Department of Pathophysiology, Hebei Medical University, Shijiazhuang, People's Republic of China.
Department of Intensive Care Unit, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China.
J Neurochem. 2019 Dec;151(5):608-625. doi: 10.1111/jnc.14824. Epub 2019 Aug 27.
Glial glutamate transporter 1 (GLT-1) plays a vital role in the induction of brain ischemic tolerance (BIT) by ischemic preconditioning (IPC). However, the mechanism still needs to be further explained. The aim of this study was to investigate whether peroxisome proliferator-activated receptor gamma (PPARγ) participates in regulating GLT-1 during the acquisition of BIT induced by IPC. Initially, cerebral IPC induced BIT and enhanced PPARγ and GLT-1 expression in the CA1 hippocampus in rats. The ratio of nuclear/cytoplasmic PPARγ was also increased. At the same time, the up-regulation of PPARγ expression in astrocytes in the CA1 hippocampus was revealed by double immunofluorescence for PPARγ and glial fibrillary acidic protein. Then, the mechanism by which PPARγ regulates GLT-1 was studied in rat cortical astrocyte-neuron cocultures. We found that IPC [45 min of oxygen glucose deprivation (OGD)] protected neuronal survival after lethal OGD (4 h of OGD), which usually leads to neuronal death. The activation of PPARγ occurred earlier than the up-regulation of GLT-1 in astrocytes after IPC, as determined by western blot and immunofluorescence. Moreover, the preadministration of the PPARγ antagonist T0070907 or PPARγ siRNA significantly attenuated GLT-1 up-regulation and the neuroprotective effects induced by IPC in vitro. Finally, the effect of the PPARγ antagonist on GLT-1 expression and BIT was verified in vivo. We observed that the preadministration of T0070907 by intracerebroventricular injection dose-dependently attenuated the up-regulation of GLT-1 and BIT induced by cerebral IPC in rats. In conclusion, PPARγ participates in regulating GLT-1 during the acquisition of BIT induced by IPC. Cover Image for this issue: doi: 10.1111/jnc.14532. Open Science: This manuscript was awarded with the Open Materials Badge For more information see: https://cos.io/our-services/open-science-badges/.
胶质谷氨酸转运体 1 (GLT-1) 在缺血预处理 (IPC) 诱导的脑缺血耐受 (BIT) 中发挥重要作用。然而，其机制仍需要进一步解释。本研究旨在探讨过氧化物酶体增殖物激活受体γ (PPARγ) 是否参与调节 IPC 诱导的 BIT 过程中 GLT-1 的表达。首先，脑 IPC 诱导 BIT，并增强大鼠 CA1 海马区的 PPARγ 和 GLT-1 表达。核/胞浆 PPARγ 比值也增加。同时，通过 PPARγ 和胶质纤维酸性蛋白的双重免疫荧光显示，CA1 海马区星形胶质细胞中 PPARγ 的表达上调。然后，在大鼠皮质星形胶质细胞-神经元共培养物中研究了 PPARγ 调节 GLT-1 的机制。我们发现，IPC[45 分钟的氧葡萄糖剥夺 (OGD)] 可保护神经元在致命 OGD(4 小时的 OGD)后的存活，而通常会导致神经元死亡。通过 Western blot 和免疫荧光，我们发现，IPC 后星形胶质细胞中 GLT-1 的上调之前发生了 PPARγ 的激活。此外，在体外，预先给予 PPARγ 拮抗剂 T0070907 或 PPARγ siRNA 可显著减弱 IPC 诱导的 GLT-1 上调和神经保护作用。最后，在体内验证了 PPARγ 拮抗剂对 GLT-1 表达和 BIT 的影响。我们观察到，通过侧脑室注射预先给予 T0070907 可剂量依赖性地减弱大鼠脑 IPC 诱导的 GLT-1 和 BIT 的上调。总之，PPARγ 参与调节 IPC 诱导的 BIT 过程中的 GLT-1。本期封面图片说明：doi: 10.1111/jnc.14532. 开放科学：本手稿获得了开放材料徽章。更多信息请访问：https://cos.io/our-services/open-science-badges/。
