P2X7 Receptor Inhibition Interrupts the Progression of Seizures in Immature Rats and Reduces Hippocampal Damage

Mesuret, Guillaume; Engel, Tobías; Hessel, Ellen V.S.; Sanz-Rodríguez, Amaya; Jimenez-Pacheco, Alba; Miras‐Portugal, M. Teresa; Dı́az-Hernández, Miguel; Henshall, David C.

doi:10.1111/cns.12272

Cited by 59 publications

(40 citation statements)

References 52 publications

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“…Early attention was on the role of P1 adenosine receptors in epileptic seizures, but more recently P2X4 and P2X7 receptor antagonists have been explored as neuroleptic agents [8,83,84]. P2Y12 knockout mice exhibited reduced seizure-induced increases in microglial process numbers and worsened kainate-induced seizure behaviours [85].…”

Section: Epileptic Seizuresmentioning

confidence: 99%

Purinergic Signalling and Neurological Diseases: An Update

Burnstock

2017

CNSNDDT

107

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Purinergic signalling, i.e. ATP as an extracellular signalling molecule and cotransmitter in both peripheral and central neurons, is involved in the physiology of neurotransmission and neuromodulation. Receptors for purines have been cloned and characterised, including 4 subtypes of the P1(adenosine) receptor family, 7 subtypes of the P2X ion channel nucleotide receptor family and 8 subtypes of the P2Y G protein-coupled nucleotide receptor family. The roles of purinergic signalling in diseases of the central nervous system and the potential use of purinergic compounds for their treatment are attracting increasing attention. In this review, the focus is on the findings reported in recent papers and reviews to update knowledge in this field about the involvement of purinergic signalling in Alzheimer's, Parkinson's and Huntington's diseases, multiple sclerosis, amyotrophic lateral sclerosis, degeneration and regeneration after brain injury, stroke, ischaemia, inflammation, migraine, epilepsy, psychiatric disorders, schizophrenia, bipolar disorder, autism, addiction, sleep disorders and brain tumours. The use in particular of P2X7 receptor antagonists for the treatment of neurodegenerative diseases, cancer, depression, stroke and ischaemia, A2A receptor antagonists for Parkinson's disease and agonists for brain injury and depression and P2X3 receptor antagonists for migraine and seizures has been recommended. P2Y receptors have also been claimed to be involved in some central nervous disorders.

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Section: Epileptic Seizuresmentioning

confidence: 99%

Purinergic Signalling and Neurological Diseases: An Update

Burnstock

2017

CNSNDDT

107

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“…Prolonged exposure to ATP leads to formation of a large opening (termed a macropore) in vitro, although the physiologic significance of this macropore formation is not clearly understood. One of the hallmark features of P2X7 activation is release of the proinflammatory cytokine interleukin (IL)-1b (Solle et al, 2001), which in turn may contribute to neuroinflammation and pain (Chessell et al, 2005;North and Jarvis, 2013), mood disorders (Iwata et al, 2013;Chrovian et al, 2014), and neurodegenerative disorders, such as Alzheimer's disease , multiple sclerosis (Sharp et al, 2008), and epilepsy (Engel et al, 2012;Mesuret et al, 2014). In addition to IL-1b, P2X7-dependent release of glutamate (Andó and Sperlágh, 2013;Ficker et al, 2014), cathepsins (Clark et al, 2010), and chemokines (Shiratori et al, 2010) have been reported, and all of these mediators can serve as "gliotransmitters" aiding in the neuroimmune cross-talk and modulating synaptic plasticity.…”

Section: Introductionmentioning

confidence: 99%

Pharmacology of a Novel Central Nervous System–Penetrant P2X7 Antagonist JNJ-42253432

Lord

Aluisio

Shoblock

et al. 2014

J Pharmacol Exp Ther

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In the central nervous system, the ATP-gated Purinergic receptor P2X ligand-gated ion channel 7 (P2X7) is expressed in glial cells and modulates neurophysiology via release of gliotransmitters, including the proinflammatory cytokine interleukin (IL)-1b. In this study, we characterized JNJ-42253432 [2-methyl-N-([1-(4-phenylpiperazin-1-yl)cyclohexyl]methyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide] as a centrally permeable (brain-to-plasma ratio of 1), high-affinity P2X7 antagonist with desirable pharmacokinetic and pharmacodynamic properties for in vivo testing in rodents. JNJ-42253432 is a high-affinity antagonist for the rat (pK i 9.1 6 0.07) and human (pK i 7.9 6 0.08) P2X7 channel. The compound blocked the ATPinduced current and Bz-ATP [29(39)-O-(4-benzoylbenzoyl)adenosine-59-triphosphate tri(triethylammonium)]-induced release of IL-1b in a concentration-dependent manner. When dosed in rats, JNJ-42253432 occupied the brain P2X7 channel with an ED 50 of 0.3 mg/kg, corresponding to a mean plasma concentration of 42 ng/ml. The compound blocked the release of IL-1b induced by Bz-ATP in freely moving rat brain. At higher doses/exposure, JNJ-42253432 also increased serotonin levels in the rat brain, which is due to antagonism of the serotonin transporter (SERT) resulting in an ED 50 of 10 mg/kg for SERT occupancy. JNJ-42253432 reduced electroencephalography spectral power in the a-1 band in a dose-dependent manner; the compound also attenuated amphetamine-induced hyperactivity. JNJ-42253432 significantly increased both overall social interaction and social preference, an effect that was independent of stress induced by foot-shock. Surprisingly, there was no effect of the compound on either neuropathic pain or inflammatory pain behaviors. In summary, in this study, we characterize JNJ-42253432 as a novel brain-penetrant P2X7 antagonist with high affinity and selectivity for the P2X7 channel.

