KN-93 is an effective, cell-membrane permeable, and selective inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMKII) with an IC50 value of 0.37μM[1, 2]. KN-93 inhibits the rapid component of the delayed rectifier potassium current (IKr) in mammalian cardiomyocytes[3]. KN-93 induces nuclear translocation of histone deacetylase 4 (HDAC4), thereby promoting fatty acid oxidation in myocardial infarction[4].
In vitro, treatment of LX-2 human hepatic stellate cells with KN-93 (0-50μM) for 24h decreased cell viability and the expression of cell cycle regulatory proteins p53 and p21 in a dose-dependent manner[5]. Treatment of NMDA-induced neuronal cells with KN-93 (1μM) significantly reduced cell apoptosis, LDH release, and intracellular calcium concentration[6].
In vivo, 21-day treatment of Parkinson's disease rats with KN-93 (2μg, 5μg) via striatal injection significantly alleviated levodopa-induced motor dysfunction, reduced phosphorylation levels of GluR1 in the nucleus accumbens, and decreased the expression levels of glutamate decarboxylase 1 (Gad1) and Nur77 (NR4A1, an orphan receptor of the nuclear receptor superfamily)[7].
References:
[1] Anderson M E, Braun A P, Wu Y, et al. KN-93, an inhibitor of multifunctional Ca++/calmodulin-dependent protein kinase, decreases early afterdepolarizations in rabbit heart[J]. The Journal of pharmacology and experimental therapeutics, 1998, 287(3): 996-1006.
[2] Agulló L, Garcia-Dorado D, Escalona N, et al. Membrane association of nitric oxide-sensitive guanylyl cyclase in cardiomyocytes[J]. Cardiovascular research, 2005, 68(1): 65-74.
[3] Hegyi B, Chen-Izu Y, Jian Z, et al. KN-93 inhibits IKr in mammalian cardiomyocytes[J]. Journal of Molecular and Cellular Cardiology, 2015, 89: 173-176.
[4] Zhao J, Li L, Wang X, et al. KN-93 promotes HDAC4 nucleus translocation to promote fatty acid oxidation in myocardial infarction[J]. Experimental Cell Research, 2024, 438(2): 114050.
[5] An P, Zhu J Y, Yang Y, et al. KN-93, a specific inhibitor of CaMKII inhibits human hepatic stellate cell proliferation in vitro[J]. World Journal of Gastroenterology: WJG, 2007, 13(9): 1445.
[6] Liu X, Ma C, Xing R, et al. The calmodulin-dependent protein kinase II inhibitor KN-93 protects rat cerebral cortical neurons from N-methyl-D-aspartic acid-induced injury☆[J]. Neural Regeneration Research, 2013, 8(2): 111-120.
[7] Yang X, Wu N, Song L, et al. Intrastriatal injections of KN-93 ameliorates levodopa-induced dyskinesia in a rat model of Parkinson’s disease[J]. Neuropsychiatric disease and treatment, 2013: 1213-1220.
KN-93是一种有效的、细胞膜通透性的、选择性Ca2+/钙调蛋白依赖性蛋白激酶II（CaMKII）抑制剂，IC50值为0.37μM[1, 2]。KN-93能够抑制哺乳动物心肌细胞中延迟整流钾电流的快速成分（IKr）[3]。KN-93能够诱导组蛋白脱乙酰酶4（HDAC4）向细胞核转位，从而促进心肌梗死中的脂肪酸氧化[4]。
在体外，KN-93（0-50μM）处理LX-2人肝星形细胞24h，以剂量依赖性方式降低了细胞活力，降低了细胞周期调节蛋白p53和p21的表达[5]。KN-93（1μM）处理N-甲基-D-天冬氨酸（NMDA）诱导损伤的神经元细胞，显著降低了细胞凋亡率，减少了乳酸脱氢酶（LDH）释放，降低了细胞内钙离子浓度[6]。
在体内，KN-93（2μg，5μg）通过纹状体注射治疗帕金森病大鼠21天，显著减轻了左旋多巴诱导的运动障碍，降低了内纹核中小鼠谷氨酸受体1（GluR1）的磷酸化水平，降低了谷氨酸脱羧酶1（Gad1）和Nur77（NR4A1，是核受体超家族的孤生受体）的表达水平[7]。