Modulation of the Purinergic P2X₇Receptor Attenuates Lipopolysaccharide-Mediated Microglial Activation and Neuronal Damage in Inflamed Brain

Abstract

We investigated the involvement and roles of the ionotropic purinergic receptor P2X 7 R in microglia in mediating lipopolysaccharide (LPS)-induced inflammatory responses and neuronal damage in rat striatum. A detailed in vivo study showed that LPS injection into striatum markedly increased the expression of P2X 7 R in microglia compared with control (saline)-injected animals. Additionally, LPS injection upregulated a broad spectrum of proinflammatory mediators, including inducible nitric oxide synthase (nitric oxide production marker), 3-nitrotyrosine (peroxynitrite-mediated nitration marker), 4-hydroxynonenal (lipid peroxidation marker), and 8-hydroxy-2Ј-deoxyguanosine (oxidative DNA damage marker), and reduced neuronal viability. The P2X 7 R antagonist oxidized ATP (oxATP) was effective in attenuating expressions of all inflammatory mediators and in addition inhibited LPS-induced activation of the cellular signaling factors p38 mitogen-activated protein kinase and transcriptional factor nuclear factor B.

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

“…In vivo studies, meanwhile, have been used to demonstrate the involvement of the P2X7 receptor in activating the inflammasome in a broad variety of rodent disease models, including cerebral ischemia (Kuan et al, 2015), epilepsy (Engel et al, 2012), Parkinson's disease (Marcellino et al, 2010), Alzheimer's disease , depression and anxiety (Basso et al, 2009) and multiple sclerosis (Sharp et al, 2008). Systemic administration of bacterial lipopolysaccharide (LPS) markedly increases the expression of P2X7 receptors in the CNS (Choi et al, 2007), offering a mechanism for changes in CNS function in response to systemic infection.…”

Neuroprotective roles of the P2Y2 receptor

“…Although the endogenous expression of P2Y 2 Rs has been reported in mouse microglia [67,214], it seems likely that increased levels of proinflammatory cytokines should further increase P2Y 2 R expression in glial cells in vivo. Our recent in vitro data show that treatment of mouse primary oligomeric/oligomeric Aβ 1-42 upregulates P2Y 2 R expression [145] via a pathway likely involving P2X7R-mediated IL-1β release [16,75,105,[154][155][156]. It also has been determined that P2X7R activation increases P2Y 2 R expression in rat astrocytes [215].…”

“…P2Y 2 R expression in mouse primary cortical neurons can be upregulated in response to the proinflammatory cytokine IL-1β [16,48], the levels of which are elevated in the AD brain [153]. Activation of the P2X7R in microglia promotes the release of IL-1β, TNF-α, and ATP [16,75,105,[154][155][156], suggesting a mechanism whereby the P2X7R regulates functional P2Y 2 R expression in neurons and other cells. The finding that P2Y 2 R expression under proinflammatory conditions is regulated by NF-κB binding to the P2Y 2 R promoter [104] is consistent with the established role of NF-κB activation in the induction of inflammation [157].…”

P2X7 receptors in cerebral ischemia

“…It markedly attenuates the activation of microglia and interferes with inflammatory signaling processes by decreasing the expression of proinflammatory cytokines [3] . Furthermore, OxATP blocks a sustained increase in [Ca 2+ ] i through the P2X 7 R pores and then inhibits the activation of caspase and apoptotic cascades in lipopolysaccharide-induced inflammatory responses [20,62] . The inhibition of P2X 7 R-mediated signals by OxATP limits post-ischemic inflammatory responses and confers neuroprotection [62] .…”

“…Furthermore, OxATP blocks a sustained increase in [Ca 2+ ] i through the P2X 7 R pores and then inhibits the activation of caspase and apoptotic cascades in lipopolysaccharide-induced inflammatory responses [20,62] . The inhibition of P2X 7 R-mediated signals by OxATP limits post-ischemic inflammatory responses and confers neuroprotection [62] . OxATP prevents both the upregulation of P2X 7 Rs and neuronal death evoked by their excitotoxic effect [3] , but only partially reduces or blocks the cellular damage in organotypic hippocampal cultures [11] .…”