PMS777, a bis-interacting ligand for PAF receptor antagonism and AChE inhibition, attenuates PAF-induced neurocytotoxicity in SH-SY5Y cells.
(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.
Li
Juan
J
Department of Pharmacology, School of Medicine, Shanghai Jiao Tong University, 280 South Chongqing Road, Shanghai, 200025, China.
Shao
Biyun
B
Zhu
Liang
L
Cui
Yongyao
Y
Dong
Changzhi
C
Miezan Ezoulin
Jean-Marc
JM
Gao
Xiaoling
X
Ren
Qiushi
Q
Heymans
Françoise
F
Chen
Hongzhuan
H
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
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
Science. 1988 Jun 24;240(4860):1792-4
3381103
Neurosci Lett. 2006 Feb 13;394(2):136-9
16269213
J Lipid Mediat Cell Signal. 1996 May;13(3):207-22
8816985
J Neurosci Res. 1999 Nov 15;58(4):593-8
10533051
Neuroreport. 2004 Mar 1;15(3):509-13
15094513
Nature. 2001 Apr 19;410(6831):988-94
11309629
Biochem Biophys Res Commun. 1995 Oct 13;215(2):572-7
7487994
Lipids. 1991 Dec;26(12):1243-6
1819710
AIDS Res Hum Retroviruses. 2002 Nov 1;18(16):1189-95
12487825
Braz J Med Biol Res. 2003 Feb;36(2):183-90
12563519
Curr Top Med Chem. 2007;7(4):375-87
17305579
Invest Ophthalmol Vis Sci. 1997 Nov;38(12):2492-501
9375567
J Bioenerg Biomembr. 2000 Feb;32(1):35-46
11768760
Planta Med. 1997 Aug;63(4):296-8
9270371
Biochem J. 1997 Aug 15;326 ( Pt 1):1-16
9337844
Prostaglandins Other Lipid Mediat. 2005 Sep;77(1-4):65-76
16099392
Ann N Y Acad Sci. 1992;664:284-92
1456659
J Med Chem. 2006 Jan 26;49(2):459-62
16420031
J Neuroinflammation. 2004 May 11;1(1):4
15285798
J Neurovirol. 2002 Dec;8 Suppl 2:49-52
12491151
Cardiol Clin. 2001 Feb;19(1):45-55
11787813
J Biol Chem. 1998 Jul 10;273(28):17660-4
9651362
J Bioenerg Biomembr. 2005 Jun;37(3):179-90
16167175
Nat Rev Mol Cell Biol. 2003 Jul;4(7):552-65
12838338
Int J Neuropsychopharmacol. 2007 Feb;10(1):21-9
16426477
J Virol. 1994 Jul;68(7):4628-35
8207837
Neurochem Int. 2004 Oct;45(5):713-9
15234114