Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, Germany.
Department of Veterinary Biosciences, The Ohio State University, OH, USA.
Neuroscience. 2018 Aug 21;386:108-120. doi: 10.1016/j.neuroscience.2018.06.031. Epub 2018 Jun 30.
Strong evidence exists that Toll-like receptor (TLR)-mediated effects on microglia functional states can promote ictogenesis and epileptogenesis. So far, research has focused on the role of high-mobility group box protein 1 as an activator of TLRs. However, the development of targeting strategies might need to consider a role of additional receptor ligands. Considering the fact that heat shock protein A1 (hsp70) has been confirmed as a TLR 2 and 4 ligand, we have explored the consequences of its overexpression in a mouse kindling paradigm. The genetic modulation enhanced seizure susceptibility with lowered seizure thresholds prior to kindling. In contrast to wildtype (WT) mice, HSPA1A transgenic (TG) mice exhibited generalized seizures very early during the kindling paradigm. Along with an increased seizure severity, seizure duration proved to be prolonged in TG mice during this phase. Toward the end of the stimulation phase seizure parameters of WT mice reached comparable levels. However, a difference between genotypes was still evident when comparing seizure parameters during the post-kindling threshold determination. Surprisingly, HSPA1A overexpression did not affect microglia activation in the hippocampus. In conclusion, the findings demonstrate that hsp70 can exert pro-convulsant effects promoting ictogenesis in naïve animals. The pronounced impact on the response to subsequent stimulations gives first evidence that genetic HSPA1A upregulation may also contribute to epileptogenesis. Thus, strategies inhibiting hsp70 or its expression might be of interest for prevention of seizures and epilepsy. However, conclusions about a putative pro-epileptogenic effect of hsp70 require further investigations in models with development of spontaneous recurrent seizures.
有充分证据表明 Toll 样受体（TLR）介导的小胶质细胞功能状态的影响可促进致痫和癫痫发生。到目前为止，研究主要集中在高迁移率族蛋白 B1 作为 TLR 激活物的作用。然而，靶向治疗策略的发展可能需要考虑其他受体配体的作用。鉴于热休克蛋白 A1（hsp70）已被证实为 TLR2 和 TLR4 的配体，我们探索了其在小鼠点燃模型中过表达的后果。遗传调节增强了癫痫易感性，使点燃前的癫痫发作阈值降低。与野生型（WT）小鼠相比，HSPA1A 转基因（TG）小鼠在点燃模型中很早就出现了全身性癫痫发作。与 WT 小鼠相比，TG 小鼠在这一阶段的癫痫发作严重程度增加，癫痫持续时间延长。在刺激阶段结束时，WT 小鼠的癫痫发作参数达到了可比水平。然而，在比较点燃后阈值确定期间的癫痫发作参数时，基因型之间仍存在差异。令人惊讶的是，hsp70 的过表达并不影响海马中小胶质细胞的激活。总之，这些发现表明 hsp70 可以发挥促惊厥作用，促进新生动物的致痫形成。hsp70 对后续刺激反应的显著影响首次表明，遗传 HSPA1A 上调也可能导致癫痫发生。因此，抑制 hsp70 或其表达的策略可能对预防癫痫发作和癫痫有意义。然而，关于 hsp70 具有潜在致癫痫作用的结论需要在具有自发性复发性癫痫发作发展的模型中进一步研究。
