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.

Protection of PMS777, a New AChE Inhibitor with PAF Antagonism, Against Amyloid-β-Induced Neuronal Apoptosis and Neuroinflammation

“…In our previous study, we have demonstrated the activities of PMS777 for AChE inhibition and PAF receptor antagonism, and its protective effect against PAF-induced neurotoxicity (Li et al 2007(Li et al , 2008. In connection with its potential value in the treatment of AD, the present study aimed to further explore its protection against Ab-induced neuronal apoptosis and neuroinflammation.…”

AChE Inhibition-based Multi-target-directed Ligands, a Novel Pharmacological Approach for the Symptomatic and Disease-modifying Therapy of Alzheimer's Disease

“…PMS777 (1-100 µM) could dose-dependently inhibit PAF-induced rabbit platelet aggregation and markedly inhibit brain AChE activity in mice with a modest selectivity for AChE [ 48 ]. It was also able to fight oxidative injury [ 49 , 50 ], modulate the release of pro-inflammatory mediators [ 51 ], attenuate PAF-induced neurocytotoxicity and neuroinflammation [ 52 , 53 ], and regulate APP processing in vitro [ 54 ]. Additionally, in vivo study found that PMS777 could reverse spatial memory deficits induced by scopolamine in mouse model [ 48 ].…”

Loss of PAFR prevents neuroinflammation and brain dysfunction after traumatic brain injury

“…A variety of potent lipid mediated receptor inhibitors, including BN52021 and WEB2086, have been characterized2029 and shown to have therapeutic potential in a number of neurological disorders, including models of ischemia-reperfusion injury30, neuroinflammatory disease31, neurotoxic injury32. PAFR inhibitors display neuroprotective properties after TBI33343536 and these compounds might exert their effects via an inhibitory mechanism involving the interaction between PAF and PAFR3738. Our studies have demonstrated that PAFR inhibitors caused a reduction in PAF release resulting in a down regualtion of TBI induced inflammatory cytokines394041 in animal models of brain injury.…”