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“…Currently, research to discover new antagonists of P2X7R has been growing and has gained high financial support from the pharmaceutical industry (Gunosewoyo & Kassiou, ). P2X7R is implicated in many pathological processes, including neuropathic pain, inflammatory, and neurodegenerative diseases and cancer (Broom et al, ; Corrêa, Marques da Silva, Abreu Moreira‐Souza, Vommaro, & Coutinho‐Silva, ; Diaz‐Hernandez et al, ; Lee et al, ; Li et al, ; Lister et al, ; Mesuret et al, ; Raffaghello et al, ; Teixeira et al, ; Zhao et al, ). The development of new antagonists with efficacy and safety that could be applied in clinical treatments is one of the major challenges of purinergic therapy.…”

Section: Discussionmentioning

confidence: 99%

“…P2X7R has roles in many physiological processes, such as activation of immune and inflammatory responses and cell death (Coddou, Yan, Obsil, Huidobro‐Toro, & Stojilkovic, ). Moreover, it was suggested that P2X7R participates in several pathologies, including neurodegenerative, inflammatory and infectious diseases, neuropathic pain, rheumatoid arthritis, and cancer (Broom et al, ; Corrêa, Marques da Silva, de Abreu Moreira‐Souza, Vommaro, & Coutinho‐Silva, ; Diaz‐Hernandez et al, ; Lee et al, ; Li, Liang, & Chen, ; Lister et al, ; Mesuret et al, ; Raffaghello, Chiozzi, Falzoni, Di Virgilio, & Pistoia, ; Teixeira, de Oliveira‐Fusaro, Parada, & Tambeli, ; Zhao et al, ). Despite its relevance as a therapeutic target, P2X7R antagonists are still not applied in clinical treatment.…”

Section: Introductionmentioning

confidence: 99%

A new insight into purinergic pharmacology: Three fungal species as natural P2X7R antagonists

Soares‐Bezerra

Ferreira

Alves

et al. 2019

Phytotherapy Research

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P2X7 is a purinergic receptor involved in important physiological functions and pathological processes, such as inflammation, neurodegeneration, and pain. Despite its relevance, there is no selective antagonist useful in the treatment of diseases related to this receptor. In this context, research for a selective, safe, and potent antagonist compound that can be used in clinical therapy has been growing. In this work, we evaluated the potential antagonistic activity of three fungal extracts, namely, Vishniacozyma victoriae, Metschnikowia australis, and Ascomycota sp., which were discovered in a high‐throughput screening campaign to search for new antagonists for P2X7R from natural products. First, the IC50 values of these fungal extracts were determined in J774.G8 (murine macrophage cell line) and U937 (human monocyte cell line) cells through dye uptake assays. The IC50 values of V. victoriae were 2.6 and 0.92 μg/mL, M. australis has IC50 values of 3.8 and 1.5 μg/mL, and Ascomycota sp. showed values of 2.1 and 0.67 μg/mL in J774.G8 and U937 cells, respectively. These extracts also significantly inhibited propidium iodide and Lucifer yellow uptake via P2X7R pore, P2X7R currents in electrophysiology, IL‐1β release, and the production of oxide nitric and reactive oxygen species. The extracts did not cause cytotoxicity within a period of 24 h. The results showed the promising antagonistic activity of these extracts toward P2X7R, thereby indicating that they can be future candidates for phytomedicines with potential clinical applicability.

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P2X7 Receptor Inhibition Interrupts the Progression of Seizures in Immature Rats and Reduces Hippocampal Damage

Abstract: These results suggest P2X7 receptor antagonists may be suitable as frontline or adjunctive treatments of pediatric status epilepticus or other early-life seizures, particularly when associated with brain damage.

Cited by 59 publications

References 52 publications

Purinergic Signalling and Neurological Diseases: An Update

Purinergic Signalling and Neurological Diseases: An Update

Pharmacology of a Novel Central Nervous System–Penetrant P2X7 Antagonist JNJ-42253432

A new insight into purinergic pharmacology: Three fungal species as natural P2X7R antagonists

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