를 들어

타우린 고갈은

비정상적인 단백질 폴딩을 유발하여

수명과 세포 노화에 영향을 미칠 수 있습니다(Ito et al., 2014).

세포 손상과 미토콘드리아 산화 스트레스는

단백질의 분해와 생합성/접힘 사이의 불균형을 유발하여

접히지 않거나 잘못 접힌 단백질의 축적을 유발하여

접히지 않은 단백질 반응 경로(UPR)를 활성화합니다(Gharibani et al., 2015; Jong et al., 2015).

타우린은

UPR을 억제함으로써

단백질 분해, 샤페론의 활성화, 자가포식 및 세포 사멸을 감소시켜 소

포체(ER) 스트레스를 약화시킵니다(Gharibani et al., 2013; Ito et al., 2015).

https://www.nature.com/articles/s41392-023-01570-w

소포체(ER)는 단백질 항상성, 즉 “단백질 항상성”을 위한 품질 관리 소기관으로 기능합니다. 단백질 품질 관리 시스템에는 ER 관련 분해, 단백질 샤프롱 및 자가포식이 포함됩니다. ER에 잘못 접히거나 펼쳐진 단백질이 축적되어 단백질 항상성이 깨지면 ER 스트레스가 활성화됩니다. ER 스트레스는 단백질 키나아제 R 유사 ER 키나아제, 전사인자 6 및 이노시톨 필요 효소 1을 활성화하여 단백질 항상성을 회복하기 위해 적응성 미접힘 단백질 반응을 활성화합니다. ER 스트레스는 전사 및 단백질 처리 등 후성유전학적 수준에서 다방면으로 작용합니다. 축적된 데이터에 따르면 녹내장, 당뇨병성 망막증, 연령 관련 황반변성, 색소성 망막염, 색소변성, 백내장, 안구 종양, 안구 표면 질환, 근시 등 다양한 안구 질환에 관련된 단백질 항상성 및 기타 다양한 기능에 중요한 역할을 하는 것으로 나타났습니다. 이 리뷰에서는 앞서 언급한 안구 질환의 근본적인 분자 메커니즘을 응급실 스트레스 관점에서 요약합니다. 약물(화학물질, 신경성장인자, 나노입자), 유전자 치료, 줄기세포 치료는 ER 스트레스를 완화하여 안구 질환을 치료하는 데 사용됩니다. 안구 질환에 대한 새로운 치료 전략을 제공하기 위해 ER 스트레스를 표적으로 하는 치료법의 발전에 대해 설명합니다.

이는

세포의 단백질 품질 관리 시스템에서

타우린의 역할과 노화 방지 기능을 설명합니다.

하이포타우린은

섭취 후 하이포타우린 탈수소효소에 의해

타우린으로 산화됩니다(Vitvitsky et al., 2011).

세포 외 타우린은

GABAA 및 글리신 수용체에 결합하여

억제 효과를 강화합니다(Jia et al., 2008).

반면 세포 내 타우린 농도는

세포 외 수준보다 높기 때문에

세포의 삼투압 스트레스 조절에 기여하는

유기 삼투물질로 작용합니다(Oja and Saransaari, 2017).

또한

타우린은

미토콘드리아와 같은 내부 저장소로부터 칼슘 방출을 억제하여

세포 내 칼슘 조절을 향상시킵니다(Wu et al., 2005; Ramila et al., 2015).

타우린이

칼슘 유입을 조절하는 다른 메커니즘으로는

칼빈딘, 칼레티쿨린 및 세포 외막의 Na+/Ca2+ 교환기를 향한 작용이 있습니다(Schaffer et al., 2002; Junyent et al., 2010).

따라서

타우린은

세포 내 다양한 생리학적 기능으로 인해

뇌졸중, 간질, 알츠하이머병(AD)과 같은 신경 퇴행성 질환,

망막 변성, 심부전, 젖산증을 동반한 미토콘드리아 뇌증 및

뇌졸중 유사 에피소드(MELAS) 등의

미토콘드리아 질환 등 많은 인간 질병의 새로운 치료제로 제안되고 있습니다(Schaffer and Kim, 2018).

타우린이 다양한 조직에 미치는 영향에 관한 이전 연구에도 불구하고

신경계에서의 역할,

특히 성상세포와의 기능적 관계는 아직 더 밝혀져야 할 부분입니다.

성상 세포는

중추 신경계(CNS)에서

타우린의 주요 생산자로 간주되기 때문에

이 측면은 중요합니다(Vitvitsky 등, 2011).

성상 세포는

또한 타우린을

신경 전달 물질로 방출하여

주로 뉴런에서 다른 세포에 작용합니다.

따라서

타우린이

성상교세포에 미치는 영향을 더 깊이 이해하면

타우린의 생리적 효과를 더 잘 파악할 수 있으며,

이는 여러 신경계 병리를 개선하는 데 잠재적으로 사용될 수 있습니다.

따라서 이 리뷰에서는

타우린과 성상세포 사이의 중요한 관계와

신경계 병리에서 타우린의 항상성 및 신경 보호 역할에 대한 개요를 제공합니다.

Taurine and Brain

Taurine is one of the most abundant amino acids in the human brain, although, its concentration declines with age, with decreasing values that range from 4–20 μmol/g during development to 1–9 μmol/g at adulthood (Wójcik et al., 2010; Roysommuti and Wyss, 2015). A study in adult male Wistar rats identified heterogeneous concentrations of taurine among different brain regions, showing higher levels in the pyriform cortex, caudate-putamen, cerebellum, and supraoptic nucleus, and lower concentrations in the midbrain reticular formation (Palkovits et al., 1986). During the rat’s postnatal growth, there is an increase in GABA, taurine and hypotaurine levels, which progressively decline until adulthood, in which its concentration reaches a plateau (Kontro et al., 1984). Moreover, a study in aged and young Wistar rats evidenced a significant decrease in the levels of taurine in the cerebellum, cortex, nucleus accumbens, and striatum of the aged animals (Benedetti et al., 1991). This suggests that taurine is required for an optimal postnatal brain development, which is supported by previous research evidencing disturbed maturation and migration of neurons, and a decreased number of astrocytes, in cat and monkey’s brains with taurine deficiency (Sturman, 1992; Pasantes-Morales, 2017).

