AA 147 is a small molecule endoplasmic reticulum (ER) proteostasis regulator. AA 147 can selectively activate the ATF6 arm of the unfolded protein response (UPR) and activate the NRF2 oxidative stress response. AA 147 can be used in research related to neurodegenerative diseases, cardiovascular diseases, and multiple sclerosis[1-4].
In vitro, AA 147 (10μM) pretreated THP1 cells and RAW264.7 mouse macrophages for 16 hours, followed by stimulation with LPS (1μg/mL) and nigericin (10μM) or ATP (5mM) for 3-24 hours. AA 147 significantly inhibited the expression of the pro-inflammatory cytokine IL-1β and reduced the inflammatory response[5]. AA 147 (10μM) treated HT22 cells for 40 hours. AA 147 protected HT22 cells against glutamate-induced oxytosis and erastin-induced ferroptosis[6].
In vivo, AA 147 (2mg/kg) was administered intraperitoneally 1 day before surgery and intravenously 15 minutes after the return of spontaneous circulation, for the treatment of C57BL/6 mice that underwent 9 minutes of cardiac arrest surgery and cardiopulmonary resuscitation. AA 147 significantly improved neurological outcomes and reduced neuronal death[7]. AA 147 (2mg/kg) was administered intraperitoneally 1 hour after stroke, followed by daily injections for 5 days, for the treatment of young (3-4 months old) and aged (18-20 months old) C57BL/6 mice that underwent permanent middle cerebral artery occlusion. AA 147 significantly improved the mice's performance in neurological scores, gait analysis, tape removal test, and Y-maze test, and promoted long-term functional recovery in the mice[8].
References:
[1] Rosarda JD, Baron KR, Nutsch K, et al. Metabolically Activated Proteostasis Regulators Protect against Glutamate Toxicity by Activating NRF2. ACS Chem Biol. 2021 Dec 17;16(12):2852-2863.
[2] Kubra KT, Akhter MS, Saini Y, et al. Activating transcription factor 6 protects against endothelial barrier dysfunction. Cell Signal. 2022 Nov;99:110432.
[3] D'Amico D, Biondi O, Januel C, et al. Activating ATF6 in spinal muscular atrophy promotes SMN expression and motor neuron survival through the IRE1α-XBP1 pathway. Neuropathol Appl Neurobiol. 2022 Aug;48(5):e12816.
[4] Li B, Yang H, Wu H, et al. Hydroquinone-induced endoplasmic reticulum stress affects TK6 cell autophagy and apoptosis via ATF6-mTOR. Environ Toxicol. 2023 Aug;38(8):1874-1890.
[5] Rosarda JD, Stanton CR, Chen EB, et al. Pharmacologic Targeting of PDIA1 Inhibits NLRP3 Inflammasome Assembly and Activation. Isr J Chem. 2024 Dec;64(12):e202300125.
[6] Kline GM, Madrazo N, Cole CM, et al. Metabolically activated proteostasis regulators that protect against erastin-induced ferroptosis. RSC Chem Biol. 2024 Jul 17;5(9):866-876.
[7] Yuan Z, Lu L, Lian Y, et al. AA147 ameliorates post-cardiac arrest cerebral ischemia/reperfusion injury through the co-regulation of the ATF6 and Nrf2 signaling pathways. Front Pharmacol. 2022 Nov 23;13:1028002.
[8] Yu X, Dang L, Dhar A, et al. Activation of ATF6 Signaling Confers Long-Term Beneficial Effects in Young and Aged Mice After Permanent Stroke. Transl Stroke Res. 2025 Oct;16(5):1799-1810.
AA 147是一种小分子内质网（ER）蛋白稳态调节剂。AA 147可选择性激活未折叠蛋白反应（UPR）的ATF6臂以及激活NRF2氧化应激反应。AA 147可用于神经退行性疾病、心血管疾病以及多发性硬化等相关研究[1-4]。
在体外，AA 147（10μM）预处理THP1细胞、RAW264.7小鼠巨噬细胞16h，随后以LPS（1μg/mL）和尼日利亚菌素（10μM）或ATP（5mM）刺激3-24h。AA 147显著抑制了促炎因子IL-1β的表达，同时降低炎症反应[5]。AA 147（10μM）处理HT22细胞40小时。AA 147保护HT22细胞免受谷氨酸诱导的氧化应激和erastin诱导的铁死亡[6]。
在体内，AA 147（2mg/kg）在手术前1天腹腔注射和自主循环恢复后15分钟静脉注射，用于处理经历9分钟心脏骤停手术和心肺复苏的C57BL/6小鼠。AA 147显著改善了神经功能结果并减少了神经元死亡[7]。AA 147（2mg/kg）在卒中后1小时腹腔注射，随后每天注射持续5天，用于处理经历永久性大脑中动脉闭塞的年轻（3-4月龄）和老年（18-20月龄）C57BL/6小鼠。AA 147显著改善了小鼠在神经功能评分、步态分析、胶带移除测试和Y迷宫测试的表现，AA 147促进了小鼠的长期功能恢复[8]。