The Role of NMDA Receptors in the Effect of Purinergic P2X7 Receptor on Spontaneous Seizure Activity in WAG/Rij Rats With Genetic Absence Epilepsy

Abstract

P2X7 receptors (P2X7Rs) are ATP sensitive cation channels and have been shown to be effective in various epilepsy models. Absence epilepsy is a type of idiopathic, generalized, non-convulsive epilepsy. Limited data exist on the role of P2X7Rs and no data has been reported regarding the interaction between P2X7Rs and glutamate receptor NMDA in absence epilepsy. Thus, this study was designed to investigate the role of P2X7 and NMDA receptors and their possible interaction in WAG/Rij rats with absence epilepsy. Permanent cannula and electrodes were placed on the skulls of the animals. After the healing period of the electrode and cannula implantation, ECoG recordings were obtained during 180 min before and after drug injections. P2X7R agonist BzATP, at doses of 50 µg and 100 µg (intracerebroventricular; i.c.v.) and antagonist A-438079, at doses of 20 µg and 40 µg (i.c.v.) were administered alone or prior to memantine (5 mg/kg, intraperitoneal; i.p.) injection. The total number (in every 20 min), the mean duration, and the amplitude of spike-wave discharges (SWDs) were calculated and compared. Rats were decapitated and the right and left hemisphere, cerebellum, and brainstem were separated for the measurements of the advanced oxidation protein product (AOPP), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), glutathione peroxide (GPx), and glutathione reductase (GR). BzATP and A-438079 did not alter measured SWDs parameters, whereas memantine reduced them, which is considered anticonvulsant. BzATP did not alter the anticonvulsant effect of memantine, while A-438079 decreased the effect of memantine. Administration of BzATP increased the levels of SOD and GR in cerebrum hemispheres. A-438079 did not alter any of the biochemical parameters. Memantine reduced the levels of MDA, GSH, and GR while increased the level of CAT in the cerebrum. Administration of BzATP before memantine abolished the effect of memantine on MDA levels. The evidence from this study suggests that P2X7Rs

Src Family Kinases Activity is Required for Transmitting Purinergic P2X7 Receptor Signaling in Cortical Spreading Depression and Neuroinflammation

“…4c d). This is consistent with previous findings that both P2X7 receptor and SFKs have functional interaction with NMDA receptor respectively in different models of neurological diseases [29,30]; Notably, functional interaction between NR2A-containing NMDA receptor and SFKs mediates CSD as evidenced by that the SFK activator, pYEEI restored the inhibitory effect of NR2A-containining NMDA receptor antagonist on CSD in mouse brain slices [21]. These data suggest that P2X7 receptor/SFKs signaling-mediated CSD is likely to be dependent on NMDA receptor activity.…”

“…Series 3: As P2X7 receptor exhibits functional interaction with NMDA receptor in neurons and a rat epilepsy model [29,30], while SFKs regulate NMDA receptor activity and function [31], both of which are required for CSD propagation [8,32,33], we then explored the involvement of NMDA receptor in SFKs-mediated P2X7 receptor signaling during CSD.…”

“…Immediately following CSD recording, the brain slices were collected for measuring IL-1β and TNFα mRNA level by qPCR and the media in the chamber during CSD recording were collected for measuring glutamate release using glutamate assay. Series 3: As P2X7 receptor exhibits functional interaction with NMDA receptor in neurons and a rat epilepsy model [29,30], while SFKs regulate NMDA receptor activity and function [31], both of which are required for CSD propagation [8,32,33], we then explored the involvement of NMDA receptor in SFKs-mediated P2X7 receptor signaling during CSD.…”

Targeting Neuroinflammation via Purinergic P2 Receptors for Disease Modification in Drug-Refractory Epilepsy

“…Moreover, no effect of P2X 7 antagonism on seizures was observed in WAG/Rij rats, a model of genetic absence epilepsy. 10 Suggesting a proconvulsive function of the P2X 7 receptor, Kim and Kang reported exacerbated seizure severity in P2X 7 -KO mice using a pilocarpine (150,175,200,225, or 250 mg/kg, IP) mouse model. 205 In addition, research by the same group using the pilocarpine (380 mg/kg, IP) rat model showed that P2X 7 antagonism (oxidized ATP [OxATP] and BBG) protected against astroglial cell death, 206 reduced the infiltration of neutrophils into the frontoparietal cortex, 207 and increased status epilepticus-induced hippocampal neurodegeneration.…”

“…1 Hippocampal sclerosis, characterized by a pattern of selective neuronal loss and reactive gliosis, is the most common pathological finding in brains of TLE patients. 9 Of note, whereas some recent studies have investigated a potential role of ATP-gated P2 receptors in epilepsies with a genetic cause (eg, use of WAG/Rij rats, which is a model of genetic absence epilepsy 10 ), most effort has been invested in studying these receptors in TLE, 11 which is thus the main focus of the present review. While there are several options for the treatment of epilepsy, which include brain surgery, use of the ketogenic diet, or vagus nerve/deep-brain stimulation, antiseizure medication remains the first-choice treatment of epilepsy, with over 25 antiseizure drugs (ASDs) available.…”