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 μM) obviously alleviated PAF-induced cell apoptosis in SH-SY5Y cells. Pretreatment with PMS777 also markedly inhibited intracellular Ca2+ 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.
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Acknowledgments
This study was sponsored by the National Natural Science Foundation of China (No. 30070860 and 30371731), the Program of Shanghai Subject Chief Scientist, the Key Project of Shanghai Municipal Science and Technology Commission (No. 03JC14064, 34319230 and 06XD14011), the National Basic Research Program of China (No. 2005CB724302) and the Project of Shanghai Municipal Education Commission (No. 02BZ30).
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Li, J., Shao, B., Zhu, L. et al. PMS777, A Bis-interacting Ligand for PAF Receptor Antagonism and AChE Inhibition, Attenuates PAF-induced Neurocytotoxicity in SH-SY5Y Cells. Cell Mol Neurobiol 28, 125–136 (2008). https://doi.org/10.1007/s10571-007-9190-9
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DOI: https://doi.org/10.1007/s10571-007-9190-9