Taurine Synthesis and Transport

Synthesis of taurine in the brain follows a similar enzymatic pathway compared with other tissues, such as muscle, adipose tissue and liver, however, the rate of production differs from one to another (Roysommuti and Wyss, 2015). This explains the slight differences in taurine concentrations between the brain and other tissues, reporting 9 μmol/g in the adult brain compared to 6 μmol/g in heart, 5 μmol/g in skeletal muscle, 2 μmol/g in the liver, and up to 40 μmol/g in retina (Wójcik et al., 2010). Three main pathways have been described for taurine synthesis in the brain (Hayes and Sturman, 1981). The first, and most common, depends on cysteine as its primary substrate, which is oxidized by cysteine dioxygenase to form cysteine sulfinic acid (CAD), and finally transformed to hypotaurine by cysteine sulfinic acid decarboxylase (CSAD) (Pasantes-Morales, 2017). The second pathway uses extracellular methionine as primary substrate, which undergoes different enzymatic reactions to form cysteine, which then follows the first pathway. The third pathway consists in the degradation of coenzyme-A yielding cysteamine, which is later transformed to hypotaurine by 2-aminoethanethiol dioxygenase (Banerjee et al., 2008). All three pathways form hypotaurine, which can be either transformed into taurine and released as such, or be released as hypotaurine and undergo its conversion to taurine in another cell, such as neurons (Roysommuti and Wyss, 2015; Figure 1).

FGURE 1

Figure 1. Mechanistic action of taurine in the brain. Taurine is synthesized in astrocytes from extracellular methionine and cysteine through three distinct pathways. It is exported as hypotaurine or taurine into the extracellular space; however, the mechanism in which hypotaurine exits the astrocyte and enters the neuron remains uncertain. Transport of taurine depends on TauT1 and TauT2 transporters, for neurons and astrocytes, respectively. The mechanism in which taurine exits the pre-synaptic neuron remains to be confirmed. Taurine acts as a full agonist for GABAA, GABAB, and glycine receptors in the post-synaptic neuron, increasing chloride conductance, and thus, hyperpolarizing the cell. The presence of a post-synaptic taurine receptor remains controversial. Taurine is represented by an inverted red triangle. ADO, aminoethanethiol dioxygenase; CBS, 2-cystathionine ß-synthase; CD, cysteine desulfurase/γ-cystathionase; CDO, cysteine dioxygenase; CSD, cysteine sulfinate decarboxylase; GlyR, glycine receptor; HD, hypotaurine dehydrogenase; TauT1, taurine transporter type 1; TauT2, taurine transporter type 2; SAT, S-adenosyl transferase; uncertain receptor/transporter–represented by a question mark.

Regarding neural cells, taurine predominates in astrocytes and neurons, demonstrated by the presence of specific enzymatic machinery needed for its synthesis (Ripps and Shen, 2012). Moreover, a metabolic coupling between astrocytes and neurons has been reported, in which astrocytes provide neurons with hypotaurine as a substrate for taurine production (Vitvitsky et al., 2011). Given the fact that neurons lack CSAD (Tappaz et al., 1994), they are unable to synthetize hypotaurine from cysteine, and thus, rely on astrocytic hypotaurine supply (Brand et al., 1997). A possible rationale behind the absence of a complete taurine synthetic pathway in neurons is that it spares cysteine for glutathione synthesis, prioritizing sulfur use for ROS buffering and xenobiotic detoxification in neurons (Banerjee et al., 2008). This suggests that de novo synthesis of taurine occurs predominantly in astrocytes, whereas neuronal concentration of taurine mostly depends on extracellular hypotaurine provided by astrocytes, and its conversion to taurine through intracellular enzymatic and non-enzymatic reactions. Furthermore, this explains why there is a lower concentration of both hypotaurine and taurine in neurons compared to that in astrocytes (Vitvitsky et al., 2011).

The cells in the brain can synthetize taurine from cysteine or methionine as mentioned above (Peck and Awapara, 1967), or import it via sodium and chloride dependent transporters TauT1 and TauT2 (Banerjee et al., 2008). TauT1 transporters predominate in cerebellar Purkinje cells and in bipolar cells in the retina, whereas TauT2 is associated with astrocytes and CA1 pyramidal cells in the hippocampus (Pow et al., 2002). In terms of regulation, Kang et al. (2002) used an in vitro BBB model to demonstrate TauT transporter upregulation in response to cellular damage, osmolality and declining taurine concentrations. Other factors such as hyperglycemia and oxidative stress also contribute to the TauT transporter regulation (Baliou et al., 2020).

Taurine Release, Degradation, and Effects on Cellular Receptors

Taurine has a high transcellular gradient, with larger intracellular than extracellular concentrations, making it susceptible to changes in ionic concentrations (Oja and Saransaari, 2017). Furthermore, taurine’s molecular characteristics makes it more hydrophilic and less capable of trespassing biological membranes due to its sulfonyl group, resulting in a slower spontaneous efflux (Saransaari and Oja, 1992). Therefore, taurine release from the nerve terminal depends mostly on neuronal depolarization (Kamisaki et al., 1996). This is supported by a study by Saransaari and Oja (1991), which demonstrated taurine release by activation of N-methyl-D-aspartic acid (NMDA) and kainate receptors in a rat model. Nonetheless, the existence of taurine synaptic vesicles has not been completely confirmed, therefore it is suspected that its release relies on calcium-independent mechanisms, including volume-sensitive organic anion channels and TauT reverse transport (Kilb and Fukuda, 2017).

