Kim Youngchul, Kim Young S, Noh Min-Young, Lee Hanchang, Joe Boyoung, Kim Hyun Y, Kim Jeongmin, Kim Seung H, Park Jiseon
Laboratory of Pharmacology & Toxicology, R&D Center, Jeil Pharmaceutical Co., Yongin-City, Kyunggi-Do, Korea.
Department of Neurology, College of Medicine, Hanyang University, Seoul, Korea.
Clin Exp Pharmacol Physiol. 2017 Jun;44(6):671-679. doi: 10.1111/1440-1681.12757.
Excessive activation of poly (ADP-ribose) polymerase-1 (PARP-1) is known to develop neuronal apoptosis, necrosis and inflammation after ischaemic brain injury. Therefore, PARP-1 inhibition after ischaemic stroke has been attempted in successful animal studies. The purpose of present work was to develop a novel water soluble PARP-1 inhibitor (JPI-289) and explore its neuroprotective effect on ischaemic injury in an in vitro model. The half-life of JPI-289 after intravenous or oral administration in rats was relatively long (1.4-1.5 hours) with 65.6% bioavailability. The inhibitor strongly inhibited PARP-1 activity (IC =18.5 nmol/L) and cellular PAR formation (IC =10.7 nmol/L) in the nanomolar range. In rat cortical neuronal cells, JPI-289 did not affect cell viability up to 1 mmol/L as assayed by Trypan blue staining (TBS) and lactate dehydrogenase (LDH) assay. Treatment of JPI-289 for 2 hours after 2 hours of oxygen glucose deprived (OGD) rat cortical neuron attenuated PARP activity and restored ATP and NAD+ levels. Apoptosis-associated molecules such as apoptosis inducing factor (AIF), cytochrome C and cleaved caspase-3 were reduced after JPI-289 treatment in the OGD model. The present findings suggest that the novel PARP-1 inhibitor, JPI-289, is a potential neuroprotective agent which could be useful as a treatment for acute ischaemic stroke.
已知聚（ADP - 核糖）聚合酶 -1（PARP -1）的过度激活会在缺血性脑损伤后引发神经元凋亡、坏死和炎症。因此，在成功的动物研究中已尝试在缺血性中风后抑制PARP -1。本研究的目的是开发一种新型水溶性PARP -1抑制剂（JPI -289），并在体外模型中探索其对缺血性损伤的神经保护作用。JPI -289在大鼠静脉或口服给药后的半衰期相对较长（1.4 - 1.5小时），生物利用度为65.6%。该抑制剂在纳摩尔范围内强烈抑制PARP -1活性（IC =18.5 nmol/L）和细胞PAR形成（IC =10.7 nmol/L）。在大鼠皮质神经元细胞中，通过台盼蓝染色（TBS）和乳酸脱氢酶（LDH）测定，高达1 mmol/L的JPI -289对细胞活力没有影响。在氧糖剥夺（OGD）2小时后的大鼠皮质神经元中，用JPI -289处理2小时可减弱PARP活性并恢复ATP和NAD +水平。在OGD模型中，JPI -289处理后凋亡相关分子如凋亡诱导因子（AIF）、细胞色素C和裂解的半胱天冬酶 -3减少。目前的研究结果表明，新型PARP -1抑制剂JPI -289是一种潜在的神经保护剂，可用于急性缺血性中风的治疗。
