Affiliated Union Hospital of Fujian Medical University, Department of Neurosurgery, Fuzhou, Fujian, China.
Affiliated Union Hospital of Fujian Medical University, Department of Neurosurgery, Fuzhou, Fujian, China.
Cell Signal. 2020 Dec;76:109787. doi: 10.1016/j.cellsig.2020.109787. Epub 2020 Sep 30.
Status epilepticus (SE) induces apoptosis of hippocampal neurons. However, the underlying mechanism in SE is not fully understood. Recently, lncRNA TUG1 is reported as a significant mediator in neuronal development. In present study, we aimed to investigate whether lncRNA TUG1 induces apoptosis of hippocampal neurons in SE rat models. TUG1 expression in serum of normal volunteers and SE patients, SE rats and neurons with epileptiform discharge was detected. SE rat model was established and intervened with TUG1 to evaluate hippocampal neuronal apoptosis. The experiments in vitro were further performed in neurons with epileptiform discharge to verify the effects of TUG1 on neuronal apoptosis of SE rats. The downstream mechanism of TUG1 was predicted and verified. miR-421 was intervened to perform the rescue experiments. Levels of oxidative stress and inflammation-related factors and mTOR pathway-related proteins in SE rats and hippocampal neurons were detected. TUG1 was highly expressed in serum of SE patients, SE rats and neurons with epileptiform discharge. Inhibition of TUG1 relieved pathological injury, oxidative stress and inflammation and reduced neuronal apoptosis in SE rats, which were further verified in hippocampal neurons. TUG1 upregulated TIMP2 expression by targeting miR-421. Overexpressed miR-421 inhibited hippocampal neuronal apoptosis. TUG1 knockout inactivated the mTOR pathway via the miR-421/TIMP2 axis to relieve neuronal apoptosis, oxidative stress and inflammation in SE rats and hippocampal neurons. Taken together, these findings showed that downregulation of lncRNA TUG1 inhibited apoptosis of hippocampal neurons in SE rats, and attenuated oxidative stress and inflammation damage through regulating the miR-421/mTOR axis.
癫痫持续状态（SE）诱导海马神经元凋亡。然而，SE 中的潜在机制尚未完全阐明。最近，lncRNA TUG1 被报道为神经元发育的重要介质。在本研究中，我们旨在研究 lncRNA TUG1 是否在 SE 大鼠模型中诱导海马神经元凋亡。检测了正常志愿者和 SE 患者、SE 大鼠和具有癫痫样放电的神经元血清中的 TUG1 表达。建立 SE 大鼠模型并进行 TUG1 干预，以评估海马神经元凋亡。进一步在具有癫痫样放电的神经元中进行体外实验，以验证 TUG1 对 SE 大鼠神经元凋亡的影响。预测并验证了 TUG1 的下游机制。干预 miR-421 进行挽救实验。检测 SE 大鼠和海马神经元中氧化应激和炎症相关因子及 mTOR 通路相关蛋白的水平。TUG1 在 SE 患者、SE 大鼠和具有癫痫样放电的神经元血清中高表达。抑制 TUG1 可缓解 SE 大鼠的病理损伤、氧化应激和炎症，减少神经元凋亡，这在海马神经元中得到了进一步验证。TUG1 通过靶向 miR-421 上调 TIMP2 的表达。过表达 miR-421 抑制海马神经元凋亡。TUG1 敲除通过 miR-421/TIMP2 轴使 mTOR 通路失活，以减轻 SE 大鼠和海马神经元中的神经元凋亡、氧化应激和炎症。总之，这些发现表明下调 lncRNA TUG1 可抑制 SE 大鼠海马神经元凋亡，并通过调节 miR-421/mTOR 轴减轻氧化应激和炎症损伤。
