Non-classical anti-inflammatory drugs (NCAIDs) ameliorates brain inflammation and improves memory in Alzheimer's diseases mice model

Abstract Alzheimer’s disease (AD) is the most common cause of dementia due to inflammatory neurodegeneration in the brain. Neuroinflammation caused by damage associated molecular pattern (DAMP: Aβ, ATP) leads to neuronal apoptosis. From our study HY209, a NCAIDs and a TGR5 agonist, inhibits neuroinflammation and neurodegeneration. In vitro, HY209 suppressed NLRP3-ASC oligomerization and production of mature IL-1β/IL-18 in microglia cells by Aβ ± ATP. HY209 inhibited Ca++ influx incurred by ATP or BzATP (P2X7 agonists). Ca++ influx of microglia from TGR5 KO was like that of P2X7 KO compared to wild type mice in response to BzATP. Suggesting that TGR5 is essential in P2X7-mediated Ca++ signaling and HY209 might play a role as an inverse agonist for TGR5 colocalized with P2X7. HY209 activates adenylate cyclase and cAMP. cAMP inhibits priming phase of inflammasomal activation, suppresses pro-inflammatory cytokine (TNF-α) production and oligomerization of NLRP3-ASC complex. Indicating that HY209 suppresses both priming and activation phase of NLRP3 inflammasome. In the 5x Familial Alzheimer’s disease (5xFAD) mice model, HY209 (1 mpk, i.p. or 30 mpk, p.o.) improves memory function, decreases Aβ plaque and neuronal apoptosis in the brain. Structure activity relationships were studied to screen out more potent HY209 derivatives (next generation NCAIDs) with increased bioavailability and higher BBB permeability. Considering efficacies of NSAIDs, PPARγ agonists, specific inhibitors (for TNF-α, ROS, RAGE, HMG-CoA, p38 MAPK, P2X7 and NLRP3) targeting limited number of proinflammatory pathways, NCAIDs could ameliorate broad spectrum of neuroinflammation that is crucial in preventing neurodegeneration and improving cognition and memory in AD.