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. Author manuscript; available in PMC: 2023 Jun 2.
Published in final edited form as: Prog Neurobiol. 2021 Jun 16;204:102105. doi: 10.1016/j.pneurobio.2021.102105

Table 3.

Impact of P2 receptor-targeting during acute seizures, epileptogenesis and epilepsy (selected examples).

 Receptor subtype

 Process

 Epilepsy model

 Strategy

 Outcome

 References

Ionotropic P2XRs
P2X7R Status epilepticus i.p. KA (25 mg/kg), i.p. picrotoxin (5 mg/kg), i.p. pilocarpine (150, 175, 200, 225, or 250 mg/kg) in mice (males) i.c.v. OxATP (5 mM), A-438079 (10 μM), A740003 (10 μM) delivered over 1 week via osmotic mini-pump before seizure induction; P2X7R KO mice Increased seizure susceptibility via P2X7R antagonism; P2X7R antagonisms did not affect seizures in KA and picrotoxin model. (Kim and Kang, 2011)
Status epilepticus i.p. pilocarpine (380 mg/kg) in rats (males) i.c.v. BZATP (5 mM), OxATP (5 mM), A-740003 (5 mM) and A-438079 (10 μM) via osmotic mini-pump Reduced neurodegeneration via BzATP; increased neurodegeneration, reduced astroglial death and reduced infiltration of neutrophils mediated via P2X7R antagonism. (Kim et al. 2009), (Kim et al. 2011), (Kim et al. 2010)
Status epilepticus i.a. KA (3 μg/2 μl) in mice (males) P2X7R agonists: i.c.v. BZATP (0.1 nmol); P2X7R antagonists: i.c.v. A438079 (1.75 nmol), i.c.v. BBG (1 pmol); i.c.v. P2X7R antibody (APR-008, 0.7 mg/mL); P2X7R KO mice P2X7R agonist-increased seizure severity; P2X7R antagonists / P2X7R-targeting antibodies / P2X7R KO leads to seizure reduction and neuroprotection in hippocampus and cortex. (Engel et al. 2012), ( Jimenez-Pacheco et al. 2013)
Status epilepticus i.m. coriaria lactone (40 mg/kg) in rats (males) Pre-treatment with P2X7R antagonists BBG (1, 5, 10 μg; i.c. v.), A438079 (10 μM, ic.v.) and A740003 (10 μM, i.c.v.) P2X7R antagonism reduced inflammation, neuronal damage, astrogliosis and microgliosis, seizures and improved cognitive function. (Huang et al. 2017)
Acute seizures (focal, generalized and generalized tonic-clonic) Timed i.v. PTZ infusion test (1% PTZ 2 ml/min) in mice (males); MES-T; 6 Hz electroshock-induced seizures (0.2 ms square pulse at 6 Hz for 3 s) in mice (males) i.p. BBG 150 mg/kg for i.v. PTZ and MES-T test and i.p. BBG 50 mg/kg for 6 Hz test Reduced seizures during 6 Hz test (focal seizure) via BBG; no significant anticonvulsive effects of BBG in i.v. PTZ and MES-T test (generalized and generalized tonic-clonic seizures). (Nieoczym et al. 2017)
Acute seizures (absence seizures) WAG/Rij rats (males) (inbred strain of rats with genetic absence epilepsy) i.c.v. BZATP (50 μg and 100 μg); i.c.v. A-438079 (20 μg and 40 μg) No effects of P2X7R agonists or antagonists on spike-wave discharges (SWDs) (Dogan et al. 2020)
Acute seizures / Epileptogenesis MES-T (inusoidal pulses 4–14 mA, 50 Hz, 0.2 s duration) and s.c. PTZ-T (87 mg/kg) in mice (males); i.p. PTZ kindling (35 mg/ kg) in rats (males) for 25 days JNJ-47965567 (15 or 30 mg/ kg),AFC-5128 (25 or 50 mg/ kg), BBG (50 mg/kg), transhinone (30 mg/kg), all drugs injected i.p. No effects on acute seizures alone; reduced seizure severity in combination with carbamazepine; reduced kindling development and glial activation. (Fischer et al. 2016)
Epileptogenesis i.p. PTZ kindling (30 mg/kg) every second day for 27 days in rats (sex not specified) BBG (15 and 30 mg/kg, i.p.) 30 min before PTZ injection Reduced seizure score and improved motor performance and cognitive deficits. (Soni et al. 2015)
Epileptogenesis i.a. KA (3 μg/2 μl)-induced epilepsy in mice (males) i.c.v. injection of antagomir-22 24 h before induction of SE Increased P2X7R; increased seizure frequency during epilepsy, increased neuroinflammation. (Jimenez-Mateos et al. 2015)
Epileptogenesis i.p. pilocarpine (370 mg/kg,i.p.) in rats (males) P2X7R antagonists AZ10606120 (3 μg/2 μl, i.c.v.) post-SE / BBG (50 mg/kg, i.p.) 1 injection per day for 4 days post-SE Neuroprotection mediated via P2X7R antagonism post-SE; P2X7R antagonisms increased seizure number and seizure severity during epilepsy. (Rozmer et al. 2017)