The existence of a specific taurine receptor in the human brain remains a controversial matter. Some authors have not ruled out its existence (Wu et al., 1992; Jakaria et al., 2019), while other evidence still questions it (Ripps and Shen, 2012). Several experimental studies in animals have explored, though not confirmed, the presence of the receptor (Kudo et al., 1988; López-Colomé et al., 1991; Frosini et al., 2003). Other authors have further proposed inhibition of the taurine receptor by guanosine-5′-triphosphate (GTP) in a dose-dependent way, implying not only its existence, but also the type of receptor as a metabotropic taurine receptor (mTauR) coupled to inhibitory G-proteins (Wu and Prentice, 2010). Nonetheless, future research is needed in order to corroborate the existence or not of the receptor, not only in neurons but also in other cell types such as glial cells. Further research showed taurine’s inhibitory effect on the protein kinase C (PKC), thereby blocking the phosphorylation and activation of voltage-gated calcium channels (VGCC), and therefore, decreasing calcium influx (Ohno and Nishizuka, 2002). Some authors propose that mTauR, if present, may have a similar effect as GABAB receptors, so that its activation by taurine may lead to the activation of coupled inhibitory G-proteins, such as Go/Gi, which result in the inhibition of L-, N-, and P/Q-type VGCC (Leon et al., 2009; Traynelis et al., 2010; Wu and Prentice, 2010). Thus, the activation of mTauR and inhibitory G-proteins, leads to inhibition of phospholipase C (PLC), reduction in IP3 levels and consequently, inhibition of IP3-mediated release of Ca2+ from the internal storage pools (Leon et al., 2009; Traynelis et al., 2010; Wu and Prentice, 2010; Figure 2).

FGURE 2

Figure 2. Acute neuroprotective effects of taurine in the post-synaptic neuron. Taurine inhibits calcium influx by inhibiting the IP3-mediated calcium release from internal storages and blocking PKC activity, which inhibits phosphorylation and activation of VGCC consequently decreasing calcium entry through these channels. Taurine is represented by an inverted red triangle, while hypotaurine is represented by a blue hexagon. DAG, diacylglycerol; IP3, inositol trisphosphate; mGluR1, metabotropic glutamate receptor type 1; PLC, phospholipase C; PKC, protein kinase C; TauT, taurine transporter; uncertain receptor/transporter–represented by a question mark; VGCC, voltage-gated calcium channels.

Taurine resembles the structure of the neurotransmitter GABA (Kletke et al., 2013; Ochoa-de la Paz et al., 2019). Such resemblance explains taurine’s ability to bind to GABAA receptor (GABAAR), presumably at the interface of α/β subunits binding site. Moreover, taurine has been proposed as an endogenous agonist of the GABAB receptors (GABABR) in adult mouse brains (Albrecht and Schousboe, 2005). The same study also evidenced, through immunocytochemical analysis, that GABABR, to which taurine binds, is located extrasynaptically. Taurine has been shown to activate both GABAA and glycine receptors (GlyR) at a 0.1 mM concentration (Song et al., 2012). Despite this, Wu et al. (2008) evidenced in adult rats that taurine’s activation of GABAAR and GlyR varies among brain regions and is concentration-dependent. These authors observed that taurine at moderate concentrations (0.3 mM) activated GlyR, whereas at high concentrations (3 mM), acted as a weak agonist to GABAAR in neurons within the substantia gelatinosa. One explanation for this phenomenon may be the structural variability of these receptors due to the broad variety of combinations among its five subunits (Sigel and Steinmann, 2012).

In Xenopus oocytes research, a comparison of native and recombinant selected types of GABAAR, showed that taurine acts as a full agonist at α1β3 receptors and as a partial agonist at α1β3γ2 receptor and GlyR, which causes an increase in chloride influx into the cell, and thus hyperpolarizes the post-synaptic neuron (Kletke et al., 2013; Ahring et al., 2016). Therefore, taurine enhancement of post-synaptic neuronal inhibition represents one of its most important neuroprotective mechanisms against excitotoxicity. Furthermore, experiments on amyloid beta (Aβ) models of neurotoxicity were carried out in chicks and rats, demonstrating that picrotoxin, a GABAA antagonist, blocked taurine’s neuroprotective inhibitory effect (Louzada et al., 2004; Paula-Lima et al., 2005). Similarly, it has been proposed that the influx of chloride caused by taurine’s agonist action over GABAAR and GlyR, counteracts glutamate-induced excitotoxicity (Paula-Lima et al., 2005). However, taurine does not interact directly with the binding site for glutamate or glycine of the NMDA receptor (Foos and Wu, 2002). Therefore, it is assumed that taurine effects on NMDA intracellular signaling are indirect.

Excitotoxicity induced by glutamate has been well established experimentally, both in vitro and in vivo, mainly in epilepsy and stroke models (Lai et al., 2014). Glutamate binds to NMDA receptor, which leads to significant increases in intracellular calcium loads and catabolic enzyme activities, triggering mitochondrial membrane depolarization, caspase activation, ROS production, apoptosis, and necrosis (Dong et al., 2009). In vitro experiments of rat cultured neurons showed that in the presence of taurine, glutamate failed to increase intracellular calcium levels, showing a reduction of more than 50% in the presence of 25 mM of taurine (Chen et al., 2001; Wu et al., 2009). Actions of taurine on neurons might be related to the Na+/Ca2+ exchanger, which is a bidirectional ion transporter that couples the Na+ in one direction with that of Ca2+ in the opposite direction, depending on the electrochemical gradient of Na+ across the membrane (Blaustein, 1988; Blaustein et al., 1991; Takuma et al., 1994). During depolarization, the exchanger adopts a reverse mode, which promotes calcium influx. Taurine acts inhibiting the Na+/Ca2+ exchanger through the following mechanisms: increasing the phospholipid N-methyltransferase activity over the exchanger, enhancing the calcium efflux from the cell, and increasing the intracellular calcium close to the exchanger (Schaffer et al., 2003, 2010). Leon et al. (2009) studied the presence of taurine in rat cultured neurons exposed to glutamate, identifying an increase in anti-apoptotic Bcl-2 together with a downregulation of Bax which works in favor of apoptosis. Taurine administration showed a 60% increase in the Bcl-2:Bax ratio, meaning an overall inhibition of programmed cell death (Elmore, 2007; Khodapasand et al., 2015; Dorstyn et al., 2018). Furthermore, taurine inhibits caspase-9 and calpain activity as part of its anti-apoptotic mechanisms (Leon et al., 2009).

