Department of Biomedical Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA.
Adv Exp Med Biol. 2013;776:241-58. doi: 10.1007/978-1-4614-6093-0_23.
Taurine is an inhibitory neurotransmitter and is one of the most abundant amino acids present in the mammalian nervous system. Taurine has been shown to provide protection against neurological diseases, such as Huntington's disease, Alzheimer's disease, and stroke. Ischemic stroke is one of the leading causes of death and disability in the world. It is generally believed that ischemia-induced brain injury is largely due to excessive release of glutamate resulting in excitotoxicity and cell death. Despite extensive research, there are still no effective interventions for stroke. Recently, we have shown that taurine can provide effective protection against endoplasmic reticulum (ER) stress induced by excitotoxicity or oxidative stress in PC12 cell line or primary neuronal cell cultures. In this study, we employed hypoxia/reoxygenation conditions for primary cortical neuronal cell cultures as an in vitro model of stroke as well as the in vivo model of rat focal middle cerebral artery occlusion (MCAO). Our data showed that when primary neuronal cultures were first subjected to hypoxic conditions (0.3%, 24 h) followed by reoxygenation (21%, 24-48 h), the cell viability was greatly reduced. In the animal model of stroke (MCAO), we found that 2 h ischemia followed by 4 days reperfusion resulted in an infarct of 47.42 ± 9.86% in sections 6 mm from the frontal pole. Using taurine greatly increased cell viability in primary neuronal cell culture and decreased the infarct area of sections at 6 mm to 26.76 ± 6.91% in the MCAO model. Furthermore, levels of the ER stress protein markers GRP78, caspase-12, CHOP, and p-IRE-1 which were markedly increased in both the in vitro and in vivo models significantly declined after taurine administration, suggesting that taurine may exert neuroprotection functions in both models. Moreover, taurine could downregulate the ratio of cleaved ATF6 and full-length ATF6 in both models. In the animal model of stroke, taurine induced an upregulation of the Bcl-2/Bax ratio and downregulation of caspase-3 protein activity indicating that it attenuates apoptosis in the core of the ischemic infarct. Our results show not only taurine elicits neuroprotection through the activation of the ATF6 and the IRE1 pathways, but also it can reduce apoptosis in these models.
牛磺酸是一种抑制性神经递质，也是哺乳动物神经系统中含量最丰富的氨基酸之一。牛磺酸已被证明可预防亨廷顿病、阿尔茨海默病和中风等神经疾病。缺血性中风是世界上导致死亡和残疾的主要原因之一。人们普遍认为，缺血引起的脑损伤主要是由于谷氨酸的过度释放导致兴奋性毒性和细胞死亡。尽管进行了广泛的研究，但目前仍没有针对中风的有效干预措施。最近，我们发现牛磺酸可以有效预防 PC12 细胞系或原代神经元细胞培养物中兴奋性毒性或氧化应激引起的内质网（ER）应激。在这项研究中，我们使用原代皮质神经元细胞培养物的缺氧/复氧条件作为中风的体外模型以及大鼠局灶性大脑中动脉闭塞（MCAO）的体内模型。我们的数据表明，当原代神经元培养物首先经历缺氧条件（0.3%，24 小时），然后再复氧（21%，24-48 小时）时，细胞活力大大降低。在中风的动物模型（MCAO）中，我们发现 2 小时缺血后再灌注 4 天导致额叶 6 毫米处的梗死面积为 47.42±9.86%。用牛磺酸处理大大增加了原代神经元细胞培养物中的细胞活力，并将 MCAO 模型中 6 毫米处的梗死面积降低至 26.76±6.91%。此外，在体外和体内模型中，内质网应激蛋白标志物 GRP78、caspase-12、CHOP 和 p-IRE-1 的水平明显升高，在用牛磺酸处理后显著下降，表明牛磺酸可能在两种模型中发挥神经保护作用。此外，牛磺酸可以下调两种模型中裂解的 ATF6 与全长 ATF6 的比值。在中风的动物模型中，牛磺酸诱导 Bcl-2/Bax 比值上调和 caspase-3 蛋白活性下调，表明它可减轻缺血性梗死核心中的细胞凋亡。我们的研究结果不仅表明牛磺酸通过激活 ATF6 和 IRE1 途径引起神经保护作用，而且可以减少这些模型中的细胞凋亡。
