NPS 2390 is a non-competitive antagonist of metabolic glutamate receptors 1 (mGluR1) and 5 (mGluR5)[1, 2]. NPS 2390 is a selective calcium-sensing receptor (CaSR) antagonist capable of regulating the phenotypic modulation of hypoxic human pulmonary arterial smooth muscle cells by modulating autophagy[3]. NPS 2390 can ameliorate cardiac injury induced by ischemia/reperfusion[4].
In vitro, treatment of human pulmonary arterial smooth muscle cells (HPASMCs) with NPS 2390 (10µM) for 24h reduced the expression of intracellular autophagy proteins and the synthetic phenotype marker protein osteopontin; it inhibited the downstream PI3K/Akt/mTOR signaling pathway while upregulating the expression of the contractile phenotype markers SMA-α and calponin[3]. Treatment of rat hippocampal cultures with NPS 2390 (10µM) reversed the neuronal injury and apoptosis induced jointly by hypoxia/reoxygenation (H/R) treatment and the calcium-sensing receptor (CaSR) agonist GdCl3; it prevented the GdCl3-induced reduction in neuronal count and decline in cell viability, and significantly lowered the expression levels of caspase-3, Bax, and cytochrome c[5].
In vivo, subcutaneous administration of NPS 2390 (1.5mg/kg) twice to rats with traumatic brain injury (TBI) significantly attenuated cerebral edema, improved neurological function, reduced levels of Caspase-3 and the number of apoptotic neurons in brain tissue, upregulated the expression of the anti-apoptotic protein Bcl-2, downregulated the expression of the pro-apoptotic protein Bax, and reduced the subsequent release of cytochrome c into the cytosol[6]. Treatment of rats with kidney stones via intraperitoneal injection of NPS 2390 (200mg/kg) for four weeks significantly reduced blood urea and serum creatinine levels, lowered the incidence of urinary tract infections, and decreased the expression levels of stone-associated proteins such as ERK, KIM-1, and OPN[7].
References:
[1] Miller B, Moreno N, Gutierrez B A, et al. Microtransplantation of postmortem native synaptic mGluRs receptors into Xenopus oocytes for their functional analysis[J]. Membranes, 2022, 12(10): 931.
[2] Vaidya A, Jain S, K. Jain A, et al. Metabotropic glutamate receptors: a review on prospectives and therapeutic aspects[J]. Mini Reviews in Medicinal Chemistry, 2013, 13(13): 1967-1981.
[3] Peng X, Wei C, Li H Z, et al. NPS2390, a selective calcium-sensing receptor antagonist controls the phenotypic modulation of hypoxic human pulmonary arterial smooth muscle cells by regulating autophagy[J]. Journal of Translational Internal Medicine, 2019, 7(2): 59-68.
[4] Gan R, Hu G, Zhao Y, et al. Post-conditioning protecting rat cardiomyocytes from apoptosis via attenuating calcium-sensing receptor-induced endo (sarco) plasmic reticulum stress[J]. Molecular and cellular biochemistry, 2012, 361(1): 123-134.
[5] Wang P, Wang L, Wang S, et al. Effects of calcium-sensing receptors on apoptosis in rat hippocampus during hypoxia/re-oxygenation through the ERK1/2 pathway[J]. International journal of clinical and experimental medicine, 2015, 8(8): 12858.
[6] Xue Z, Song Z, Wan Y, et al. Calcium-sensing receptor antagonist NPS2390 attenuates neuronal apoptosis though intrinsic pathway following traumatic brain injury in rats[J]. Biochemical and biophysical research communications, 2017, 486(2): 589-594.
[7] Li X, Chen S, Feng D, et al. Calcium-sensing receptor promotes calcium oxalate crystal adhesion and renal injury in Wistar rats by promoting ROS production and subsequent regulation of PS ectropion, OPN, KIM-1, and ERK expression[J]. Renal failure, 2021, 43(1): 465-476.
NPS 2390是代谢性谷氨酸受体1（mGluR1）和5（mGluR5）的非竞争性拮抗剂[1, 2]。NPS 2390是一种选择性钙感应受体拮抗剂，能够通过调控自噬来控制缺氧人类肺动脉平滑肌细
NPS 2390是代谢性谷氨酸受体1（mGluR1）和5（mGluR5）的非竞争性拮抗剂[1, 2]。NPS 2390是一种选择性钙感应受体（CaSR）拮抗剂，能够通过调控自噬来控制缺氧人类肺动脉平滑肌细胞的表型调节[3]。NPS 2390能够改善缺血/再灌注引起的心脏损伤[4]。
在体外，NPS 2390（10µM）处理人类肺动脉平滑肌细胞（HPASMCs）24h，降低了细胞内自噬蛋白和合成表型标记蛋白骨质素的表达，抑制了下游 PI3K/Akt/mTOR信号通路，提高了收缩表型标记蛋白SMA-ɑ和钙基素的表达[3]。NPS 2390（10µM）处理大鼠海马体培养物，逆转了由缺氧/复氧（H/R）处理和钙敏感受体（CaSR）激动剂GdCl3共同导致的大鼠海马神经元损伤与凋亡，阻止了GdCl3所引起的神经元数量减少和细胞活力下降，显著降低了caspase-3、Bax和细胞色素c的表达水平[5]。
在体内，NPS 2390（1.5mg/kg）通过皮下注射治疗创伤性脑损伤（TBI）大鼠2次，显著减轻了脑水肿，改善了神经功能，降低了脑组织中Caspase-3的水平及凋亡神经元的数量，上调了抗凋亡蛋白Bcl-2的表达，下调了促凋亡蛋白Bax的表达，并减少了随后细胞色素c向细胞溶质的释放[6]。NPS 2390（200mg/kg）通过腹腔注射治疗肾结石大鼠4周，显著降低了血尿素和血清肌酐值，降低了尿路感染率，降低了ERK、KIM-1和OPN等结石相关蛋白表达水平[7]。