After its release, taurine undergoes three different processes for its degradation including transamination, oxidation and oxygenation (Caspi et al., 2018). The process of transamination consists in the formation of L-alanine and sulfoacetaldehyde from taurine and pyruvate (Shimamoto and Berk, 1979). Oxidation involves the formation of isethionate (2-hydroxyethane sulfonate) from taurine (Kondo et al., 1971). The oxygenation process consists of the use of taurine as a sulfur source by the sulfoacetaldehyde acetyltransferase, and finally into acetyl-CoA by the phosphate acetyltransferase (Eichhorn et al., 1997).

Taurine has been proposed as a neurotransmitter in the mammalian CNS (Huxtable, 1989; Wu and Prentice, 2010; Ripps and Shen, 2012; Kumari et al., 2013; Oja and Saransaari, 2017). This proposal has been based on the fact that taurine can be produced and released by pre-synaptic neurons, and exerts effects on post-synaptic neurons. However, for a substance to be considered a neurotransmitter it must meet the following criteria: (i) its synthesizing enzyme is present in the neuron; (ii) it is released upon neuron depolarization; (iii) it acts on a post-synaptic receptor; (iv) it causes a biological response on the post-synaptic neuron; and (v) it has an inactivation process after its release (Purves et al., 2001). So far, taurine complies with all but one of the mentioned criteria to be considered a neurotransmitter, which is the confirmation of the presence of a taurine specific receptor on the post-synaptic neuron. Furthermore, the intracellular gradient of taurine (around 400) has an intermediate position between established neurotransmitters (around 2000) and non-neurotransmitter aminoacids (less than 100) (Lerma et al., 1986; Oja and Saransaari, 2017).

Taurine in Astrocytes

The cysteine dependent pathway is believed to be the main pathway for taurine biosynthesis in the brain (Banerjee et al., 2008). The cellular localization of CSAD has yielded controversial results in vivo. Nevertheless, incorporation of the radioactive 35S from cysteine into taurine has confirmed the presence of CSAD in astrocytes (Vitvitsky et al., 2011), making them fully capable of synthesis and accumulation of taurine (Hertz, 1979). In contrast, low CSAD activity, if any, is found in neurons (Pasantes-Morales, 2017), making neurons dependent on astrocytes for provision of hypotaurine and/or taurine (Banerjee et al., 2008). When co-cultured with neurons in a rat model, astrocytic hypotaurine decreased and taurine levels increased, revealing the crosstalk between these cell types for regulation of taurine synthesis (Brand et al., 1997). Although astrocytes have the enzymatic machinery for taurine synthesis, taurine can also be transported into the astrocyte through TauT2 transporters from interstitial fluid (Pow et al., 2002; Junyent et al., 2011). TauT has 12 hydrophobic transmembrane domains with cytosolic N- and C- terminals, and for each taurine molecule to be passed across the membrane, two Na+ ions and one Cl– ion are required as a cotransport mechanism (Han et al., 2006).

Taurine has long been known to have an osmoregulatory role in the mammalian brain (Oja and Saransaari, 2017). Its release from neurons and astrocytes is directly proportional to a decrease in osmolarity (Pasantes-Morales and Schousboe, 1997). It has been shown that the replacement of 50 mM sodium ions by potassium evokes taurine release from rat’s cerebellar astrocytes (Schousboe and Pasantes-Morales, 1989). The same study evidenced that taurine release in a hyperosmotic media is decreased from both cerebellar astrocytes and granule cells, even when 50 mM of potassium is added. This is supported by Vitvitsky et al. (2011), who demonstrated that exposure to hypertonic conditions increases taurine levels in astrocytes up to 14% in 48 h. Contrastingly, there are other release mechanisms described for taurine, namely, a dose-dependent taurine release mediated by glutamate and kainate in animal cultured cerebellar astrocytes (Dutton et al., 1991). Such different release mechanisms of taurine from astrocytes support an astrocytic high concentration gradient and high affinity transport systems.

Astrocytic taurine concentration can vary according to different neurotoxic stimuli. Morken et al. (2005), working in mice, reported that when exposed to methylmercury (MeHg), the concentration of taurine increased in astrocytic monocultures, whereas it decreased in neurons in co-cultures. This suggests that there is a compensatory increase in levels of taurine in astrocytes in response to toxic stimuli, depicting another important neuroprotective effect of astrocytic taurine. Taurine release in neurons and astrocytes share similarities, including a delayed onset of taurine release after stimulation, however, some level of discrepancy exists between them. For example, exposure to tetrodotoxin and dihydropyridines inhibit neuronal taurine release, whereas taurine release from astrocytes remains intact despite the presence of a sodium or calcium channel blocker, respectively (Dutton et al., 1991).

