Research Unit of Functional Neurophysiology and Pathology, 00/UR/08-01, Department of Biological Sciences, Faculty of Science of Tunis, University of Tunis El Manar, 2092, Tunis, Tunisia.
Neurotox Res. 2018 Oct;34(3):559-573. doi: 10.1007/s12640-018-9911-5. Epub 2018 Jul 13.
In the CNS, including the optic nerve, oligodendrocytes play a critical role in the myelination of axons. Oligodendrocytes are exceptionally sensitive to insults to the CNS, such as injury, ischemia, or inflammation, which result in the loss of oligodendrocytes and myelin and eventually secondary axon degeneration. Oligodendrocytes are sensitive to excitotoxic insults mediated by overactivation of their AMPA ionotropic glutamate receptors. Phenolic compounds, which are widely distributed in fruits and vegetables, received the great attention of scientists due to their antioxidant activities and free radical scavenging abilities. Chlorogenic acid (CGA) has been demonstrated to possess potent neuroprotective activities against oxidative stress in various cellular models and pathological conditions. Hence, CGA protect against oxidative stress and excitotoxic insults mediated by AMPA receptors and that the protective mechanisms involve free radical scavenging, Ca handling in the cytosol, and modulating antioxidant enzyme system. CGA was associated with the protein kinase A (PKC) signaling pathways transduction. Caspases and calpains have been studied as apoptotic mediators and cell death in this model of AMPA toxicity. Inhibitors of caspases initiators, caspases 1, 8, and 9, the upstream of caspase 3 effectors, have totally abrogated the protective activity of CGA. Inhibitors of calpains also totally abrogated the protective activity of CGA. In addition, a potential role for the CGA in inhibiting Bax in oligodendrocyte cell model undergoing AMPA is inducing excitotoxic death. Our results indicate that CGA exhibits a protective potential via antioxidant and apoptosis caspases and calpains dependent against AMPA-mediated excitotoxicity, and these finding indicate that CGA is able to be a good candidate for preventive approach for neurodegenerative disorders associated with loss and damage in oligodendrocytes and AMPA-mediated excitotoxicity.
在中枢神经系统（CNS）中，包括视神经在内，少突胶质细胞在轴突的髓鞘形成中起着至关重要的作用。少突胶质细胞对中枢神经系统的损伤、缺血或炎症等非常敏感，这些损伤会导致少突胶质细胞和髓鞘的丧失，最终导致轴突继发性变性。少突胶质细胞对其 AMPA 离子型谷氨酸受体过度激活介导的兴奋毒性损伤敏感。酚类化合物广泛存在于水果和蔬菜中，由于其抗氧化活性和自由基清除能力，受到了科学家的广泛关注。绿原酸（CGA）已被证明在各种细胞模型和病理条件下具有强大的抗氧化应激活性。因此，CGA 可以防止 AMPA 受体介导的氧化应激和兴奋毒性损伤，其保护机制涉及自由基清除、细胞质中的 Ca 处理以及调节抗氧化酶系统。CGA 与蛋白激酶 A（PKC）信号通路转导有关。半胱天冬酶和钙蛋白酶已被研究为这种 AMPA 毒性模型中的凋亡介质和细胞死亡。Caspase 起始抑制剂、Caspase 1、8 和 9（Caspase 3 效应器的上游）完全阻断了 CGA 的保护活性。钙蛋白酶抑制剂也完全阻断了 CGA 的保护活性。此外，CGA 在抑制 AMPA 诱导的少突胶质细胞模型中的 Bax 方面可能发挥作用，从而诱导兴奋毒性死亡。我们的结果表明，CGA 通过抗氧化和凋亡 Caspase 和钙蛋白酶依赖的方式表现出保护潜力，可防止 AMPA 介导的兴奋毒性，这些发现表明 CGA 能够成为预防与少突胶质细胞丢失和损伤以及 AMPA 介导的兴奋毒性相关的神经退行性疾病的良好候选药物。
