Zaprinast is a phosphodiesterase inhibitor that targets PDE5 and PDE6, with the IC50 values of 0.8µM and 0.15µM, respectively[1]. Zaprinast acts as an agonist for rat GPR35, with a geometric mean EC50 value of 16nM[2]. Through inhibition of phosphodiesterases, especially PDE5 and PDE6, Zaprinast increases intracellular cGMP levels, which modulates downstream signaling pathways such as protein kinase G (PKG) and cyclic nucleotide gated ion channels[3]. Zaprinast has been widely used in different animal models to regulate smooth muscle contraction and coronary artery relaxation[4].
In vitro, Zaprinast treatment for 48 hours significantly inhibited SK-N-MC cell proliferation with an IC50 value of 3.3µM[5]. Zaprinast (100µM) treatment for 1 hour significantly activated ERK1/2, p38 MAPK, JNK, NFκB and PI3K/Akt signaling pathways in rat microglia[6]. Pretreatment of neonatal rat-derived astrocytes with 100μM Zaprinast for 1h significantly inhibited H2O2-induced lactate dehydrogenase release and cell death[7].
In vivo, Zaprinast treatment via intraperitoneal injection at a dose of 10mg/kg at 2 hours before and 24 and 48 hours after focal cryolesion of cortex significantly enhanced astrogliosis and reduced oxidative stress and cell death at 3 days after focal cryolesion in male Sprague-Dawley rats[8]. A single intraperitoneal injection of Zaprinast (30mg/kg) for 18 hours significantly improved glucose tolerance in diet-induced obese (DIO) mice[9].
References:
[1] Mackenzie A E, Milligan G. The emerging pharmacology and function of GPR35 in the nervous system[J]. Neuropharmacology, 2017, 113: 661-671.
[2] Taniguchi Y, Tonai-Kachi H, Shinjo K. Zaprinast, a well-known cyclic guanosine monophosphate-specific phosphodiesterase inhibitor, is an agonist for GPR35[J]. FEBS letters, 2006, 580(21): 5003-5008.
[3] Halene T B, Siegel S J. PDE inhibitors in psychiatry–future options for dementia, depression and schizophrenia?[J]. Drug discovery today, 2007, 12(19-20): 870-878.
[4] Gibson A. Phosphodiesterase 5 inhibitors and nitrergic transmission—from zaprinast to sildenafil[J]. European journal of pharmacology, 2001, 411(1-2): 1-10.
[5] Giorgi M, Leonetti C, Citro G, et al. In vitro and in vivo inhibition of SK-N-MC neuroblastoma growth using cyclic nucleotide phosphodiesterase inhibitors[J]. Journal of neuro-oncology, 2001, 51(1): 25-31.
[6] Lee H S, Kwon S H, Ham J E, et al. Zaprinast activates MAPKs, NFκB, and Akt and induces the expressions of inflammatory genes in microglia[J]. International immunopharmacology, 2012, 13(3): 232-241.
[7] Choi J H, Kim D H, Yun I J, et al. Zaprinast inhibits hydrogen peroxide-induced lysosomal destabilization and cell death in astrocytes[J]. European journal of pharmacology, 2007, 571(2-3): 106-115.
[8] Pifarré P, Prado J, Giralt M, et al. Cyclic GMP phosphodiesterase inhibition alters the glial inflammatory response, reduces oxidative stress and cell death and increases angiogenesis following focal brain injury[J]. Journal of neurochemistry, 2010, 112(3): 807-817.
[9] Hodges W T, Jarasvaraparn C, Ferguson D, et al. Mitochondrial pyruvate carrier inhibitors improve metabolic parameters in diet-induced obese mice[J]. Journal of Biological Chemistry, 2022, 298(2): 101554.
Zaprinast是一种磷酸二酯酶抑制剂，主要靶向PDE5和PDE6，IC50值分别为0.8µM和0.15µM[1]。Zaprinast可作为大鼠GPR35受体的激动剂，几何平均EC50值为16nM[2]。通过抑制磷酸二酯酶活性，Zaprinast能提高细胞内cGMP水平，进而调控蛋白激酶G(PKG)及环核苷酸门控离子通道等下游信号通路[3]。Zaprinast已广泛应用于多种动物模型中调节平滑肌收缩和冠状动脉舒张[4]。
在体外，Zaprinast处理48小时可显著抑制SK-N-MC细胞增殖，IC50值为3.3µM[5]。使用100µM的Zaprinast处理大鼠小胶质细胞1小时，能显著激活ERK1/2、p38 MAPK、JNK、NFκB和PI3K/Akt信号通路[6]。用100μM的Zaprinast预处理新生大鼠星形胶质细胞1小时，可显著抑制H2O2诱导的乳酸脱氢酶释放和细胞死亡[7]。
在体内，在雄性Sprague-Dawley大鼠皮层冷冻损伤前2小时及损伤后24、48小时分别腹腔注射10mg/kg剂量的Zaprinast，能增强冷冻损伤后3天的星形胶质细胞增生，并降低氧化应激和细胞死亡率[8]。对饮食诱导的肥胖(DIO)小鼠单次腹腔注射30mg/kg剂量的Zaprinast 18小时，可显著改善葡萄糖耐受性[9]。