Endoplasmic reticulum stress produced by Thapsigargin affects the occurrence of spike-wave discharge by modulating unfolded protein response pathways and activating immune responses in a dose-dependent manner,European Journal of Pharmacology

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Endoplasmic reticulum stress produced by Thapsigargin affects the occurrence of spike-wave discharge by modulating unfolded protein response pathways and activating immune responses in a dose-dependent manner
European Journal of Pharmacology ( IF 4.2 ) Pub Date : 2024-04-25 , DOI: 10.1016/j.ejphar.2024.176613
Sabriye Karadenizli Taşkin ₁ , Deniz Şahin ₁ , Fazilet Dede ₁ , Zehra Seda Ünal Halbutoğullari ₂ , Mehmet Sarihan ₃ , Sema Kurnaz Özbek ₄ , Özgür Doğa Özsoy ₅ , Murat Kasap ₃ , Yusufhan Yazir ₆ , Nurbay Ateş ₁

Affiliation

The Endoplasmic Reticulum (ER) is associated with many cellular functions, from post-transcriptional modifications to the proper folding of proteins, and disruption of these functions causes ER stress. Although the relationship between epileptic seizures and ER stress has been reported, the contribution of ER stress pathways to epileptogenesis is still unclear. This study aimed to investigate the possible effects of ER stress-related molecular pathways modulated by mild- and high-dose Thapsigargin (Tg) on absence epileptic activity, CACNA1H and immune responses in WAG/Rij rats. For this purpose, rats were divided into four groups; mild-dose (20 ng) Tg, high-dose (200 ng) Tg, saline, and DMSO and drugs administered intracerebroventriculary. EEG activity was recorded for 1 h and 24 h after drug administration following the baseline recording. In cortex and thalamus tissues, GRP78, ERp57, GAD153 protein changes (Western Blot), mRNA expressions (RT-PCR), NF-κB and TNF-α levels (ELISA) were measured. Mild-dose-Tg administration resulted in increased spike-wave discharge (SWD) activity at the 24th hour compared to administration of saline, and high-dose-Tg and it also significantly increased the amount of GRP78 protein, the expression of , and mRNA in the thalamus tissue. In contrast, high-dose-Tg administration suppressed SWD activity and significantly increased and mRNA expression in the thalamus, and increased NF-κB and TNF-α levels. In conclusion, our findings indicate that Tg affects SWD occurrence by modulating the unfolded protein response pathway and activating inflammatory processes in a dose-dependent manner.

中文翻译：

Thapsigargin 产生的内质网应激通过调节未折叠蛋白反应途径并以剂量依赖性方式激活免疫反应来影响棘波放电的发生

内质网 (ER) 与许多细胞功能相关，从转录后修饰到蛋白质的正确折叠，这些功能的破坏会导致 ER 应激。尽管癫痫发作与内质网应激之间的关系已有报道，但内质网应激途径对癫痫发生的贡献仍不清楚。本研究旨在探讨低剂量和高剂量毒胡萝卜素 (Tg) 调节的内质网应激相关分子通路对 WAG/Rij 大鼠失神癫痫活动、CACNA1H 和免疫反应的可能影响。为此，将大鼠分为四组；低剂量（20 ng）Tg、高剂量（200 ng）Tg、盐水和 DMSO 以及脑室内给药的药物。基线记录后，记录给药后 1 小时和 24 小时的脑电图活动。在皮质和丘脑组织中，测量了 GRP78、ERp57、GAD153 蛋白变化（Western Blot）、mRNA 表达（RT-PCR）、NF-κB 和 TNF-α 水平（ELISA）。与施用盐水和高剂量 Tg 相比，低剂量 Tg 施用导致第 24 小时的棘波放电 (SWD) 活性增加，并且还显着增加了 GRP78 蛋白的量、GRP78 蛋白的量以及 mRNA 的表达。在丘脑组织中。相反，高剂量 Tg 给药抑制了 SWD 活性，显着增加了丘脑中 mRNA 的表达，并增加了 NF-κB 和 TNF-α 的水平。总之，我们的研究结果表明，Tg 通过调节未折叠蛋白反应途径并以剂量依赖性方式激活炎症过程来影响 SWD 的发生。

更新日期：2024-04-25

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