The NLRP3 inhibitor Dapansutrile improves the therapeutic action of lonafarnib on progeroid mice

IF 7.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology
Aging Cell Pub Date : 2024-08-27 DOI:10.1111/acel.14272
Inés Muela-Zarzuela, Juan Miguel Suarez-Rivero, Daniel Boy-Ruiz, Juan López-Pérez, Marta Sotelo-Montoro, Maria del Mar Navarrete-Alonso, Isidro G. Collado, José Manuel Botubol-Ares, Alberto Sanz, Mario D. Cordero
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Abstract

The role of the inflammasomes in aging and progeroid syndromes remain understudied. Recently, MCC950, a NLRP3 inhibitor, was used in Zmpste24−/− mice to ameliorate the phenotypes. However, the safety of MCC950 was questioned due to liver toxicity observed in humans. Nevertheless, inhibition of the inflammasomes would be a beneficial therapy for progeria. Here, we show that OLT1177 (dapansutrile), other NLRP3 inhibitor, improved cellular and animal phenotypes using progeroid fibroblasts and a LmnaG609G/G609G mouse model. In both cases dapansutrile reduced progerin accumulation, NLRP3-inflammasome activation and secretory phenotype of senescence, extended the lifespan of progeroid animals, preserved bodyweight, and reduced kyphosis, inflammation, and senescence. Interestingly, dapansutrile further improved the effect of lonafarnib, the only FDA-approved drug for the progeria. The combination of both drugs reduced the inflammation and senescence, extended survival and ameliorated various progeroid defects both in vitro and in vivo, compared with treatment using lonafarnib alone. These findings and the safety of dapansutrile demonstrated in several clinical trials proposes it as a possible co-adjuvant treatment with lonafarnid in HGPS.

Abstract Image

Abstract Image

NLRP3抑制剂Dapansutrile可改善长春瑞滨对早衰症小鼠的治疗作用。
炎性体在衰老和类早衰综合征中的作用仍未得到充分研究。最近,一种NLRP3抑制剂MCC950被用于Zmpste24-/-小鼠,以改善其表型。然而,由于在人体中观察到肝脏毒性,MCC950 的安全性受到质疑。然而,抑制炎性体将是治疗早衰症的一种有益疗法。在这里,我们利用类早衰成纤维细胞和 LmnaG609G/G609G 小鼠模型证明,OLT1177(dapansutrile)(另一种 NLRP3 抑制剂)可改善细胞和动物表型。在这两种情况下,dapansutrile 都能减少早老素的积累、NLRP3-炎症小体的激活和衰老的分泌表型,延长类早衰动物的寿命,保持体重,减少驼背、炎症和衰老。有趣的是,达潘苏曲进一步改善了美国食品及药物管理局批准的唯一一种治疗早衰症的药物--洛纳法尼的效果。与单独使用lonafarnib治疗相比,这两种药物的联合使用在体外和体内都减少了炎症和衰老,延长了存活时间,改善了各种早衰缺陷。这些研究结果以及在多项临床试验中证实的达潘苏肽的安全性,使其有可能成为 HGPS 患者与洛纳法尼联合治疗的辅助药物。
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来源期刊
Aging Cell
Aging Cell 生物-老年医学
CiteScore
14.40
自引率
2.60%
发文量
212
审稿时长
8 weeks
期刊介绍: Aging Cell, an Open Access journal, delves into fundamental aspects of aging biology. It comprehensively explores geroscience, emphasizing research on the mechanisms underlying the aging process and the connections between aging and age-related diseases.
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