Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, 33431, USA.
Adv Exp Med Biol. 2017;975 Pt 1:193-205. doi: 10.1007/978-94-024-1079-2_17.
Taurine, as a free amino acid, is found at high levels in many tissues including brain, heart and skeletal muscle and is known to demonstrate neuroprotective effects in a range of disease conditions including stroke and neurodegenerative disease. Using in vitro culture systems we have demonstrated that taurine can elicit protection against endoplasmic reticulum stress (ER stress) from glutamate excitotoxicity or from excessive reactive oxygen species in PC12 cells or rat neuronal cultures. In our current investigation we hypothesized that taurine treatment after stroke in the rat middle cerebral artery occlusion (MCAO) model would render protection against ER stress processes as reflected in decreased levels of expression of ER stress pathway components. We demonstrated that taurine elicited high level protection and inhibited both ATF-6 and IRE-1 ER stress pathway components. As ischemic stroke has a complex pathology it is likely that certain combination treatment approaches targeting multiple disease mechanisms may have excellent potential for efficacy. We have previously employed the partial NMDA antagonist DETC-MeSO to render protection against in vivo ischemic stroke using a rat cerebral ischemia model. Here we tested administration of subcutaneous administration of 0.56 mg/kg DETC-MeSO or 40 mg/kg of taurine separately or as combined treatment after a 120 min cerebral ischemia in the rat MCAO model. Neither drug alone demonstrated protection at the low doses employed. Remarkably however the combination of low dose DETC-MeSO plus low dose taurine conferred a diminished infarct size and an enhanced Neuroscore (reflecting decreased neurological deficit). Analysis of ER stress markers pPERK, peIF-2-alpha and cleaved ATF-6 all showed decreased expression demonstrating that all 3 ER stress pathways were inhibited concurrent with a synergistic protective effect by the post-stroke administration of this DETC-MeSO-taurine combination treatment.
牛磺酸作为一种游离氨基酸，在包括大脑、心脏和骨骼肌在内的许多组织中含量都很高，并且已知在多种疾病状态下具有神经保护作用，包括中风和神经退行性疾病。我们通过体外培养系统证明，牛磺酸可以防止 PC12 细胞或大鼠神经元培养物中谷氨酸兴奋性毒性或过量活性氧引起的内质网应激（ER 应激）。在我们目前的研究中，我们假设在大鼠大脑中动脉闭塞（MCAO）模型中的中风后给予牛磺酸治疗，将减轻 ER 应激过程的保护作用，表现为 ER 应激途径成分的表达水平降低。我们证明，牛磺酸引起高水平的保护作用，并抑制 ATF-6 和 IRE-1 ER 应激途径成分。由于缺血性中风具有复杂的病理学，因此针对多种疾病机制的某些联合治疗方法可能具有出色的疗效潜力。我们之前曾使用部分 NMDA 拮抗剂 DETC-MeSO 在使用大鼠脑缺血模型的体内缺血性中风中提供保护。在这里，我们测试了在大鼠 MCAO 模型中，在 120 分钟脑缺血后，分别给予皮下注射 0.56mg/kg DETC-MeSO 或 40mg/kg 牛磺酸，或联合治疗。单独使用这两种药物的低剂量均未显示出保护作用。然而，令人惊讶的是，低剂量 DETC-MeSO 加上低剂量牛磺酸的联合治疗可减少梗塞面积并提高神经评分（反映出神经功能缺损减少）。内质网应激标志物 pPERK、peIF-2-alpha 和 cleaved ATF-6 的分析均显示表达减少，表明所有 3 种 ER 应激途径均被抑制，同时通过这种 DETC-MeSO-牛磺酸联合治疗的中风后给药产生协同保护作用。
