PK 11195 is an isoquinoline carboxamide derivative and a non-benzodiazepine translocator protein (TSPO) selective ligand[1]. PK 11195 selectively labeled microglia in the central nervous system (CNS), and PK 11195 binding was significantly increased in activated microglia[2]. PK11195 has been widely used as a neuroimaging agent in positron emission tomography (PET) studies and as a neuromodulator to control neurological function in animal models[3].
In vitro, PK 11195 treatment for 72h inhibited cell viability of MCF-7 and T47D cells, with IC50 values of 5.4 and 6.0nM[4]. PK 11195 treatment for 72 hours significantly inhibited the viability of IOMM-LEE cells with an IC50 value of 1.505 ± 0.08nM, and reversed the increase in allopregnanolone level promoted by AC-5216[5]. Treatment with 50μM PK 11195 for 24h inhibited SMS-KCN proliferation, induced apoptosis, and caused G1/S cell cycle arrest, accompanied by decreased mRNA expression of chemotherapy resistance efflux pumps ABCA3, ABCB1, and ABCC1[6].
In vivo, PK 11195 (3mg/kg/day) administered intraperitoneally to C57/BL6 mice for 14 consecutive days prevented cognitive dysfunction induced by systemic lipopolysaccharide (500μg/kg/day; i.p.) injection, reduced neuroinflammation, and increased neurosteroid synthesis[7]. Intraperitoneal injection of PK 11195 (3 mg/kg/week for 5 weeks) in 16-month-old female 3xTg-AD mice improved cognitive and behavioral performance and reduced both soluble and deposited β-amyloid[8].
References:
[1] Rupprecht R, Papadopoulos V, Rammes G, et al. Translocator protein (18 kDa)(TSPO) as a therapeutic target for neurological and psychiatric disorders[J]. Nature reviews Drug discovery, 2010, 9(12): 971-988.
[2] Venneti S, Lopresti B J, Wang G, et al. PK11195 labels activated microglia in Alzheimer's disease and in vivo in a mouse model using PET[J]. Neurobiology of aging, 2009, 30(8): 1217-1226.
[3] Scott G, Mahmud M, Owen D R, et al. Microglial positron emission tomography (PET) imaging in epilepsy: applications, opportunities and pitfalls[J]. Seizure, 2017, 44: 42-47.
[4] Xu J N, Shen D, Mao W D, et al. The effects of PK11195 on the MCF-7 and T47D were associated with the allopregnanolone biosynthesis, which was mediated by Translocator Protein 18 KDa[J]. Cancer Biomarkers, 2016, 17(1): 11-16.
[5] Gao Z W, Huang J B, Lin Q, et al. The effects of PK11195 on meningioma was associated with allopregnanolone biosynthesis, which was mediated by translocator protein 18 kDa[J]. Cancer Biomarkers, 2016, 16(1): 65-69.
[6] Mendonça-Torres M, Roberts S. The translocator protein (TSPO) ligand PK11195 induces apoptosis and cell cycle arrest and sensitizes to chemotherapy treatment in pre-and post-relapse neuroblastoma cell lines[J]. Cancer Biology & Therapy, 2013, 14(4): 319-326.
[7] Ma L, Zhang H, Liu N, et al. TSPO ligand PK11195 alleviates neuroinflammation and beta-amyloid generation induced by systemic LPS administration[J]. Brain research bulletin, 2016, 121: 192-200.
[8] Christensen A, Pike C J. TSPO ligand PK11195 improves Alzheimer-related outcomes in aged female 3xTg-AD mice[J]. Neuroscience letters, 2018, 683: 7-12.
PK 11195是一种异喹啉甲酰胺衍生物，作为非苯二氮䓬类转运蛋白（TSPO）选择性配体[1]。PK 11195可特异性标记中枢神经系统（CNS）中的小胶质细胞，其结合活性在活化的小胶质细胞中显著增强[2]。PK 11195已广泛应用于正电子发射断层扫描（PET）神经成像研究，并在动物模型中作为神经调节剂调控神经功能[3]。
在体外，PK 11195处理72小时可抑制MCF-7和T47D细胞活力，IC50值分别为5.4nM和6.0nM[4]。PK 11195处理72小时抑制IOMM-LEE细胞活力，IC50值为1.505 ± 0.08nM，并能逆转AC-5216促进的allopregnanolone水平升高[5]。50μM的PK 11195处理SMS-KCN细胞24小时可抑制细胞增殖、诱导凋亡并引起G1/S期细胞周期阻滞，同时降低化疗耐药外排泵ABCA3、ABCB1和ABCC1的mRNA表达[6]。
在体内，C57/BL6小鼠连续14天腹腔注射PK 11195（3mg/kg/day）可预防脂多糖（500μg/kg/day；腹腔注射）诱导的认知功能障碍，减轻神经炎症并促进神经类固醇合成[7]。16月龄雌性3xTg-AD小鼠每周腹腔注射PK 11195（3mg/kg/week；持续5周）能改善认知行为表现，并减少可溶性及沉积性β-淀粉样蛋白[8]。