Upregulated P2X3 Receptor Expression in Patients with Intractable Temporal Lobe Epilepsy and in a Rat Model of Epilepsy

Zhou, Xin; Ma, Limin; Xiong, Yan; Huang, Hao; Yuan, Jinxian; Li, Ruo-Han; Li, Jiani; Chen, Yangmei

doi:10.1007/s11064-015-1820-x

Cited by 16 publications

(13 citation statements)

References 27 publications

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“…They suggested that with upregulated P2X3 receptors, expression exists in both epileptic humans and rats and may aggravate the epileptic state. Our study clearly supports the notion of Zhou et al [ 10 ], as the central administration of the potent inhibitor of P2X3 receptor, NF110, significantly attenuated the PTZ-kindling.…”

Section: Discussionsupporting

confidence: 92%

“…It is also reported that, for NF110, the K i values are 36, 82 and 4144 nM for P2X3, P2X1, and P2X2 receptors, respectively [ 25 ], suggesting that the doses of NF110 used in this study may have preferential action on P2X3 receptors. Zhou et al [ 10 ] reported that P2X3 receptors were located at the cell bodies and dendrites of neurons with significantly increased expression in temporal lobe epilepsy. They also found that P2X3 receptors activation accelerated sustained repetitive firing, whereas their inhibition led to relatively low-frequency discharges in epilepsy.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, these purinergic receptors produce a positive current and play key roles in neuropathic pain, inflammatory mediation, and increased neuronal excitability [ 9 ]. Very recently it has been reported that P2X3Rs were located at the cell bodies and dendrites of neurons with significantly increased expression in temporal lobe epilepsy, and P2X3R activation accelerated sustained repetitive firing in vitro [ 10 ], but not much is known about the utility of P2X3 receptors modulators in kindling epilepsy-induced behavioral changes, motor activity, locomotor activity, discrimination, learning, memory, anxiety, emotional tension, mitochondrial dysfunction, oxidative stress, or inflammation. Thus, we designed this study which provides the first proof of concept of the broad-spectrum utility of a potential P2X3 antagonist, NF110, in the rat epilepsy model of pentylenetetrazole (PTZ)-induced kindling.…”

Section: Introductionmentioning

confidence: 99%

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Modulation of P2X Purinoceptor 3 (P2X3) in Pentylenetetrazole-Induced Kindling Epilepsy in Rats

et al. 2018

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BackgroundEpilepsy is a complex neurologic disorder with abnormal electrical impulses in the brain. A crucial role of purinergic signalling in the proper working of the nervous system has been reported but much less is known about the modulation of P2X3 purinergic receptors in epilepsy. This study investigated the effect of NF110, a potent P2X3 receptor antagonist, in the rat epilepsy model of pentylenetetrazole (PTZ)-induced kindling.Material/MethodsThe mean kindling score, motor activity, locomotion, emotional tension, anxiety, discrimination ability, learning, memory, serum neuron-specific enolase (sNSE), hippocampal IL-1β and TNF-α, thiobarbituric acid-reactive substance (TBARS), catalase (CAT) and reduced glutathione (GSH), and mitochondrial complex I, II, and IV levels of PTZ-kindling animals were assessed.ResultsThe PTZ-kindling animals have shown impaired motor activity, locomotion, discrimination ability, learning, and memory, along with increased emotional tension, anxiety, neuronal damage (increased sNSE), hippocampal pro-inflammatory mediators (increased IL-1β and TNF-α), oxidative stress (increased TBARS, decreased GSH and CAT), and mitochondrial dysfunction. The administration of NF110 in 3 different doses has significantly and dose-dependently corrected PTZ-kindling-induced impaired behavior, learning, memory, locomotion, motor activity, discrimination ability, neuronal damage, hippocampal inflammation, oxidative stress, and mitochondrial dysfunction. These beneficial effects of NF110 in PTZ-kindling animals were significantly abolished by the administration of the P2X agonist α, β methylene-ATP.ConclusionsP2X3 receptors play a very important role in kindling epilepsy and further research should be done to design P2X3 modulators for their possible therapeutic benefits in epileptic disorders.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Modulation of P2X Purinoceptor 3 (P2X3) in Pentylenetetrazole-Induced Kindling Epilepsy in Rats

et al. 2018

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“…Antiepileptic consequences of deep brain stimulation may be mediated by P1R activation ( Miranda et al, 2014 ). P2X3R expression was upregulated in epileptic rats and humans and it was postulated that P2X3R antagonists might be therapeutically effective ( Zhou X. et al, 2016 ). The release of adenosine and ATP during on-going epileptiform activity was measured with microelectrode biosensors ( Frenguelli and Wall, 2016 ).…”

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

confidence: 99%

Purinergic Signalling: Therapeutic Developments

2017

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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.

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“…Experiments support a role for post-transcriptional regulation of the P2X7 receptors and it was suggested that therapeutic targeting of microRNA-22 may prevent inflammation and development of epilepsy [87]. Upregulated expression of P2X3 receptors was demonstrated in both epileptic humans and rats and it was suggested that P2X3 receptor antagonists may represent novel therapeutic targets for antiepileptic drugs [88]. Microelectrode biosensors have been used to measure the release of ATP and adenosine during ongoing epileptiform activity [89].…”

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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Upregulated P2X3 Receptor Expression in Patients with Intractable Temporal Lobe Epilepsy and in a Rat Model of Epilepsy

Cited by 16 publications

References 27 publications

Modulation of P2X Purinoceptor 3 (P2X3) in Pentylenetetrazole-Induced Kindling Epilepsy in Rats

Modulation of P2X Purinoceptor 3 (P2X3) in Pentylenetetrazole-Induced Kindling Epilepsy in Rats

Purinergic Signalling: Therapeutic Developments

Purinergic Signalling and Neurological Diseases: An Update

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