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

Abstract

Amyloid-beta (Abeta) plays a central role in the neuroinflammation and cholinergic neuronal apoptosis in Alzheimer's disease, and thus has been considered as a main determinant of this disease. In the previous study, we reported that PMS777, a novel bis-interacting ligand for acetylcholinesterase (AChE) inhibition and platelet-activating factor (PAF) receptor antagonism, could significantly attenuate PAF-induced neurotoxicity. Continuing our efforts, we further investigated the protective effect of PMS777 on Abeta-induced neuronal apoptosis in vitro and neuroinflammation in vivo. PMS777 (1-100 microM) was found to inhibit Abeta-induced human neuroblastoma SH-SY5Y cell apoptosis in a concentration-dependent manner. Concurrently, PMS777 increased ratio of bcl-2 to bax mRNA, and inhibited both mRNA expression and activity of caspase-3 in SH-SY5Y cells after the exposure with Abeta. In vivo experimental study demonstrated that PMS777 could attenuate Abeta-induced microglial and astrocytic activation in the rat hippocampus after systemic administration. These results suggest that PMS777 potently protects against Abeta-induced neuronal apoptosis and neuroinflammation, and warrants further investigations in connection with its potential value in the treatment of Alzheimer's disease.

Beta-Asarone Improves Cognitive Function by Suppressing Neuronal Apoptosis in the Beta-Amyloid Hippocampus Injection Rats

“…22) The role of apoptosis in in vitro models and transgenic animal models of neuro-degeneration has been largely documented, and direct neurotoxic effects of Ab involve activation of apoptosis pathways. 23,24) In the present study, Ab hippocampus injection increased neuronal cell apoptosis, one of the most important pathological hallmarks of AD. Beta-asarone administration attenuated neuronal apoptosis in the hippocampus in a dose-dependent manner.…”

Platelet‐Activating Factor Mediates the Cytotoxicity Induced by W7FW14F Apomyoglobin Amyloid Aggregates in Neuroblastoma Cells

“…We demonstrated that the cytotoxicity induced by W7FW14F ApoMb is closely related to oxidative stress [Sirangelo et al, ; Vilasi et al, ]. Similarly to previous studies aimed at evaluating the mechanisms of amyloid‐β‐induced neurotoxicity [Bate et al, ; Li et al, ], our data show that the time‐dependent decrease of cell viability elicited by W7FW14F ApoMb insult is prevented by PAF‐R antagonist, CV3988, thus suggesting the involvement of PAF signaling in the apoptotic pathway activated by W7FW14F ApoMb.…”

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

“…In addition loss of PAFR may ameliorate the loss of spatial learning ability and reduced memory and cognitive function after TBI. 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.…”