Dutysheva Elizaveta A, Mikeladze Marina A, Trestsova Maria A, Aksenov Nikolay D, Utepova Irina A, Mikhaylova Elena R, Suezov Roman V, Charushin Valery N, Chupakhin Oleg N, Guzhova Irina V, Margulis Boris A, Lazarev Vladimir F
Institute of Cytology of the Russian Academy of Sciences, 194064 St. Petersburg, Russia.
Ural Federal University, 620002 Ekaterinburg, Russia.
Pharmaceutics. 2020 Apr 30;12(5):414. doi: 10.3390/pharmaceutics12050414.
Traumatic brain injury (TBI) often causes massive brain cell death accompanied by the accumulation of toxic factors in interstitial and cerebrospinal fluids. The persistence of the damaged brain area is not transient and may occur within days and weeks. Chaperone Hsp70 is known for its cytoprotective and antiapoptotic activity, and thus, a therapeutic approach based on chemically induced Hsp70 expression may become a promising approach to lower post-traumatic complications. To simulate the processes of secondary damage, we used an animal model of TBI and a cell model based on the cultivation of target cells in the presence of cerebrospinal fluid (CSF) from injured rats. Here we present a novel low molecular weight substance, PQ-29, which induces the synthesis of Hsp70 and empowers the resistance of rat C6 glioma cells to the cytotoxic effect of rat cerebrospinal fluid taken from rats subjected to TBI. In an animal model of TBI, PQ-29 elevated the Hsp70 level in brain cells and significantly slowed the process of the apoptosis in acceptor cells in response to cerebrospinal fluid action. The compound was also shown to rescue the motor function of traumatized rats, thus proving its potential application in rehabilitation therapy after TBI.
创伤性脑损伤(TBI)常导致大量脑细胞死亡,并伴有间质液和脑脊液中有毒因子的积累。受损脑区的持续存在并非短暂性的,可能在数天和数周内发生。伴侣蛋白Hsp70以其细胞保护和抗凋亡活性而闻名,因此,基于化学诱导Hsp70表达的治疗方法可能成为降低创伤后并发症的一种有前景的方法。为了模拟继发性损伤的过程,我们使用了TBI动物模型和基于在来自受伤大鼠的脑脊液(CSF)存在下培养靶细胞的细胞模型。在此,我们介绍一种新型低分子量物质PQ-29,它可诱导Hsp70的合成,并增强大鼠C6胶质瘤细胞对取自遭受TBI的大鼠的脑脊液细胞毒性作用的抵抗力。在TBI动物模型中,PQ-29提高了脑细胞中的Hsp70水平,并显著减缓了受体细胞因脑脊液作用而发生的凋亡过程。该化合物还被证明可挽救受创伤大鼠的运动功能,从而证明了其在TBI后康复治疗中的潜在应用价值。