AC 253 is an amylin (AMY3) receptor antagonist. AC 253 inhibits 125I-adrenomedullin binding (IC50=25nM) and blocks adrenomedullin-stimulated cAMP generation[1-2]. AC 253 is used in research related to Alzheimer's disease and diabetes[3-4].
In vitro, N2a cells were pre-treated with AC 253 (10μM) for 8 hours, followed by co-culture with AMY3 receptor-enriched extracellular vesicles (EVs) and Aβ (10μM) for 48 hours. AC 253 blocked the protective effect of AMY3 EVs against Aβ-induced cytotoxicity[5]. Human fetal microglial cells were pre-treated with AC 253 (10μM) for 24 hours, followed by exposure to Amylin (1μM) or Aβ1-42 (1μM) for 6 hours. AC 253 blocked the Aβ- or Amylin-induced increase in intracellular calcium and attenuated the activation of NLRP3 and caspase-1 as well as the release of TNFα and IL-1β[6].
In vivo, Sprague-Dawley rats fasted for 24 hours were pre-treated with an intraperitoneal injection of AC 253 (500μg/kg) 1 hour before the onset of darkness. AC 253 significantly attenuated the anorectic effects induced by cholecystokinin (CCK; 0.5μg/kg) and bombesin (BBS; 0.5μg/kg)[7]. AC 253 (2.4μg/day) was continuously administered via intracerebroventricular infusion to TgCRND8 Alzheimer's disease model mice for 5 months. AC 253 significantly improved the spatial memory and learning ability of the mice, increased the expression of synaptic proteins (synapsin 1 and synaptophysin), and reduced the activation of the microglial marker Iba-1[8].
References:
[1] Coppock HA, Owji AA, Austin C, et al. Rat-2 fibroblasts express specific adrenomedullin receptors, but not calcitonin-gene-related-peptide receptors, which mediate increased intracellular cAMP and inhibit mitogen-activated protein kinase activity. Biochem J. 1999 Feb 15;338 ( Pt 1)(Pt 1):15-22.
[2] Jhamandas JH, Li Z, Westaway D, et al. Actions of β-amyloid protein on human neurons are expressed through the amylin receptor. Am J Pathol. 2011 Jan;178(1):140-9.
[3] Lutz TA, Tschudy S, Rushing PA, et al. Attenuation of the anorectic effects of cholecystokinin and bombesin by the specific amylin antagonist AC 253. Physiol Behav. 2000 Sep 15;70(5):533-6.
[4] Soudy R, Kimura R, Patel A, et al. Short amylin receptor antagonist peptides improve memory deficits in Alzheimer's disease mouse model. Sci Rep. 2019 Jul 29;9(1):10942.
[5] Soudy R, Kimura R, Fu W, et al. Extracellular vesicles enriched with amylin receptor are cytoprotective against the Aß toxicity in vitro. PLoS One. 2022 Apr 14;17(4):e0267164.
[6] Fu W, Vukojevic V, Patel A, et al. Role of microglial amylin receptors in mediating beta amyloid (Aβ)-induced inflammation. J Neuroinflammation. 2017 Oct 6;14(1):199.
[7] Lutz TA, Tschudy S, Rushing PA, et al. Attenuation of the anorectic effects of cholecystokinin and bombesin by the specific amylin antagonist AC 253. Physiol Behav. 2000 Sep 15;70(5):533-6.
[8] Soudy R, Patel A, Fu W, et al. Cyclic AC253, a novel amylin receptor antagonist, improves cognitive deficits in a mouse model of Alzheimer's disease. Alzheimers Dement (N Y). 2016 Dec 10;3(1):44-56.
AC 253是一种amylin（AMY3）受体拮抗剂。AC 253可抑制125I-adrenomedullin结合（IC50=25nM）并阻断adrenomedullin刺激的cAMP生成[1-2]。AC 253可用于阿尔茨海默病和糖尿病的相关研究[3-4]。
在体外，AC 253（10μM）预处理N2a细胞8小时，随后加入富含AMY3受体的细胞外囊泡（EVs）和Aβ（10μM）共培养48小时。AC 253阻断了AMY3 EVs对Aβ诱导的细胞毒性的保护作用[5]。AC 253（10μM）预处理人胎小胶质细胞24小时，随后暴露于Amylin（1μM）或Aβ1-42（1μM）6小时。AC 253阻断了Aβ或Amylin诱导的细胞内钙离子增加，并减弱了NLRP3和caspase-1的活化以及TNFα和IL-1β的释放[6]。
在体内，AC 253（500μg/kg）在黑暗开始前1小时腹腔注射预处理，用于处理24小时禁食的Sprague-Dawley大鼠。AC 253显著减弱了胆囊收缩素（CCK；0.5μg/kg）和铃蟾肽（BBS；0.5μg/kg）引起的厌食效应[7]。AC 253（2.4μg/天）通过脑室内连续输注于TgCRND8阿尔茨海默病模型小持续5个月。AC 253显著改善了小鼠的空间记忆和学习能力，增加了突触蛋白（synapsin 1和synaptophysin）的表达，并减少了小胶质细胞标记物（Iba-1）的激活[8]。