PNU-120596 is a positive allosteric modulator of α7 neuronal nicotinic acetylcholine receptor (α7nAChR) with an EC50 value of 216nM[1]. α7nAChR is a ligand-gated ion channel. Activation of α7nAChR can affect a series of cellular physiological processes, such as calcium influx, neurotransmitter release, synaptic plasticity and excitatory transmission, and can also induce inflammation, autophagy, necrosis, transcription and apoptosis[2]. PNU-120596 can be used to study neurological diseases[3]. In the presence of PNU-120596 and possibly other positive allosteric modulators, endogenous choline may continuously activate CA1 pyramidal α7nAChR and enhance the excitability of CA1 pyramidal neurons[4].
In vivo, PNU-120596 (3mg/kg) was intraperitoneally injected into 6-OHDA-induced Parkinson's disease (PD) rats for 14 days, which improved motor dysfunction, inhibited neuroinflammation, reduced the expression of JAK2/NF-κB/GSk3β, and promoted the regeneration of dopaminergic neurons in the substantia nigra and striatum[5]. PNU-120596 (1mg/kg) was intravenously injected into rats with myocardial ischemia-reperfusion injury (MIRI), which significantly reduced myocardial infarction area, ultrastructural damage, serum creatine kinase and lactate dehydrogenase, serum proinflammatory cytokine production, myocardial endothelial activation and neutrophil infiltration[6]. PNU-120596 (4mg/kg) was intraperitoneally injected into LPS-induced depression mice, which reduced the expression of 3-hydroxyanthranilic acid dioxygenase (HAAO) in the hippocampus and prefrontal cortex and the formation of microglial quinolinic acid (QUIN)[7].
References:
[1] Uwada J, Nakazawa H, Mikami D, et al. PNU-120596, a positive allosteric modulator of α7 nicotinic acetylcholine receptor, directly inhibits p38 MAPK[J]. Biochemical pharmacology, 2020, 182: 114297.
[2] Xu Z Q, Zhang W J, Su D F, et al. Cellular responses and functions of α7 nicotinic acetylcholine receptor activation in the brain: A narrative review[J]. Annals of translational medicine, 2021, 9(6).
[3] Sun F, Jin K, Uteshev V V. A type-II positive allosteric modulator of α7 nAChRs reduces brain injury and improves neurological function after focal cerebral ischemia in rats[J]. PloS one, 2013, 8(8): e73581.
[4] Kalappa B I, Gusev A G, Uteshev V V. Activation of functional α7-containing nAChRs in hippocampal CA1 pyramidal neurons by physiological levels of choline in the presence of PNU-120596[J]. PloS one, 2010, 5(11): e13964.
[5] Gowayed M A, El-Sayed N S, Matar N A, et al. The α7 nAChR allosteric modulator PNU-120596 amends neuroinflammatory and motor consequences of parkinsonism in rats: role of JAK2/NF-κB/GSk3β/TNF-α pathway[J]. Biomedicine & Pharmacotherapy, 2022, 148: 112776.
[6] Li H, Zhang Z Z, Zhan J, et al. Protective Effect of PNU-120596, a Selective Alpha7 Nicotinic Acetylcholine Receptor–positive Allosteric Modulator, on Myocardial Ischemia–reperfusion Injury in Rats[J]. Journal of Cardiovascular Pharmacology, 2012, 59(6): 507-513.
[7] Alzarea S, Abbas M, Ronan P J, et al. The effect of an α-7 nicotinic allosteric modulator PNU120596 and NMDA receptor antagonist memantine on depressive-like behavior induced by LPS in mice: the involvement of brain microglia[J]. Brain Sciences, 2022, 12(11): 1493.
PNU-120596是α7神经元烟碱乙酰胆碱受体（α7nAChR）的正变构调节剂，EC50值为216nM[1]。α7nAChR是一种配体门控离子通道，α7nAChR的激活能够影响一系列细胞生理过程，例如钙内流、神经递质释放、突触可塑性和兴奋性传递等，还能诱导炎症、自噬、坏死、转录和细胞凋亡等[2]。PNU-120596能够用于神经疾病的研究[3]。在PNU-120596和可能的其他阳性变构调节剂存在的情况下，内源性胆碱可能会持续激活含有CA1锥体α7nAChR，增强CA1锥体神经元的兴奋性[4]。
在体内，PNU-120596（3mg/kg）通过腹腔注射治疗6-OHDA诱导的帕金森症（PD）大鼠14天，改善了大鼠的运动功能障碍，抑制了神经炎症，降低了JAK2/NF-κB/GSk3β的表达，促进了黑质和纹状体中多巴胺能神经元的再生[5]。PNU-120596（1mg/kg）通过静脉注射治疗心肌缺血再灌注损伤（MIRI）大鼠，显著降低了心肌梗死面积、超微结构损伤、血清肌酸激酶和乳酸脱氢酶，降低了血清促炎细胞因子产生、心肌内皮活化和中性粒细胞浸润[6]。PNU-120596（4mg/kg）通过腹腔注射治疗LPS诱导的抑郁症小鼠， 降低了海马和前额叶皮层中3-羟基邻氨基苯甲酸双加氧酶（HAAO）的表达和小胶质细胞喹啉酸（QUIN）的形成[7]。