title: PMS777, a bis-interacting ligand for PAF receptor antagonism and AChE inhibition, attenuates PAF-induced neurocytotoxicity in SH-SY5Y cells.
abstract: (1) HIV-1 and viral proteins-evoked chronic brain inflammation, which is characterized by microglial activation, is the pivotal neuropathogenesis of HIV-1-associated dementia (HAD). Platelet-activating factor (PAF), mainly released from activated microglia and acts as a high potent inflammatory mediator and a neurotoxin, is indicated to be a principle initiator of neuroinflammation, neuronal dysfunction, and apoptosis related to HAD. Thus, bis-interacting ligands of acetylcholinesterase (AChE) inhibition and PAF receptor antagonism would be of great interest in the therapeutic potential of HAD not only for improvement of cognitive performance, but also for disease-modifying. (2). We have previously reported that a novel tetrahydrofuran-derived bis-interacting ligand PMS777 had satisfying potencies for PAF receptor blockade and AChE inhibition, and markedly improved cholinergic dysfunction-induced cognitive impairment in mice. Continuing with our research, we further investigated the neuroprotective activities of PMS777 on PAF-triggered neuronal injury in human neuroblastoma SH-SY5Y cells. (3) The bis-interacting ligand PMS777 (10 muM) obviously alleviated PAF-induced cell apoptosis in SH-SY5Y cells. Pretreatment with PMS777 also markedly inhibited intracellular Ca(2+) overload, down-regulation of anti-apoptotic bcl-2 mRNA, stimulation of pro-apoptotic bax mRNA expression and activation of caspase-3 pathway. Also, PMS777 could fine-tune pro-inflammatory cyclooxygenase-2 (cox-2) mRNA expression in PAF-treated cells. (4) These results suggest that PMS777 possesses a neuroprotective profile via anti-apoptotic/inflammatory signaling and warrant further investigations in connection with the potential value of this compound in HAD treatment.
authors: Department of Pharmacology, School of Medicine, Shanghai Jiao Tong University, 280 South Chongqing Road, Shanghai, 200025, China.
authors: Juan
authors: J
authors: Li
authors: Biyun
authors: B
authors: Shao
authors: Liang
authors: L
authors: Zhu
authors: Yongyao
authors: Y
authors: Cui
authors: Changzhi
authors: C
authors: Dong
authors: Jean-Marc
authors: JM
authors: Miezan Ezoulin
authors: Xiaoling
authors: X
authors: Gao
authors: Qiushi
authors: Q
authors: Ren
authors: Françoise
authors: F
authors: Heymans
authors: Hongzhuan
authors: H
authors: Chen
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005663:Furans / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D009498:Neurotoxins / Q000633:toxicity; D010972:Platelet Activating Factor / Q000031:analogs & derivatives* / Q000633:toxicity; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C036761:1-alkyl-2-acyl-sn-glycero-3-phosphocholine; D061945:Caspase Inhibitors; D002800:Cholinesterase Inhibitors; D005663:Furans; D008024:Ligands; D009498:Neurotoxins; C507206:PMS 777; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011480:Protease Inhibitors; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D051028:bcl-2-Associated X Protein; C039351:platelet activating factor receptor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000110:Acetylcholinesterase; D002118:Calcium
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