P2x7 deficiency suppresses development of experimental autoimmune encephalomyelitis

Sharp, Anthony; Polak, Paul; Simonini, Vittoria; Lin, Shao; Richardson, Jill C.; Bongarzone, Ernesto R.; Feinstein, Douglas L.

doi:10.1186/1742-2094-5-33

Cited by 137 publications

(123 citation statements)

References 40 publications

Supporting

Mentioning

114

Contrasting

Order By: Relevance

“…a (Solle et al, 2001;Sim et al, 2004;Nicke et al, 2009;Masin et al, 2012); b (Gartland et al, 2003;Ke et al, 2003); c (Labasi et al, 2002;Taylor et al, 2008Taylor et al, , 2009a; d (Chen and Brosnan, 2006;Sharp et al, 2008). 650 all cloned mammalian P2X7 receptors, except rat, when expressed in HEK-293 cells (Fonfria et al, 2008;Donnelly-Roberts et al, 2009;Roman et al, 2009;Bradley et al, 2011b).…”

Section: Modulators Of P2x7 Receptor Activationmentioning

confidence: 99%

The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

2014

View full text Add to dashboard Cite

Section: Modulators Of P2x7 Receptor Activationmentioning

confidence: 99%

The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

2014

View full text Add to dashboard Cite

“…Gene-linking and epidemiological studies have implicated P2X7 in a host of CNS diseases (Hansen et al, 2008;Ursu et al, 2014). 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.…”

Section: The Role Of P2x Receptors In Neuroinflammationmentioning

confidence: 99%

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

et al. 2016

View full text Add to dashboard Cite

a b s t r a c tThe principle functions of neuroinflammation are to limit tissue damage and promote tissue repair in response to pathogens or injury. While neuroinflammation has utility, pathophysiological inflammatory responses, to some extent, underlie almost all neuropathology. Understanding the mechanisms that control the three stages of inflammation (initiation, propagation and resolution) is therefore of critical importance for developing treatments for diseases of the central nervous system. The purinergic signaling system, involving adenosine, ATP and other purines, plus a host of P1 and P2 receptor subtypes, controls inflammatory responses in complex ways. Activation of the inflammasome, leading to release of pro-inflammatory cytokines, activation and migration of microglia and altered astroglial function are key regulators of the neuroinflammatory response. Here, we review the role of P1 and P2 receptors in mediating these processes and examine their contribution to disorders of the nervous system. Firstly, we give an overview of the concept of neuroinflammation. We then discuss the contribution of P2X, P2Y and P1 receptors to the underlying processes, including a discussion of cross-talk between these different pathways. Finally, we give an overview of the current understanding of purinergic contributions to neuroinflammation in the context of specific disorders of the central nervous system, with special emphasis on neuropsychiatric disorders, characterized by chronic low grade inflammation or maternal inflammation. An understanding of the important purinergic contribution to neuroinflammation underlying neuropathology is likely to be a necessary step towards the development of effective interventions.

show abstract

“…Prolonged exposure to ATP leads to formation of a large opening (termed a macropore) in vitro, although the physiologic significance of this macropore formation is not clearly understood. One of the hallmark features of P2X7 activation is release of the proinflammatory cytokine interleukin (IL)-1b (Solle et al, 2001), which in turn may contribute to neuroinflammation and pain (Chessell et al, 2005;North and Jarvis, 2013), mood disorders (Iwata et al, 2013;Chrovian et al, 2014), and neurodegenerative disorders, such as Alzheimer's disease , multiple sclerosis (Sharp et al, 2008), and epilepsy (Engel et al, 2012;Mesuret et al, 2014). In addition to IL-1b, P2X7-dependent release of glutamate (Andó and Sperlágh, 2013;Ficker et al, 2014), cathepsins (Clark et al, 2010), and chemokines (Shiratori et al, 2010) have been reported, and all of these mediators can serve as "gliotransmitters" aiding in the neuroimmune cross-talk and modulating synaptic plasticity.…”

Section: Introductionmentioning

confidence: 99%

Pharmacology of a Novel Central Nervous System–Penetrant P2X7 Antagonist JNJ-42253432

Lord

Aluisio

Shoblock

et al. 2014

J Pharmacol Exp Ther

View full text Add to dashboard Cite

In the central nervous system, the ATP-gated Purinergic receptor P2X ligand-gated ion channel 7 (P2X7) is expressed in glial cells and modulates neurophysiology via release of gliotransmitters, including the proinflammatory cytokine interleukin (IL)-1b. In this study, we characterized JNJ-42253432 [2-methyl-N-([1-(4-phenylpiperazin-1-yl)cyclohexyl]methyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide] as a centrally permeable (brain-to-plasma ratio of 1), high-affinity P2X7 antagonist with desirable pharmacokinetic and pharmacodynamic properties for in vivo testing in rodents. JNJ-42253432 is a high-affinity antagonist for the rat (pK i 9.1 6 0.07) and human (pK i 7.9 6 0.08) P2X7 channel. The compound blocked the ATPinduced current and Bz-ATP [29(39)-O-(4-benzoylbenzoyl)adenosine-59-triphosphate tri(triethylammonium)]-induced release of IL-1b in a concentration-dependent manner. When dosed in rats, JNJ-42253432 occupied the brain P2X7 channel with an ED 50 of 0.3 mg/kg, corresponding to a mean plasma concentration of 42 ng/ml. The compound blocked the release of IL-1b induced by Bz-ATP in freely moving rat brain. At higher doses/exposure, JNJ-42253432 also increased serotonin levels in the rat brain, which is due to antagonism of the serotonin transporter (SERT) resulting in an ED 50 of 10 mg/kg for SERT occupancy. JNJ-42253432 reduced electroencephalography spectral power in the a-1 band in a dose-dependent manner; the compound also attenuated amphetamine-induced hyperactivity. JNJ-42253432 significantly increased both overall social interaction and social preference, an effect that was independent of stress induced by foot-shock. Surprisingly, there was no effect of the compound on either neuropathic pain or inflammatory pain behaviors. In summary, in this study, we characterize JNJ-42253432 as a novel brain-penetrant P2X7 antagonist with high affinity and selectivity for the P2X7 channel.

show abstract

P2x7 deficiency suppresses development of experimental autoimmune encephalomyelitis

Abstract: Background: The purinergic receptor P2x7 is expressed on myeloid cells as well as on CNS glial cells, and P2x7 activation has been shown to increase both glial and T-cell activation. These properties suggest a role in the development of autoimmune disease including multiple sclerosis.

Cited by 137 publications

References 40 publications

The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

Pharmacology of a Novel Central Nervous System–Penetrant P2X7 Antagonist JNJ-42253432

Contact Info

Product

Resources

About