Different studies have shown that taurine is released from astrocytes through the volume-regulated anion channels (VRACs) (Choe et al., 2012; Schober et al., 2017). These channels, discovered in 2014, are structured as an hetero-hexamer complex formed by the leucine-rich repeat-containing 8 (LRRC8) proteins (the essential LRRC8A and complementary LRRC8B to E), which are also involved in the release of other metabolites like glutamate and aspartate (Qiu et al., 2014; Voss et al., 2014). For instance, a recent study in mice showed that cerebral ischemia increased neuronal LRRC8A-dependent VRAC activity in the hippocampus, suggesting that VRAC contributed to increased glutamatergic release during ischemic damage (Zhou et al., 2020). Importantly, VRAC channels mediate swelling-activated Cl– currents during decreases in systemic osmolarity and have been extensively studied in astrocytes, neurons and other non-neuronal cells like pituicytes and retinal Müller cells (Choe et al., 2012; Qiu et al., 2014; Mongin, 2016; Netti et al., 2018). Furthermore, it has been shown that primary rat astrocytes express LRRC8A, and that knockdown of astrocytic LRRC8A expression‎ inhibits swelling-activated release of taurine (Hyzinski-García et al., 2014; Mongin, 2016; Schober et al., 2017). Expression‎ of LRRC8A has been observed in rat astrocytes from brain regions such as cortex and hippocampus (Hyzinski-García et al., 2014; Formaggio et al., 2019). Thus, VRAC, LRRC8A, and taurine, seem to play a critical role in astrocytic homeostasis. Moreover, previous studies have shown that the highest levels of taurine in the brain are found in cerebral cortex, hippocampus, caudate-putamen, cerebellum, and in hypothalamic supraoptic nucleus (Hussy et al., 1997, 2000; Hatton, 2002). VRAC and VRAC-like currents have been reported in mice and rats in several brain regions including cervical sympathetic ganglions, CA1 region of the hippocampus, cerebral cortex, hypothalamus, and cerebellum (Leaney et al., 1997; Patel et al., 1998; Inoue et al., 2005; Sato et al., 2011; Zhang et al., 2011). For example, in the study by Choe et al. (2012), whole-cell voltage clamp recording demonstrated the absence of VRACs in rat’s neurons from the supraoptic nucleus, while confirm‎ing its presence in cultured astrocytes from the same site. This suggests that astrocytes, in contrast to neurons, may be the main responsible cells for the VRAC-mediated taurine release in the brain. However, the relation of this channel with taurine in humans and in other neural cells such as oligodendrocytes, NG2 glia, or microglia, has not been completely clarified (Wang et al., 2022). Moreover, some reports have shown that taurine acts as a potent GlyR and GABA agonist, reducing the release of vasopressin and oxytocin in magnocellular neurons (Deleuze et al., 1998; Song and Hatton, 2003). In rats, these two hormones regulate taurine secretion from pituicytes, thus creating a loop of paracrine intercellular communication (Rosso et al., 2004). Regarding its effects as a GlyR agonist, it has been shown that taurine activates GlyR through binding with homomeric subunits αH1 and αH2 in both animal and human cells (De Saint Jan et al., 2001). Consequently, transport inhibition of endogenous amino acids, such as taurine, contributes to the preservation of tonic activity in glycine receptors as well as in inhibitory neurons in the hippocampus (Mori et al., 2002), suggesting that taurinergic gliotransmission enhances inhibition on neurons.

As previously mentioned, taurine is mainly produced and released by astrocytes in the CNS. Therefore, metabolic and physiological aspects of taurine depend on an adequate function of these glial cells. This includes the communication between astrocytes and other cells, in particular, neurons. As mentioned above, astrocytes release hypotaurine, which then becomes the precursor for neuronal taurine production (Vitvitsky et al., 2011). Astrocytic taurine acts on GABA and GlyR favoring inhibitory activity in neurons (Song et al., 2012; Ochoa-de la Paz et al., 2019). Furthermore, taurine helps to control intracellular calcium levels and reduces the risk of developing excitotoxicity and apoptosis (Leon et al., 2009; Wu et al., 2009). Although not tested in co-culture with astrocytes, rat neurons treated with taurine increased both the incidence of synapse formation and the efficacy of synaptic transmission (Mersman et al., 2020). This suggests astrocytes may be involved in taurine-related neuronal synaptogenesis, as astrocytes have been reported to play a central role in synapse formation, function, and elimination (Chung et al., 2015). However, taurine metabolic coupling between astrocytes and neurons may be affected by external factors. For instance, in vitro treatment with manganese induced an increase in astrocytic taurine and a decrease in neuronal and astrocytic-neuronal co-culture taurine (Zwingmann et al., 2003). Another in vitro study in rat astrocytes, reported that rapid taurine accumulation is enhanced by hyperosmotic conditions (Beetsch and Olson, 1998). Despite these observations, it is still not clear whether other important coupling functions between astrocytes and neurons, such as the astrocyte-neuron lactate shuttle, or purinergic signaling, are affected by taurine.

Despite the controversy regarding taurine’s condition as a neurotransmitter, its categorization as a gliotransmitter can be clearly elucidated. For instance, for a substance to be considered an astrocyte gliotransmitter it must comply with the following criteria: (i) be synthesized and/or stored in astrocytes, (ii) have a physiologically triggered release, (iii) activate rapid responses in adjacent cells, and (iv) influence physiological processes (Volterra and Meldolesi, 2005). Other authors have proposed that substances that act as gliotransmitters can be released by calcium-independent non-exocytotic ways, as happens with taurine (Malarkey and Parpura, 2008; Hussaini and Jang, 2018). Taurine has proven to be synthesized and released from astrocytes, execute an inhibitory effect on neurons and influence multiple physiological processes. Therefore, taurine’s status as a gliotransmitter can be confirmed. However, whether its main effect is directly over the pre-synaptic or post-synaptic neuron, remains to be established.

Other aspects merit further exploration such as if any difference in taurine takes place in the functional regions of the astrocytes (i.e., endfeet vs. soma), in astrocytic subtypes (i.e., protoplasmatic gray matter vs. fibrous white matter astrocytes), and if taurine is somehow involved in the function of glymphatic system.

Neuroprotective Effects of Taurine Released From Astrocytes

As mentioned above, taurine acts as a gliotransmitter with a neuroprotective role in the brain. When released from astrocytes, it can either bind to neuronal post-synaptic receptors such as GABAAR and GlyR (Wu and Prentice, 2010), or enter the neuron via TauT1 and TauT2 transport proteins where it triggers intracellular signaling pathways. However, taurine’s overall inhibitory effects combine both extracellular and intracellular processes.

Regarding the extracellular effects of taurine, it involves binding to neuronal GABAAR and GlyR, augmenting chloride conductance, thereby hyperpolarizing the cell and neutralizing NMDA-mediated glutamate excitotoxicity (Wu and Prentice, 2010). Furthermore, taurine release from the cells decreases Ca2+ entry by limiting the available Na+ needed for the adequate functioning of the Na+/Ca2+ exchanger in the cell membrane (Schaffer and Kim, 2018).

