Necrostatin 2 racemate is a highly specific receptor-interacting protein kinase 1 (RIPK1) inhibitor that does not affect indoleamine 2,3-dioxygenase (IDO) activity[1]. Necrostatin 2 racemate is commonly used in research on inflammatory diseases (such as rheumatoid arthritis), neurodegenerative diseases (such as Alzheimer's disease and Parkinson's disease), and organ protection[2, 3].
In vitro, treatment of pro-B exosomes+ lymphocytes with Necrostatin 2 racemate (1μM) for 48h significantly enhanced cytosporone B (10μM)-induced apoptosis, resulting in an average apoptosis rate of 63.14%, which was approximately 628% higher than that of the control group (10%)[4]. Pretreatment of wild-type bone marrow-derived macrophages (BMDMs) with Necrostatin 2 racemate (45μM), followed by co-treatment with heme and Pam3CSK4 (Pam3) for 48h, partially inhibited heme- and Pam3-induced cell death; this protective effect was further enhanced when combined with z-VAD-FMK (zVAD)[5]. Co-treatment of A549 and H358 cells with Necrostatin 2 racemate (10μM) and copper-based metal-organic frameworks (Cu-MOF) for 72h significantly reversed Cu-MOF-induced cytotoxicity and partially restored cell viability[6].
In vivo, daily intraperitoneal administration of Necrostatin 2 racemate (1.6mg/kg/day) in apolipoprotein E-deficient (ApoE-/-) mice, starting from angiotensin II (Ang II) infusion and continuing for 28 days, significantly alleviated abdominal aortic aneurysm (AAA) formation and reduced AAA incidence[7]. Daily intraperitoneal administration of Necrostatin 2 racemate (2mg/kg/day; once daily) in a neonatal mouse model of necrotizing enterocolitis (NEC), starting from NEC induction and continuing for 3 days, significantly improved survival rates, alleviated intestinal histopathological damage, and reduced the expression of pro-inflammatory cytokines (IL-1β, IL-17, TNF-α, and IFN-γ)[8].
References:
[1] YU J, ZHONG B, ZHAO L, et al. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitors Necrostatin-1 (Nec-1) and 7-Cl-O-Nec-1 (Nec-1s) are potent inhibitors of NAD(P)H: Quinone oxidoreductase 1 (NQO1)[J]. Free Radical Biology and Medicine, 2021, 173: 64-69.
[2] YU Z, JIANG N, SU W, et al. Necroptosis: a novel pathway in neuroinflammation[J]. Frontiers in Pharmacology, 2021, 12: 701564.
[3] MIFFLIN L, OFENGEIM D, YUAN J. Receptor-interacting protein kinase 1 (RIPK1) as a therapeutic target[J]. Nature Reviews Drug Discovery, 2020, 19(8): 553-571.
[4] GENTIMIR C A, GELEŢU G, CHELARU L, et al. Biochemical effects of TLRs, CXCL12, and necrosome activation on pro-B lymphocyte apoptosis in the presence of fibroblasts[J]. Romanian Journal of Oral Rehabilitation, 2022, 14(3).
[5] SUNDARAM B, PANDIAN N, MALL R, et al. NLRP12-PANoptosome activates PANoptosis and pathology in response to heme and PAMPs[J]. Cell, 2023, 186(13): 2783-2801.
[6] LI K, WU L, WANG H, et al. Apoptosis and cuproptosis co-activated copper-based metal-organic frameworks for cancer therapy[J]. Journal of Nanobiotechnology, 2024, 22(1): 546.
[7] WANG Q, ZHOU T, LIU Z, et al. Inhibition of Receptor-Interacting Protein Kinase 1 with Necrostatin-1s ameliorates disease progression in elastase-induced mouse abdominal aortic aneurysm model[J]. Scientific Reports, 2017, 7(1): 42159.
[8] LIU T, ZONG H, CHEN X, et al. Toll-like receptor 4-mediated necroptosis in the development of necrotizing enterocolitis[J]. Pediatric Research, 2022, 91(1): 73-82.
Necrostatin 2 racemate是一种不影响吲哚胺2,3-双加氧酶（IDO）活性的，具有高度特异性的受体相互作用蛋白激酶1（RIPK1）抑制剂[1]。Necrostatin 2 racemate通常用于炎症性疾病（如类风湿性关节炎）、神经退行性疾病（如阿尔茨海默病和帕金森病）和器官保护的研究[2,3]。
在体外，Necrostatin 2 racemate（1μM）处理pro-B exosomes+淋巴细胞48h，显著增强了由cytosporone B（10μM）诱导的细胞凋亡，凋亡率平均达到63.14%，较对照组（10%）提高约628%[4]。Necrostatin 2 racemate（45μM）预处理野生型骨髓来源巨噬细胞（BMDMs）后，与血红素和Pam3CSK4 (Pam3)共处理48h，可部分抑制由血红素和Pam3诱导的细胞死亡；当与z-VAD-FMK（zVAD）联用时可进一步增强保护作用[5]。Necrostatin 2 racemate（10μM）与铜金属有机骨架（Cu-MOF）共同处理A549和H358细胞72h，能显著逆转由Cu-MOF诱导的细胞毒性，部分恢复细胞活力[6]。
在体内，Necrostatin 2 racemate（1.6mg/kg/day）通过腹腔注射处理载脂蛋白E缺陷（ApoE-/- ）小鼠，从血管紧张素II（Ang II）灌注开始，持续28天，显著减轻了腹主动脉瘤（AAA）的形成，并降低了AAA发生率[7]。Necrostatin 2 racemate（2mg/kg/day; once daily）通过腹腔注射治疗坏死性小肠结肠炎（NEC）模型新生小鼠，从NEC诱导开始持续3天，显著提高了小鼠的生存率，减轻了肠道组织病理损伤，并降低了促炎细胞因子（IL-1β、IL-17、TNF-α和IFN-γ）的表达[8]。