Ma Xinxin, Hao Junnian, Wu Jianrong, Li Yuehua, Cai Xiaojun, Zheng Yuanyi
Department of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Shanghai, 200233, P. R. China.
Radiology Department, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Shanghai, 200233, P. R. China.
Adv Mater. 2022 Apr;34(15):e2106723. doi: 10.1002/adma.202106723. Epub 2022 Mar 1.
Current pharmacological interventions for Parkinson's disease (PD) remain unsatisfactory in clinical settings. Inflammasome-mediated pyroptosis represents a potential therapeutic target for the alleviation of neurodegenerative diseases. The development of inflammasome-mediated pyroptosis agonists or antagonists may transform the treatment of neurodegenerative diseases. However, the identification of specific compounds that inhibit pyroptosis remains challenging. Herein, Prussian blue nanozyme (PBzyme) is revealed as a pyroptosis inhibitor to alleviate the neurodegeneration in mouse and cell models of PD. PBzyme protects the microglia and neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). PBzyme alleviates motor deficits, attenuates the damage of mitochondrial membrane potential, and rescues dopaminergic neurons. Furthermore, intra-cerebroventricular injection of PBzyme reduces dopaminergic degeneration and inhibits neuroinflammation in an MPTP-induced PD mouse model. Both in vitro and in vivo results demonstrate that PBzyme reduces the activation of microglial nucleotide-binding domain and leucine-rich repeat family pyrin domain containing 3 (NLRP3) inflammasomes and caspase-1 by scavenging reactive oxygen species, thereby downregulating gasdermin D (GSDMD) cleavage as well as inflammatory factor production, and eventually leading to the inhibition of microglia pyroptosis. Overall, this work highlights the neuroprotective effects of PBzyme as a pyroptosis inhibitor and provides valuable mechanistic insights and a potential therapeutic strategy for the treatment of PD.
目前用于帕金森病（PD）的药物干预在临床环境中仍不尽人意。炎性小体介导的细胞焦亡是缓解神经退行性疾病的一个潜在治疗靶点。炎性小体介导的细胞焦亡激动剂或拮抗剂的开发可能会改变神经退行性疾病的治疗方式。然而，鉴定抑制细胞焦亡的特定化合物仍然具有挑战性。在此，普鲁士蓝纳米酶（PBzyme）被揭示为一种细胞焦亡抑制剂，可减轻PD小鼠和细胞模型中的神经退行性变。PBzyme保护小胶质细胞和神经元免受1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）的损伤。PBzyme减轻运动功能障碍，减弱线粒体膜电位的损伤，并挽救多巴胺能神经元。此外，在MPTP诱导的PD小鼠模型中，脑室内注射PBzyme可减少多巴胺能神经元变性并抑制神经炎症。体外和体内结果均表明，PBzyme通过清除活性氧减少小胶质细胞含核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）炎性小体和半胱天冬酶-1的激活，从而下调gasdermin D（GSDMD）的切割以及炎症因子的产生，最终导致小胶质细胞焦亡的抑制。总体而言，这项工作突出了PBzyme作为细胞焦亡抑制剂的神经保护作用，并为PD的治疗提供了有价值的机制见解和潜在的治疗策略。