On the other hand, intracellular effects of taurine released from astrocytes involve direct and indirect actions on calcium homeostatic pathways in neurons. By reducing calcium overload, taurine prevents excitotoxicity, mitochondrial stress, and activation of apoptotic pathways (Junyent et al., 2010). Studies with cultured neurons treated with glutamate showed a significant increase in intracellular calcium levels, however, when taurine was added, such calcium elevation returned to near basal levels (Foos and Wu, 2002). As glutamate binds to its metabotropic receptor, IP3 increases, as does IP3-mediated calcium release from internal storages. However, when taurine was added, there was no increase in IP3 nor in intracellular calcium levels (Foos and Wu, 2002). This suggests taurine’s neuroprotective effect toward glutamate-induced calcium overload and consequent excitotoxicity. Furthermore, authors have proposed that taurine activates coupled inhibitory G-proteins, which in turn, inhibit phosphorylation of VGCC, thus preventing its activation induced by glutamate (Wu and Prentice, 2010). Therefore, by inhibiting calcium influx from VGCC, taurine provides another mechanism for regulation of intracellular calcium concentrations.

In a type II diabetes mellitus rat model, intracellular taurine has proven to inhibit neuronal apoptosis in the brain, more specifically in the hippocampal CA1 pyramidal cells by acting on the NGF/Akt/Bad pathway (Wu et al., 2020). The addition of taurine to rat’s hippocampal cultured neurons increased the expression‎ of nerve growth factor (NGF) and augmented phosphorylation of the NGF receptor, tyrosine kinase receptor type A (TrkA), activating an important anti-apoptotic pathway. Furthermore, hippocampal rat neurons treated with taurine showed a decreased expression‎ of Bax, a diminished release of cytochrome C and a reduction in caspase-3 and caspase-8 activity, thereby contributing to neuronal survival by inhibiting apoptotic signaling pathways (Li et al., 2017). Finally, some evidence has emerged suggesting that taurine concentration may be related with the development of Parkinson’s disease (PD) (Zhang et al., 2016; Che et al., 2018). For example, a study with 110 PD treated and untreated patients, found that PD patients exhibited lower levels of plasma taurine than control individuals (51.01 ± 29.07 vs. 133.83 ± 45.91 μmol/L, p < 0.001) (Zhang et al., 2016). Moreover, in a mice PD model, using primary neuron-glia cultures, it was found that taurine administration (150 mg/kg), attenuated the aggregation of α-synuclein, decreased the inflammatory response by microglia and provided dopaminergic neuroprotection (Che et al., 2018). Furthermore, a study in C57Bl/6j male mice showed that taurine administration significantly decreased the total number of ionized calcium-binding adapter molecule 1 (Iba1)-expressing microglia in the dentate gyrus supporting its anti-inflammatory role (Gebara et al., 2015). These combined results suggest the importance of taurine neuroprotection in neurodegenerative diseases such as PD. Moreover, as astrocytes are the main taurine releasing cells in the CNS, we suggest most of these neuroprotective effects may be attributed to astrocytes (Figure 3).

FGURE 3

Figure 3. Delayed neuroprotective effects of taurine in the post-synaptic neuron. Taurine increases the expression‎ of NGF, presumably in astrocytes from where it is released. Additionally, intracellular taurine increases phosphorylation of TrkA, a specific receptor for NGF, thus enhancing the NGF/Akt/Bad anti-apoptotic pathway. By activating this pathway, taurine enhances Bax inhibition, which blocks Cytochrome C release from mitochondria, and inhibits caspase-mediated apoptotic pathways. Taurine is represented by an inverted red triangle, while NGF is represented by a magenta circle. HD, hypotaurine dehydrogenase; NGF, nerve growth factor; PI3K, phosphatidylinositol 3-kinase; TrkA, tropomyosin receptor kinase A.

Taurine as a Therapeutic Alternative in Nervous System Pathologies

Taurine’s neuroprotective role in neurons and astrocytes represent a novel potential therapeutic approach toward several nervous system diseases. By augmenting neuronal inhibition mediated by GABAAR and GlyR, taurine has proven to enhance neuronal inhibition, which remains useful in diseases such as epilepsy, characterized by a hypersynchronous and hyperexcitable neuronal circuit. Winkler et al. (2019) identified that the addition of 0.5 μmol/L of taurine significantly increased the anticonvulsant effect of 100–200 μmol/L of pentobarbital in mice. Kainic acid administration is one of the most frequently used models to mimic human temporal lobe epilepsy in animals. Either subcutaneous or intraperitoneal injection of taurine, preceding kainic acid administration, resulted in seizure prevention and significant reduction in neuronal cell death in the hippocampus of male mice (El Idrissi et al., 2003; Junyent et al., 2009). This suggests that taurine’s action as a positive modulator of GABAAR could be considered as part of epilepsy therapy. In humans with epilepsy, including in children (Fukuyama and Ochiai, 1982), the effects of taurine oral administration on seizures has been examined (as reviewed by Oja and Saransaari, 2013). Most of these studies were conducted in the 70’s and 80’s, and showed a wide variation in the results. For instance, some reported disappearance of seizures in patients with intractable epilepsy, while others failed to show any improvement, despite comparable dosages. However, these clinical trials had many issues, such as a small number of participants, diverse range of epilepsy types and no control groups, among others. According to the webpage, clinicaltrials.gov, no clinical trial examining effects of taurine on epilepsy is currently ongoing. Therefore, novel and much better designed clinical trials examining taurine effects on epilepsy should be proposed in the future. On the other hand, taurine’s role in the inhibition of neuronal apoptotic pathways and attenuation of oxidative stress, could represent a potential adjuvant therapy, particularly in neurodegenerative diseases such as AD. It has been shown that small concentrations of taurine in neuronal cultures from chick embryo retinas can decrease Aβ peptide aggregation and the underlying neuronal death (Louzada et al., 2004). In APP/PS1 AD transgenic mice, taurine administration was shown to bind oligomeric Aβ peptides and improve cognition (Jang et al., 2017). Moreover, decreased taurine levels, as detected by ion exchange in the temporal cortices of patients with AD could lead to higher aggregation and more rapid disease progression, highlighting the potential role of taurine as co-adjuvant in the delaying of neurodegenerative processes (Arai et al., 1985; Chen et al., 2019).

