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Recent Advances in CNS P2X7 Physiology and Pharmacology: Focus on Neuropsychiatric Disorders.

ABSTRACT: The ATP-gated P2X7 ion channel is an abundant microglial protein in the CNS that plays an important pathological role in executing ATP-driven danger signal transduction. Emerging data has generated scientific interest and excitement around targeting the P2X7 ion channel as a potential drug target for CNS disorders. Over the past years, a wealth of data has been published on CNS P2X7 biology, in particular the role of P2X7 in microglial cells, and in vivo effects of brain-penetrant P2X7 antagonists. Likewise, significant progress has been made around the medicinal chemistry of CNS P2X7 ligands, as antagonists for in vivo target validation in models of CNS diseases, to identification of two clinical compounds (JNJ-54175446 and JNJ-55308942) and finally, discovery of P2X7 PET ligands. This review is an attempt to bring together the current understanding of P2X7 in the CNS with a focus on P2X7 as a drug target in neuropsychiatric disorders.

SUBMITTER: Bhattacharya A

PROVIDER: S-EPMC5799703 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Recent Advances in CNS P2X7 Physiology and Pharmacology: Focus on Neuropsychiatric Disorders.

Bhattacharya Anindya A

Frontiers in pharmacology 20180201

The ATP-gated P2X7 ion channel is an abundant microglial protein in the CNS that plays an important pathological role in executing ATP-driven danger signal transduction. Emerging data has generated scientific interest and excitement around targeting the P2X7 ion channel as a potential drug target for CNS disorders. Over the past years, a wealth of data has been published on CNS P2X7 biology, in particular the role of P2X7 in microglial cells, and <i>in vivo</i> effects of brain-penetrant P2X7 an ...[more]

PMID: 29449810

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Project description:To present a summary of current scientific evidence about the cannabinoid, cannabidiol (CBD) with regard to its relevance to epilepsy and other selected neuropsychiatric disorders. We summarize the presentations from a conference in which invited participants reviewed relevant aspects of the physiology, mechanisms of action, pharmacology, and data from studies with animal models and human subjects. Cannabis has been used to treat disease since ancient times. ?(9) -Tetrahydrocannabinol (?(9) -THC) is the major psychoactive ingredient and CBD is the major nonpsychoactive ingredient in cannabis. Cannabis and ?(9) -THC are anticonvulsant in most animal models but can be proconvulsant in some healthy animals. The psychotropic effects of ?(9) -THC limit tolerability. CBD is anticonvulsant in many acute animal models, but there are limited data in chronic models. The antiepileptic mechanisms of CBD are not known, but may include effects on the equilibrative nucleoside transporter; the orphan G-protein-coupled receptor GPR55; the transient receptor potential of vanilloid type-1 channel; the 5-HT1a receptor; and the ?3 and ?1 glycine receptors. CBD has neuroprotective and antiinflammatory effects, and it appears to be well tolerated in humans, but small and methodologically limited studies of CBD in human epilepsy have been inconclusive. More recent anecdotal reports of high-ratio CBD:?(9) -THC medical marijuana have claimed efficacy, but studies were not controlled. CBD bears investigation in epilepsy and other neuropsychiatric disorders, including anxiety, schizophrenia, addiction, and neonatal hypoxic-ischemic encephalopathy. However, we lack data from well-powered double-blind randomized, controlled studies on the efficacy of pure CBD for any disorder. Initial dose-tolerability and double-blind randomized, controlled studies focusing on target intractable epilepsy populations such as patients with Dravet and Lennox-Gastaut syndromes are being planned. Trials in other treatment-resistant epilepsies may also be warranted. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Dataset Information

Recent Advances in CNS P2X7 Physiology and Pharmacology: Focus on Neuropsychiatric Disorders.

Publications

Recent Advances in CNS P2X7 Physiology and Pharmacology: Focus on Neuropsychiatric Disorders.

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