Abstract
The P2X7 receptor is a cation channel activated by high concentrations of adenosine triphosphate (ATP). Upon long-term activation, it complexes with membrane proteins forming a wide pore that leads to cell death and increased release of ATP into the extracellular milieu. The P2X7 receptor is widely expressed in the CNS, such as frontal cortex, hippocampus, amygdala and striatum, regions involved in neurodegenerative diseases and psychiatric disorders. Despite P2X7 receptor functions in glial cells have been extensively studied, the existence and roles of this receptor in neurons are still controversially discussed. Regardless, P2X7 receptors mediate several processes observed in neuropsychiatric disorders and brain tumors, such as activation of neuroinflammatory response, stimulation of glutamate release and neuroplasticity impairment. Moreover, P2X7 receptor gene polymorphisms have been associated to depression, and isoforms of P2X7 receptors are implicated in neuropsychiatric diseases. In view of that, the P2X7 receptor has been proposed to be a potential target for therapeutic intervention in brain diseases. This review discusses the molecular mechanisms underlying P2X7 receptor-mediated signaling in neurodegenerative diseases, psychiatric disorders, and brain tumors. In addition, it highlights the recent advances in the development of P2X7 receptor antagonists that are able of penetrating the central nervous system.
Highlights
The P2X7 ReceptorThe investigation of receptors activated by adenosine triphosphate (ATP) has been largely widened since their discovery in 1960s by Geoffrey Burnstock
This study provides evidence to support the idea that ATP- or Bz-ATPmediated amyloid-α peptide (Aα) release is mediated by P2X7 receptor activation: (1) three pharmacological inhibitors of P2X7 receptor blocked the release of Aα mediated by Bz-ATP; (2) inhibition of P2X7 receptor synthesis by RNA interference reduced Aα production; and (3) stimulation by Bz-ATP of mouse primary astrocytes and neural progenitor cells from P2X7 receptor-deficient mice did not induce Aα release, while it did in cells derived from wild type animals (Delarasse et al, 2011)
Microinjection of P2X7 receptor antagonists (BBG or A-438079) into the rat hippocampus during 3 weeks prevented the development of depression-related behaviors induced by chronic unpredictable mild stress (CUMS) exposure, while the administration of P2 receptors agonists (ATP or Bz-ATP) for the same period caused depressivelike behaviors similar to those observed after stress exposure (Yue et al, 2017)
Summary
The P2X7 ReceptorThe investigation of receptors activated by adenosine triphosphate (ATP) has been largely widened since their discovery in 1960s by Geoffrey Burnstock. A recent study evidenced that the selective P2X7 receptor antagonist, JNJ55308942, inhibited neuroinflammation development induced in different rodent models by LPS, BCG or chronic stress (Bhattacharya et al, 2018). In accordance with the detrimental role of P2X7 receptor activation in AD, systemic administration of a P2X7 receptor antagonist, BBG, diminished spatial memory impairment and cognitive deficits along with reduced loss of filopodia and spine density induced by the injection of soluble Aβ1-42 into the hippocampal CA1 region of mice, an animal model of AD (Chen et al, 2014).
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