Taurine’s neuroinflammatory modulation represents another viable mechanism in which it can be implemented in therapeutic approaches toward diseases such as traumatic brain injury and ischemic stroke, characterized by enhanced neuroinflammatory processes. By decreasing the expression‎ of proinflammatory cytokines through the inactivation of microglia-mediated NOX2-NF-κB cascade, taurine may contribute to the amelioration of inflammatory changes (Che et al., 2018; Bhat et al., 2020; Tian et al., 2020). For example, administration of high doses of taurine in a rat model of intracerebral hemorrhage resulted in inactivation of proinflammatory pathways, thereby limiting neuronal damage and white matter injury, accompanied by a decrease in neutrophil infiltration and glial activation (Zhao et al., 2018). Furthermore, in an in vitro model for ischemic stroke, 88% of neurons pretreated with taurine survived after being exposed to high levels of glutamate (Prentice et al., 2017). Similarly, in the same study, the administration of taurine in an in vivo rat stroke model resulted in the inhibition of components within the ER stress pathway, reducing neuronal glutamate excitotoxicity. Therefore, taurine could have a beneficial effect in neuroinflammatory diseases and ischemic or traumatic brain injury.

The development of biological markers, or biomarkers, for nervous system diseases is actually one of the most important research topics in the field of neuroscience. The interest in the development of biomarkers is based on several current challenges these group of diseases pose, such as the lack of comprehension of the pathological mechanism, together with difficulties in the prevention, in particular early interventions, confirm‎atory diagnosis and treatment. According to the most accepted definition, a biomarker should be objectively measured or eval‎uated, and must be able to indicate (and differentiate) physiological activity from pathological processes or from pharmacological responses (Strimbu and Tavel, 2010). In addition, ideal biomarkers should benefit from being less invasive and fast to measure, providing results in minutes or hours, rather than days or weeks. Therefore, many biomarkers are explored in blood, saliva, or urine samples, as well as in imaging techniques including magnetic resonance or positron emission tomography (PET) (Young et al., 2020; Zetterberg and Schott, 2022). In fact, live imaging of brain metabolism is currently proposed as an interesting biomarker method both in preclinical and clinical settings (Zhu et al., 2018). Therefore, as taurine plays and important role in brain metabolism, and is mainly produced in astrocytes (the principal homeostatic regulators in the SNC), taurine can be suggested as a possible brain biomarker.

Several techniques exist to determine the metabolic activity of the brain in living individuals. The most commonly used in humans are functional magnetic resonance imaging (fMRI), PET, magnetic resonance spectroscopy (MRS) and metabolomics in tissue samples (Barros et al., 2018). Taurine is one of the metabolites that can be determined through MRS thus possibly serving as a biomarker. For instance, taurine concentrations, determined through MRS, were measured in primitive neuroectodermal tumors (PNT) of pediatric patients, finding a significant increase of this metabolite, which helped to differentiate PNT from other tumors (Kovanlikaya et al., 2005). Metabolic profiling of taurine has also been extended to other neural derived tumors such as medulloblastoma, neuroblastoma, and retinoblastoma (Kohe et al., 2018). Recently, a brain MRS study in cannabinoid users, found that taurine concentration was directly correlated with glutamate, and with the frequency of cannabinoid use (Newman et al., 2022). Furthermore, MRS measurements determined elevated concentrations of taurine in the cerebellar vermis of bipolar patients (Magnotta et al., 2022), and levels of taurine were significantly related to the duration of illness in schizophrenic patients (Shirayama et al., 2010). Hence, taurine MRS measurements can be applied to a large extent of neurological and neuropsychiatric diseases.

Taurine values have also been examined in biological samples such as blood and cerebrospinal fluid (CSF). A recent study found that taurine plasma levels correlated with the strength-duration time constant, an axonal excitability indicator, established to predict survival in amyotrophic lateral sclerosis (ALS) (Nakazato et al., 2022). Furthermore, taurine was selected as a biomarker metabolite that helps to distinguish between patients with amnestic mild cognitive impairment and healthy controls (Sun et al., 2020). Plasmatic taurine has also been used as a predictor of poor outcome in patients with subarachnoid hemorrhage, finding that those patients with a sixfold increase in taurine at admission ended with a poor outcome, compared with those with a favorable outcome who had only a twofold increase (Barges-Coll et al., 2013). Similar findings were observed in the CSF of severe brain-injured patients, where taurine was significantly increased in subdural or epidural hematomas, contusions and generalized brain edema (Stover et al., 1999). Elevated concentrations of taurine in plasma have also been reported in psychiatric diseases, such as depression (Altamura et al., 1995). Similar findings have been observed in preclinical models. Song et al. (2021) studied a rat model treated with 20 mg/kg of fluoxetine daily, evidencing that repeated doses of fluoxetine, a selective serotonin reuptake inhibitor, led to decreased concentrations of taurine and other astrocytic metabolites in the medial prefrontal cortex. Moreover, Wu et al. (2017) reported that taurine pre-administration in a rat depression model counteracts the rise in glutamate and inflammatory mediators such as corticosterone. Furthermore, in the same study, the administration of taurine prevented the reduction in substances such as 5-hydroxytryptamine (5-HT), dopamine, noradrenaline, and even upregulated the expression‎ of neurotrophic factors like fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor (VEGF), and brain derived neurotrophic factor (BDNF), that tend to fall under stress conditions. This suggests taurine’s compensatory effects in response to stress-induced depression, demonstrating that taurine’s antidepressant properties could possibly contribute to neuropsychiatric disease therapeutics.

