Increased expression of the P2X7 receptor in temporal lobe epilepsy: Animal models and clinical evidence

Song, Penghui; Hu, Jing; Liu, Xijin; Deng, Xuejun

doi:10.3892/mmr.2019.10202

Cited by 20 publications

(15 citation statements)

References 34 publications

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“…This is in agreement with the association of P 2X7 R polymorphisms with depressive symptoms (see meta-analysis in Czamara et al, 2018) and reinforces the concept of ATP as a danger signal in brain dysfunction (reviewed in Rodrigues et al, 2015). As observed by others in different animal models of brain dysfunction (Jimenez-Pacheco et al, 2013;Wang et al, 2017;Martínez-Frailes et al, 2019;Song et al, 2019), namely upon chronic stress (Yue et al, 2017;Dang et al, 2018; but see Kongsui et al, 2014), we identified an up-regulation of P 2X7 R and an ability of P 2X7 R to control different markers of neuroinflammation, as also reported in other animal models of depression (Yue et al, 2017;Bhattacharya and Jones, 2018), to mediate stress-induced behavioral modifications (Rial et al, 2016;Deng et al, 2020;Troubat et al, 2021).…”

Section: Discussionsupporting

confidence: 89%

Crosstalk Between ATP-P2X7 and Adenosine A2A Receptors Controlling Neuroinflammation in Rats Subject to Repeated Restraint Stress

Dias

Lopes

Gonçalves

et al. 2021

Front. Cell. Neurosci.

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Depressive conditions precipitated by repeated stress are a major socio-economical burden in Western countries. Previous studies showed that ATP-P2X7 receptors (P2X7R) and adenosine A2A receptors (A2AR) antagonists attenuate behavioral modifications upon exposure to repeated stress. Since it is unknown if these two purinergic modulation systems work independently, we now investigated a putative interplay between P2X7R and A2AR. Adult rats exposed to restraint stress for 14 days displayed an anxious (thigmotaxis, elevated plus maze), depressive (anhedonia, increased immobility), and amnesic (modified Y maze, object displacement) profile, together with increased expression of Iba-1 (a marker of microglia “activation”) and interleukin-1β (IL1β) and tumor necrosis factor α (TNFα; proinflammatory cytokines) and an up-regulation of P2X7R (mRNA) and A2AR (receptor binding) in the hippocampus and prefrontal cortex. All these features were attenuated by the P2X7R-preferring antagonist brilliant blue G (BBG, 45 mg/kg, i.p.) or by caffeine (0.3 g/L, p.o.), which affords neuroprotection through A2AR blockade. Notably, BBG attenuated A2AR upregulation and caffeine attenuated P2X7R upregulation. In microglial N9 cells, the P2X7R agonist BzATP (100 μM) or the A2AR agonist CGS26180 (100 nM) increased calcium levels, which was abrogated by the P2X7R antagonist JNJ47965567 (1 μM) and by the A2AR antagonist SCH58261 (50 nM), respectively; notably JNJ47965567 prevented the effect of CGS21680 and the effect of BzATP was attenuated by SCH58261 and increased by CGS21680. These results provide the first demonstration of a functional interaction between P2X7R and A2AR controlling microglia reactivity likely involved in behavioral adaptive responses to stress and are illustrative of a cooperation between the two arms of the purinergic system in the control of brain function.

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Section: Discussionsupporting

confidence: 89%

Crosstalk Between ATP-P2X7 and Adenosine A2A Receptors Controlling Neuroinflammation in Rats Subject to Repeated Restraint Stress

Dias

Lopes

Gonçalves

et al. 2021

Front. Cell. Neurosci.

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“…The original finding, that SE induces an up-regulation of P2X7R-IR in epilepsy-relevant areas of the brain (hippocampus, neocortex), was observed repeatedly both in human and rodent tissues (e.g., [ 87 , 88 , 89 ]. In consequence, it was logical to suggest that damage to neurons by pathological, high frequency firing during epileptic fits may cause a massive release of ATP and the consecutive activation of P2X7Rs located in the first line at microglial cells; this is expected to release bioactive, detrimental molecules (see Section 2 ).…”

Section: Epilepsymentioning

confidence: 99%

P2X7 Receptors Amplify CNS Damage in Neurodegenerative Diseases

Illéš

2020

IJMS

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ATP is a (co)transmitter and signaling molecule in the CNS. It acts at a multitude of ligand-gated cationic channels termed P2X to induce rapid depolarization of the cell membrane. Within this receptor-channel family, the P2X7 receptor (R) allows the transmembrane fluxes of Na+, Ca2+, and K+, but also allows the slow permeation of larger organic molecules. This is supposed to cause necrosis by excessive Ca2+ influx, as well as depletion of intracellular ions and metabolites. Cell death may also occur by apoptosis due to the activation of the caspase enzymatic cascade. Because P2X7Rs are localized in the CNS preferentially on microglia, but also at a lower density on neuroglia (astrocytes, oligodendrocytes) the stimulation of this receptor leads to the release of neurodegeneration-inducing bioactive molecules such as pro-inflammatory cytokines, chemokines, proteases, reactive oxygen and nitrogen molecules, and the excitotoxic glutamate/ATP. Various neurodegenerative reactions of the brain/spinal cord following acute harmful events (mechanical CNS damage, ischemia, status epilepticus) or chronic neurodegenerative diseases (neuropathic pain, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis) lead to a massive release of ATP via the leaky plasma membrane of neural tissue. This causes cellular damage superimposed on the original consequences of neurodegeneration. Hence, blood-brain-barrier permeable pharmacological antagonists of P2X7Rs with excellent bioavailability are possible therapeutic agents for these diseases. The aim of this review article is to summarize our present state of knowledge on the involvement of P2X7R-mediated events in neurodegenerative illnesses endangering especially the life quality and duration of the aged human population.

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“…Similarly to AD, P2X7R protein levels are upregulated in regions damaged by seizures and in the hippocampus of animal models. As previously summarized (Engel et al, 2012;Engel et al, 2016), the lack of the P2X7R promotes susceptibility to status epilepticus, while P2X7R antagonists are potent anticonvulsants (Engel et al, 2012;Engel et al, 2016;Beamer et al, 2017;Zeng et al, 2017;Burnstock and Knight, 2018;Song et al, 2019;Doǧan et al, 2020;Hong et al, 2020;Morgan et al, 2020). P2Y2R knockout animals present higher glutamate release in the hippocampus (Alhowail et al, 2020), and uridine triphosphate administration had sleep-promoting and anti-epileptic actions, improved memory function and affected neuronal plasticity (Dobolyi et al, 2011;Alves et al, 2017).…”

Section: Epilepsymentioning

confidence: 89%