(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.