An important question about the possible use of taurine as a therapeutic option in nervous system pathologies refers to the delivery mode in the organism. Oral delivery is the most common and easy method of taurine administration, and most trials in humans use this form of delivery. In fact, oral taurine administration, up to 4 grams in healthy adults or up to 6 grams daily for 6 months in children with fatty liver, has been given without toxic side effects (Obinata et al., 1996; Ghandforoush-Sattari et al., 2010). However, despite encouraging results in many preclinical works, some reports in animal studies have shown that oral administration is not as effective as taurine injection, and that prolonged consumption may even produce some negative effects in rats (Eppler et al., 1999; El Idrissi et al., 2003). Therefore, the need to explore additional and more efficient administration routes. For instance, intravenous delivery of taurine (up to five grams) has been given safely to patients during myocardial revascularization (Milei et al., 1992). However, intravenous delivery of taurine has not been tested in humans with neurological or neuropsychiatric diseases. In addition to oral and intravenous delivery, other systemic administration routes such as intraperitoneal injection may be implemented, although they tend to be more invasive and risky, increasing the possibility of bleeding or infection. Systemic administration is also limited by the BBB, which restricts taurine passage into CNS parenchyma. Furthermore, the BBB transport of taurine into the brain can be affected by the presence of cytokines such as tumor necrosis factor (TNF) (Kang et al., 2002; Lee and Kang, 2004). Therefore, novel methods that bypass the BBB should be tested. For instance, intranasal delivery of medications have been shown to be a practical and non-invasive method to evade the BBB and reach the CNS (Hanson and Frey, 2008). In mice, intranasal delivery of taurine produced anxiolytic effects in animals treated with strychnine, picrotoxin, yohimbine, or isoniazid (Jung and Kim, 2019). Another strategy may involve the use of taurine nanocarriers aimed at CNS cells. Recently, a functionalized nanoparticle with taurine and graphene oxide was designed, and tested successfully in rats (Pan et al., 2021).

Conclusion

There is compelling evidence of taurine’s neuroprotective and homeostatic effects in the CNS, including maintenance of cellular energy processes, intracellular calcium modulation, osmotic stress regulation, and protection against glutamate-induced excitotoxicity, among others. The metabolic coupling for taurine synthesis and degradation between astrocytes and neurons, evidence neuronal dependence on astrocytes for the adequate functioning of the mentioned effects in the brain. Finally, it could be relevant to explore the effects of taurine in other glial cells such as microglia or oligodendrocytes, in functions such as antioxidative protection and demyelination and its association with astrocytes. Therefore, the astrocyte’s role in taurine-induced neuroprotective functions should be considered as a promising therapeutic target in the management of several neurodegenerative and neuropsychiatric diseases in the near future.

Author Contributions

SR-G: literature review, writing the manuscript, and making the figures. SG-M, GM-R, and EO-G: literature review and writing the manuscript. RC-P: writing and editing the manuscript. RG-R: original draft preparation and writing and editing the manuscript. All authors contributed to the article and approved the submitted version.

Funding

Funds received for open access publication fees from Universidad del Rosario.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be eval‎uated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Acknowledgments

We thank Universidad del Rosario for the administrative support with this publication.

References

Ahring, P. K., Bang, L. H., Jensen, M. L., Strøbæk, D., Hartiadi, L. Y., Chebib, M., et al. (2016). A pharmacological assessment of agonists and modulators at α4β2γ2 and α4β2δ GABAA receptors: the challenge in comparing apples with oranges. Pharmacol. Res. 111, 563–576. doi: 10.1016/j.phrs.2016.05.014

PubMed Abstract | CrossRef Full Text | Google Scholar

Albrecht, J., and Schousboe, A. (2005). Taurine interaction with neurotransmitter receptors in the CNS: an update. Neurochem. Res. 30, 1615–1621. doi: 10.1007/s11064-005-8986-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Altamura, C., Maes, M., Dai, J., and Meltzer, H. Y. (1995). Plasma concentrations of excitatory amino acids, serine, glycine, taurine and histidine in major depression. Eur. Neuropsychopharmacol. 5, 71–75. doi: 10.1016/0924-977x(95)00033-l

CrossRef Full Text | Google Scholar

Arai, H., Kobayashi, K., Ichimiya, Y., Kosaka, K., and Iizuka, R. (1985). Free amino acids in post-mortem cerebral cortices from patients with Alzheimer-type dementia. Neurosci. Res. 2, 486–490. doi: 10.1016/0168-0102(85)90020-3

CrossRef Full Text | Google Scholar

Baliou, S., Kyriakopoulos, A. M., Goulielmaki, M., Panayiotidis, M. I., Spandidos, D. A., and Zoumpourlis, V. (2020). Significance of taurine transporter (TauT) in homeostasis and its layers of regulation (Review). Mol. Med. Rep. 22, 2163–2173. doi: 10.3892/mmr.2020.11321

PubMed Abstract | CrossRef Full Text | Google Scholar

Banerjee, R., Vitvitsky, V., and Garg, S. K. (2008). The undertow of sulfur metabolism on glutamatergic neurotransmission. Trends Biochem. Sci. 33, 413–419. doi: 10.1016/j.tibs.2008.06.006

PubMed Abstract | CrossRef Full Text | Google Scholar

Barges-Coll, J., Pérez-Neri, I., Avendaño, J., Mendez-Rosito, D., Gomez-Amador, J. L., and Ríos, C. (2013). Plasma taurine as a predictor of poor outcome in patients with mild neurological deficits after aneurysmal subarachnoid hemorrhage. J. Neurosurg. 119, 1021–1027. doi: 10.3171/2013.4.JNS121558

PubMed Abstract | CrossRef Full Text | Google Scholar

Barros, L. F., Bolaños, J. P., Bonvento, G., Bouzier-Sore, A.-K., Brown, A., Hirrlinger, J., et al. (2018). Current technical approaches to brain energy metabolism. Glia 66, 1138–1159. doi: 10.1002/glia.23248

PubMed Abstract | CrossRef Full Text | Google Scholar

Beetsch, J. W., and Olson, J. E. (1998). Taurine synthesis and cysteine metabolism in cultured rat astrocytes: effects of hyperosmotic exposure. Am. J. Physiol. 274, C866–C874. doi: 10.1152/ajpcell.1998.274.4.C866

PubMed Abstract | CrossRef Full Text | Google Scholar

Benedetti, M. S., Russo, A., Marrari, P., and Dostert, P. (1991). Effects of ageing on the content in sulfur-containing amino acids in rat brain. J. Neural Transm. Gen. Sect. 86, 191–203. doi: 10.1007/BF01250705

PubMed Abstract | CrossRef Full Text | Google Scholar

Bhat, M. A., Ahmad, K., Khan, M. S. A., Bhat, M. A., Almatroudi, A., Rahman, S., et al. (2020). Expedition into taurine biology: structural insights and therapeutic perspective of taurine in neurodegenerative diseases. Biomolecules 1: 863. doi: 10.3390/biom10060863

PubMed Abstract | CrossRef Full Text | Google Scholar