Effects of P2X7 receptor antagonists on hypoxia-induced neonatal seizures in mice

Rodriguez-Alvarez, Natalia; Jiménez-Mateos, Eva M.; Engel, Tobías; Quinlan, Sean; Reschke, Cristina R.; Conroy, Ronán; Bhattacharya, Anindya; Boylan, Geraldine B.; Henshall, David C.

doi:10.1016/j.neuropharm.2017.01.005

Cited by 39 publications

(46 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Purinergic signalling, via P2X7R, regulates neonatal seizures associated with hypophosphatasia, an inherited metabolic bone disease characterised by spontaneous seizures ( Sebastián-Serrano et al, 2016 ). P2X7R antagonists were effective against hypoxia-induced neonatal seizures in mice ( Rodriguez-Alvarez et al, 2017 ).…”

Section: Disorders Of the Central Nervous System (Cns)mentioning

confidence: 99%

Purinergic Signalling: Therapeutic Developments

2017

View full text Add to dashboard Cite

Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.

show abstract

Section: Disorders Of the Central Nervous System (Cns)mentioning

confidence: 99%

Purinergic Signalling: Therapeutic Developments

2017

View full text Add to dashboard Cite

show abstract

“…However, in spite of these uncertainties, it is believed by most authors that P2X7R antagonists are potential drugs to prevent epilepsy as based on experiments carried out both in mouse [ 101 , 102 ], and rat animal models [ 103 ].…”

Section: Epilepsymentioning

confidence: 99%

P2X7 Receptors Amplify CNS Damage in Neurodegenerative Diseases

Illéš

2020

IJMS

View full text Add to dashboard Cite

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.

show abstract

“…While some studies have shown this upregulation to occur primarily on microglia (Rappold et al, 2006 ; Kaczmarek-Hajek et al, 2018 ), others have suggested that P2X7 receptor expression is also increased in neurons (Doná et al, 2009 ; Engel et al, 2012 ; Jimenez-Pacheco et al, 2016 ). There is also evidence that P2X7 receptor antagonism can be anticonvulsive and neuroprotective following acute seizures (Engel et al, 2012 ; Jimenez-Pacheco et al, 2013 ; Mesuret et al, 2014 ; Huang et al, 2017 ; Rodriguez-Alvarez et al, 2017 ). However, others have observed limited or no protection by P2X7 receptor antagonism (Fischer et al, 2016 ; Nieoczym et al, 2017 ), and in some studies P2X7 receptor antagonism was reported to promote seizures (Kim and Kang, 2011 ; Rozmer et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

P2X7 Receptor-Dependent microRNA Expression Profile in the Brain Following Status Epilepticus in Mice

Conte

Nguyen

Alves

et al. 2020

Front. Mol. Neurosci.

Self Cite

View full text Add to dashboard Cite

The ionotropic ATP-gated P2X7 receptor is an important contributor to inflammatory signaling cascades via the release of Interleukin-1β, as well as having roles in cell death, neuronal plasticity and the release of neurotransmitters. Accordingly, there is interest in targeting the P2X7 receptor for the treatment of epilepsy. However, the signaling pathways downstream of P2X7 receptor activation remain incompletely understood. Notably, recent studies showed that P2X7 receptor expression is controlled, in part, by microRNAs (miRNAs). Here, we explored P2X7 receptor-dependent microRNA expression by comparing microRNA expression profiles of wild-type (wt) and P2X7 receptor knockout mice before and after status epilepticus. Genome-wide microRNA profiling was performed using hippocampi from wt and P2X7 receptor knockout mice following status epilepticus induced by intra-amygdala kainic acid. This revealed that the genetic deletion of the P2X7 receptor results in distinct patterns of microRNA expression. Specifically, we found that in vehicle-injected control mice, the lack of the P2X7 receptor resulted in the up-regulation of 50 microRNAs and down-regulation of 35 microRNAs. Post-status epilepticus, P2X7 receptor deficiency led to the up-regulation of 44 microRNAs while 13 microRNAs were down-regulated. Moreover, there was only limited overlap among identified P2X7 receptor-dependent microRNAs between control conditions and post-status epilepticus, suggesting that the P2X7 receptor regulates the expression of different microRNAs during normal physiology and pathology. Bioinformatic analysis revealed that genes targeted by P2X7 receptor-dependent microRNAs were particularly overrepresented in pathways involved in intracellular signaling, inflammation, and cell death; processes that have been repeatedly associated with P2X7 receptor activation. Moreover, whereas genes involved in signaling pathways and inflammation were common among up- and down-regulated P2X7 receptor-dependent microRNAs during physiological and pathological conditions, genes associated with cell death seemed to be restricted to up-regulated microRNAs during both physiological conditions and post-status epilepticus. Taken together, our results demonstrate that the P2X7 receptor impacts on the expression profile of microRNAs in the brain, thereby possibly contributing to both the maintenance of normal cellular homeostasis and pathological processes.

show abstract

Effects of P2X7 receptor antagonists on hypoxia-induced neonatal seizures in mice

Cited by 39 publications

References 70 publications

Purinergic Signalling: Therapeutic Developments

Purinergic Signalling: Therapeutic Developments

P2X7 Receptors Amplify CNS Damage in Neurodegenerative Diseases

P2X7 Receptor-Dependent microRNA Expression Profile in the Brain Following Status Epilepticus in Mice

Contact Info

Product

Resources

About