The roles of P2X7 receptor in regional-specific microglial responses in the rat brain following status epilepticus

Abstract

Recently, we have reported that astroglial activations in response to status epilepticus (SE) show regional-specific manners in the rat hippocampus. However, it is unknown that microglial responses to SE would show regional-specific patterns. Therefore, the present study was designed to elucidate the regional-specific microglial activation and relationship between P2X7 receptor functions and SE-induced microglial responses in the rat brain. Following SE, microglia appeared amoeboid or phagocytic in the dentate gyrus and the piriform cortex. In contrast, elongated microglia were observed in the CA1 hippocampal regions and the frontoparietal cortex. In the dentate gyrus, the CA1 hippocampal regions, and the frontoparietal cortex, these microglial activation accelerated by BzATP (a P2X7 receptor agonist)-infusion, but inhibited by OxATP (a P2X7 receptor antagonist). However, SE-induced microglial activation in the piriform cortex was not affected by BzATP or OxATP-infusion. Therefore, our findings indicate that SE-induced microglial activation may show regional-specific manners, and suggest that P2X7 receptor function differently modulates SE-induced microglial responses in distinct brain regions.

P2X receptors as targets for the treatment of status epilepticus

“…Activation of the pore-forming function of the P2X 7 R was also found to be required for microglial proliferation (Monif et al, 2009). Consistent with this model, blockade of P2X 7 R reduces microglia activation after status epilepticus (Kim et al, 2009; Choi et al, 2012; Engel et al, 2012a). Targeting the pore-forming functions of the P2X 7 R may therefore be a novel approach to limit microglia responses following status epilepticus.…”

“…KA, intra-peritoneal KA; Pilo, Pilocarpine; i.p. Pic, intra-peritoneal Picrotoxin; IgG-P2X 7 , anti-P2X 7 antibodies; Il-1β, interleukin-1beta; qPCR, quantitative polymerase chain reaction; IH, Immunohistochemistry; TNF-α, Tumor necrosis factor alpha; W, Western blot .aCavaliere et al, 2007;bLalo et al, 2008;cEngel et al, 2012a;dAvignone et al, 2008;eKanjhan et al, 1999;fRubio and Soto, 2001;gDona et al, 2009;hSeguela et al, 1996;iCollo et al, 1996;jLe et al, 1998;kUlmann et al, 2013;lGuo et al, 2008;mArmstrong et al, 2002;nYu et al, 2008;oJimenez-Pacheco et al, 2013;pRappold et al, 2006;qKim and Kang, 2011;rChoi et al, 2012;sKim et al, 2011a;t Kim et al, 2011b .…”

Silencing of P2X7R by RNA interference in the hippocampus can attenuate morphological and behavioral impact of pilocarpine-induced epilepsy

“…Previous studies have shown that P2X7R antagonists trigger anticonvulsant effect, reducing electrographic and behavioral seizures, microglia activation, decrease IL-1β production and prevent cell damage resulting from seizures [14,15,33,38,41,42]. Studies using P2X7R (Pfizer) [46] knockout mice also show reduction in the severity of seizures compared to wild-type mice [33].…”

“…There are many studies aimed at elucidating the role of P2X7R in epilepsy using agonists and antagonists. The activation of P2X7R with Bz-ATP (P2X7R agonist) causes microglial activation, enhances TNF-α immunoreactivity, reduces astrocytes, and intensifies seizures expression [19,[38][39][40]. Conversely, P2X7R blockage promotes anticonvulsant effects and reduces electroencephalographic and behavioral seizures, IL-1β production, microglial activation, recruitment and infiltration of neutrophils into the frontoparietal cortex, and damage resulting from seizure [14,15,33,38,[41][42][43][44].…”

“…The activation of P2X7R with Bz-ATP (P2X7R agonist) causes microglial activation, enhances TNF-α immunoreactivity, reduces astrocytes, and intensifies seizures expression [19,[38][39][40]. Conversely, P2X7R blockage promotes anticonvulsant effects and reduces electroencephalographic and behavioral seizures, IL-1β production, microglial activation, recruitment and infiltration of neutrophils into the frontoparietal cortex, and damage resulting from seizure [14,15,33,38,[41][42][43][44]. Surprisingly, P2X7R antagonists have been described to exacerbate seizures and enhance cell death in the hippocampal CA3 subfield in the pilocarpine and intraamygdala kainic acid models, but do not change behavioral pattern in the intraperitoneal kainic acid and picrotoxin models of epilepsy [39,41,45].…”