Institute of Pharmacology, Toxicology, and Pharmacy , Ludwig-Maximilians-University Munich , Koeniginstraße 16 , D-80539 Munich , Germany.
Department of Radiation Oncology , The Houston Methodist Research Institute , 6550 Fannin Street SM8-024 , Houston , Texas 77030 , United States.
ACS Chem Neurosci. 2019 Mar 20;10(3):1434-1444. doi: 10.1021/acschemneuro.8b00475. Epub 2018 Nov 16.
Inflammatory responses involving Toll-like receptor signaling represent a key factor contributing to epileptogenesis. Thus, it is of particular interest to explore the relevance of toll-like receptor ligands and modulators, such as heat shock protein 70 (HSP70). Motivated by recent findings demonstrating an upregulation of HSP70 in a model of epileptogenesis, we analyzed the consequences of genetic and pharmacological targeting of HSP70 expression in a mouse kindling paradigm. Lack of inducible HSP70 resulted in increased prekindling seizure thresholds. However, at threshold stimulation the deficiency-promoted seizure spread, as indicated by an increased seizure severity. Subsequent kindling stimulations elicited more severe seizures in knockout mice, whereas endogenous termination of seizure activity remained unaffected with duration of behavioral and electrographic seizure activity comparable to that of wild-type mice. Interestingly, HSP70 deficiency resulted in enhanced microglia activation in the CA1 region. Next, we assessed a pharmacological targeting approach aiming to promote HSP70 expression. Celastrol treatment had no impact on kindling progression but reduced postkindling seizure thresholds and enhanced microglia activation in CA1 and CA3. In conclusion, the findings from HSP70-knockout mice support a protective role of HSP70 with an effect on microglia activation and spread of seizure activity. Unexpectedly, celastrol administration resulted in detrimental consequences. These findings should be considered as a warning about the general safety of celastrol as a drug candidate. The impact of pathophysiological mechanisms on the quality of celastrol effects requires comprehensive future studies exploring influencing factors. Moreover, alternate strategies to increase HSP70 expression should be further developed and validated.
涉及 Toll 样受体信号的炎症反应是促成癫痫发生的关键因素。因此，探索 Toll 样受体配体和调节剂（如热休克蛋白 70 (HSP70)）的相关性尤其具有意义。鉴于最近的研究发现癫痫发生模型中 HSP70 的表达上调，我们分析了 HSP70 表达的遗传和药理学靶向在小鼠点燃模型中的后果。缺乏诱导型 HSP70 导致预点燃发作阈值增加。然而，在阈值刺激下，缺乏促进了发作的传播，这表现为发作严重程度增加。随后的点燃刺激在敲除小鼠中引起更严重的发作，而内源性发作活动的终止不受影响，行为和脑电图发作活动的持续时间与野生型小鼠相当。有趣的是，HSP70 缺乏导致 CA1 区小胶质细胞激活增强。接下来，我们评估了一种旨在促进 HSP70 表达的药理学靶向方法。塞拉托林治疗对点燃进展没有影响，但降低了点燃后的发作阈值，并增强了 CA1 和 CA3 中的小胶质细胞激活。总之，HSP70 敲除小鼠的研究结果支持 HSP70 具有保护作用，对小胶质细胞激活和发作活动的传播有影响。出乎意料的是，塞拉托林的给药导致了有害的后果。这些发现应被视为对塞拉托林作为候选药物的一般安全性的警告。生理病理机制对塞拉托林效果质量的影响需要全面的未来研究来探索影响因素。此外，应进一步开发和验证增加 HSP70 表达的替代策略。
