SR 8278 is an antagonist of the nuclear receptor REV-ERBα that can inhibit the transcription of REV-ERBα with an EC50 value of 0.47μM[1]. SR 8278 can be used to regulate metabolism in vivo, study biological rhythms, and treat mood disorders caused by Parkinson's disease[2, 3]. SR 8278 can effectively enhance the tear secretion function of jet-lagged mice by targeting NR1D1 inhibition[4].
In vitro, SR 8278 (50μM) pretreatment of HaCaT keratinocytes for 24h can protect keratinocytes from UVB radiation damage, but can make keratinocytes sensitive to UVA radiation and produce reactive oxygen species[5].
In vivo, SR 8278 (20μg/mouse) was slowly injected into the ventral tegmental area (VTA) of the midbrain to treat Parkinson's disease mice, which restored the emotion-related behavioral defects exhibited by the mice and restored the binding activity of REV-ERBα and NURR1[3]. SR 8278 (5mg/kg) was intraperitoneally injected into rats with acute lung injury (ALI) induced by ischemia-reperfusion (IR). It completely abolished the protective effect of SR9009 in IR-ALI and reversed the protective mechanisms of SR9009, including reducing pulmonary edema, inhibiting the production of inflammatory factors in bronchoalveolar lavage fluid (BALF), and reducing the accumulation of nuclear NF-κB p65 in lung tissue[6].
References:
[1] Kojetin D, Wang Y, Kamenecka T M, et al. Identification of SR8278, a synthetic antagonist of the nuclear heme receptor REV-ERB[J]. ACS chemical biology, 2011, 6(2): 131-134.
[2] Dong D, Sun H, Wu Z, et al. A validated ultra-performance liquid chromatography-tandem mass spectrometry method to identify the pharmacokinetics of SR8278 in normal and streptozotocin-induced diabetic rats[J]. Journal of Chromatography B, 2016, 1020: 142-147.
[3] Kim J, Park I, Jang S, et al. Pharmacological rescue with SR8278, a circadian nuclear receptor REV-ERBα antagonist as a therapy for mood disorders in Parkinson's disease[J]. Neurotherapeutics, 2022, 19(2): 592-607.
[4] Huang S, QI D, Pei X, et al. Transcriptomic analysis of SR8278 improving lacrimal gland dysfunction in-duced by jet lag in mice[J]. Recent Advances in Ophthalmology, 2024: 264-269.
[5] Cvammen W, Kemp M G. The REV‐ERB antagonist SR8278 modulates keratinocyte viability in response to UVA and UVB radiation[J]. Photochemistry and Photobiology, 2024, 100(6): 1864-1873.
[6] Chu S J, Liao W I, Pao H P, et al. Targeting Rev-Erbα to protect against ischemia-reperfusion-induced acute lung injury in rats[J]. Respiratory Research, 2023, 24(1): 247.
SR 8278是一种核受体REV-ERBα的拮抗剂，能够抑制REV-ERBα的转录，EC50 值为0.47μM[1]。SR 8278能够用于调节生物体内代谢，研究生物节律，还能够用于治疗帕金森病引起的情绪障碍[2, 3]。SR 8278能够通过靶向抑制NR1D1有效增强时差小鼠的泪液分泌功能[4]。
在体外，SR 8278（50μM）预处理HaCaT角质形成细胞24h，可保护角质形成细胞免受UVB辐射的伤害，但能够使角质形成细胞对UVA辐射敏感并产生活性氧[5]。
在体内，SR 8278（20μg/只小鼠）通过微量缓慢注射到中脑腹侧被盖区（VTA）治疗帕金森病小鼠，恢复了小鼠表现出的情绪相关行为缺陷，恢复了REV-ERBα和NURR1的结合活性[3]。SR 8278（5mg/kg）通过腹腔注射治疗缺血-再灌注（IR）诱发的急性肺损伤（ALI）大鼠，完全消除了SR9009在IR-ALI中的保护作用，逆转了SR9009减少肺水肿、抑制支气管肺泡灌洗液（BALF）中炎症因子生成、减少肺组织中核NF-κB p65的积累等保护机制[6]。