朊病毒病是动物和人类致命的神经退行性疾病,导致神经组织的破坏并诱发行为表现。热休克蛋白(Hsps),作为分子伴侣,通过支持蛋白质的适当折叠和消除错误折叠的蛋白质,以及在细胞信号传导中起着至关重要的作用,细胞周期,和细胞凋亡控制。SW02是Hsp70kDa(Hsp70)的有效激活剂。
■在当前的研究中,研究了SW02对朊病毒蛋白106-126(PrP106-126)诱导的人神经母细胞瘤细胞(SH-SY5Y)的神经毒性的保护作用。此外,评估SW02在ME7瘙痒病感染小鼠中的治疗效果。
■结果表明,SW02处理显着增加了Hsp70mRNA表达水平和Hsp70ATP酶活性(p<0.01)。SW02还显著抑制PrP106-126诱导的细胞毒性和细胞凋亡(p<0.01)并促进神经突延伸。在体内,腹膜内施用SW02在生存时间上没有显示统计学上的显著差异(p=0.16);然而,SW02治疗组的存活时间为223.6±6.0天,未治疗对照组的存活时间为217.6±5.4天。此外,在注射后5个月,SW02减少了ME7瘙痒病感染的小鼠中的PrPSc积累(p<0.05)。GFAP表达没有观察到显著差异,星形胶质细胞标记,在治疗组和未治疗组之间。
■总而言之,在本研究中确定了Hsp70激活剂SW02的潜在治疗作用,并且可能是减轻朊病毒疾病和其他神经退行性疾病病理的新型有效药物。需要使用两种Hsp70药理激活剂的组合进行进一步的研究,以最大化每种干预的有效性。
UNASSIGNED: Prion diseases are deadly neurodegenerative disorders in both animals and humans, causing the destruction of neural tissue and inducing behavioral manifestations. Heat shock proteins (Hsps), act as molecular chaperones by supporting the appropriate folding of proteins and eliminating the misfolded proteins as well as playing a vital role in cell signaling transduction, cell cycle, and apoptosis control. SW02 is a potent activator of Hsp 70 kDa (Hsp70).
UNASSIGNED: In the current study, the protective effects of SW02 against prion protein 106-126 (PrP106-126)-induced neurotoxicity in human neuroblastoma cells (SH-SY5Y) were investigated. In addition, the therapeutic effects of SW02 in ME7 scrapie-infected mice were evaluated.
UNASSIGNED: The results showed that SW02 treatment significantly increased Hsp70 mRNA expression levels and Hsp70 ATPase activity (p < 0.01). SW02 also significantly inhibited cytotoxicity and apoptosis induced by PrP106-126 (p < 0.01) and promoted neurite extension. In vivo, intraperitoneal administration of SW02 did not show a statistically significant difference in survival time (p = 0.16); however, the SW02-treated group exhibited a longer survival time of 223.6 ± 6.0 days compared with the untreated control group survival time of 217.6 ± 5.4 days. In addition, SW02 reduced the PrPSc accumulation in ME7 scrapie-infected mice at 5 months post-injection (p < 0.05). A significant difference was not observed in GFAP expression, an astrocyte marker, between the treated and untreated groups.
UNASSIGNED: In conclusion, the potential therapeutic role of the Hsp70 activator SW02 was determined in the present study and may be a novel and effective drug to mitigate the pathologies of prion diseases and other neurodegenerative diseases. Further studies using a combination of two pharmacological activators of Hsp70 are required to maximize the effectiveness of each intervention.