Epileptogenesis i.p. pilocarpine (370 mg/kg) in rats (males) P2X7R-targeting siRNA (i.c.v.) 6 h post-SE P2X7R antagonisms mediated neuroprotection in hippocampus, reduced edema, reduced mortality following SE, delayed seizure onset and seizure numbers during chronic epilepsy. (Amorim et al. 2017)
Epilepsy Multiple low-dose i.p. KA-induced epilepsy in rats (males) (total KA = 22.2 ± 2.02 mg/kg) JNJ-47965567 during 1 week via osmotic mini-pump (0.6 g/ kg/2 ml) Decreased seizure severity without changes in total number of seizures, no change in inflammation. (Amhaoul et al. 2016)
Epilepsy i.a. KA (3 μg/2 μl)-induced-epilepsy in mice (males) JNJ-47965567 (30 mg/kg, i.p.) twice daily for 5 days during epilepsy Reduced seizure frequency during treatment and during washout-period; decreased inflammation (astrogliosis and microgliosis). (Jimenez-Pacheco et al. 2016)
P2X3R Epileptogenesis i.p. PTZ (30 mg/kg) administered on alternate days for a maximum of up to 35 days to rats (males) P2X3R antagonist i.c.v. delivery of P2X3 antagonist NF110 in 3 different doses (20 nM, 40 nM, and 60 nM) from day 1 until the end of the study (day 42) P2X3R antagonisms improved impaired behavior, learning, memory, locomotion, motor activity, discrimination ability, neuronal damage, hippocampal inflammation, oxidative stress, and mitochondrial dysfunction (Xia et al. 2018)
P2X4R Status epilepticus i.p. KA (8–22 mg/kg) in mice (sex not specified) P2X4R KO mice Impaired microglial function; neuroprotection in hippocampus. (Ulmann et al. 2013)
Metabotropic P2Y receptors
P2Y 1 R Status epilepticus i.p. KA (10 mg/kg) in rats (males); intrahippocampal injection of quinolinic acid (1 μl at the rate of 0.2 μL/min) in rats (males) One single injection of MRS2500 (nmol, i.c.v.) P2Y1R antagonist-mediated neuroprotection; no impact on seizure severity. (Simoes et al. 2018)
Status epilepticus / Epileptogenesis / Epilepsy i.a. KA (3 μg/2 μl) in mice; i.p. pilocarpine (340 mg/kg) in mice (males) P2Y1R antagonist MRS2500 (1 nmol, i.c.v.) before and during SE, post-SE and during chronic epilepsy once daily for 5 days, P2Y1R KO mice; P2Y1R agonist MRS2365 (0.3 and 1 nmol, i.c. v.) before and during SE P2Y1R KO mice: Increase in seizure severity during SE and neurodegeneration. Pre-treatment: P2Y1R agonist reduces seizure severity during SE and protects brain from damage; P2Y1R antagonism increases seizure severity and brain damage during SE. Treatment during SE: P2Y1R agonist increases seizure severity during SE; P2Y1R antagonism decreases seizure severity and brain damage (hippocampus and cortex). P2Y1R antagonism post-SE: Delay in epilepsy development. P2Y1R antagonism during epilepsy: Suppression of epileptic seizures. (Alves et al. 2019); ( Alves et al. 2019)
P2Y 12 R Status epilepticus i.p. KA (18–22 mg/kg) or i.c.v. KA (0.12–0.18 μg)and KA in mice (males and females) P2Y12R KO mice Increased seizure phenotype; reduced hippocampal microglial processes. (Eyo et al. 2014)
Broad-spectrum targeting
Status epilepticus i.a. KA (3 μg/2 μl) in mice (males) ADP and UTP (P2Y agonists) (9 nmol i.c.v.) ADP exacerbates seizure severity; UTP reduces seizure severity and neuronal death. (Alves, Gomez-Villafuertes et al. 2017)
Epilepsy Amygdala kindling in rats (males) (1 s, monophasic square-wave pulses) Reactive Blue (P2YR antagonists, 20 μg) and PPADS (P2 antagonist, 10, 20, 30 μg) once daily i.c.v. Reduced seizure severity. (Sun et al. 2018)

Abbreviations: ADP, Adenosine diphosphate; BBG, brilliant blue G; BzATP, 2’(3’)-O-(4-Benzoylbenzoyl)adenosine-5’-triphosphate; i.a., intraamygdala; i.m. intra-muscular; i.p., intraperitoneal; i.c.v., intracerebroventricular; i.v., intravenous; KA, Kainic acid; KO, Knock out; MES-T, Maximal electroshock seizure threshold test; PPADS, Pyridoxalphosphate-6-azophenyl-2’,4’-disulfonic; PTZ-T, Pentylenetetrazol seizure threshold test; SE, Status epilepticus; UDP, Uridine diphosphate; UTP, Uridine triphosphate.