• Alzheimer’s disease
• Mitochondrial dysfunction
• Neuroinflammation
• Oxidative stress
• P2X7R

• Receptors, Purinergic P2X7/metabolism
• Humans
• Alzheimer Disease/metabolism
• Alzheimer Disease/pathology
• Animals
• Molecular Targeted Therapy
• Purinergic P2X Receptor Antagonists/pharmacology
• Purinergic P2X Receptor Antagonists/therapeutic use
• Oxidative Stress/physiology

• 82060219 National Natural Science Foundation of China
• 20212ACB216009 Natural Science Foundation of Jiangxi Province
• (jxsq2019201023 Jiangxi Province "Double Thousand Plan"
• 2019YNTD12003 Youth Team Project of the Second Affiliated Hospital of Nanchang University
• YC2022-S225 Postgraduate Innovation Special Foundation of Jiangxi Province
• Jiangxi Province “Double Thousand Plan”

• ATP-induced cell death
• Breast cancer
• Prognostic model
• mRNA
• miRNA

• Adenosine triphosphate homeostasis
• Adenosine triphosphate induced cell death
• Cancer signaling pathways
• Cancer treatment
• Mechanism
• Prognosis and clinical values

• Cell death
• Enteric nervous system
• Gastroenterology
• Inflammatory bowel diseases
• P2X7 receptor
• Purinergic signaling

• Animals
• Male
• Mice
• Calbindin 2
• Caspase 3
• Colitis
• Colitis, Ulcerative/chemically induced
• Colitis, Ulcerative/genetics
• Inflammatory Bowel Diseases
• Mice, Inbred C57BL
• NF-kappa B

• ATP
• Antagonists
• Inflammatory cytokines
• P2X7 receptor
• Pain

Infantile neuronal ceroid lipofuscinosis (INCL), the most severe form of neuronal ceroid lipofuscinoses, is caused by mutations in the lysosomal enzyme palmitoyl protein thioesterase 1 (PPT1). Typical symptoms of this disease include progressive psychomotor developmental retardation, visual failure, seizures, and premature death. Here, we investigated seizure activity and relevant pathological changes in PPT1 knock-in mice (PPT1 KI). The behavior studies in this study demonstrated that PPT1 KI mice had no significant seizure activity until 7 months of age, and local field potentials also displayed epileptiform activity at the same age. The expression levels of Iba-1 and CD68 demonstrated, by Western blot analysis, the inflammatory cytokine TNF-α content measured with enzyme-linked immunosorbent assay, and the number of microglia demonstrated by immunohistochemistry (IHC) were significantly increased at age of 7 months, all of which indicate microglia activation at an age of seizure onset. The increased expression of GFAP were seen at an earlier age of 4 months, and such an increase reached its peak at age of 6 months, indicating that astrocyte activation precedes microglia. The purinergic P2X7 receptor (P2X7R) is an ATP-sensitive ionic channel that is highly expressed in microglia and is fundamental to microglial activation, proliferation, cytokines release and epilepsy. We show that the ATP concentration in hippocampal tissue in PPT1 KI mice was increased using an enhanced ATP assay kit and demonstrated that the antagonist of P2X7R, A-438079, significantly reduced seizures in PPT1 KI mice. In contrast to glial cell activation and proliferation, a significant reduction in synaptic proteins GABA_AR was seen in PPT1 KI mice. These results indicate that seizure in PPT1 KI mice may be associated with microglial activation involved in ATP-sensitive P2X7R signaling and impaired inhibitory neurotransmission.

• A 438079
• PPT1 KI mice
• hippocampus
• microglia
• seizures

• Chemical coding
• Enteric nervous system
• Gastroenterology
• Inflammatory bowel diseases
• P2X7 receptor
• Purinergic signaling

• Animals
• Colitis, Ulcerative/drug therapy
• Enteric Nervous System
• Humans
• Inflammatory Bowel Diseases/drug therapy
• Receptors, Purinergic P2X7
• Submucous Plexus

• CRAMP
• EGFR
• GAS
• LL-37
• P2X7R
• group A Streptococcus
• host-defense peptides
• innate immunity
• murine models of human GAS soft-tissue infections
• neutrophils

• Animals
• Anti-Bacterial Agents/pharmacology
• Antimicrobial Cationic Peptides/metabolism
• Antimicrobial Cationic Peptides/pharmacology
• Bacterial Proteins/metabolism
• Cathelicidins/genetics
• Cathelicidins/metabolism
• Cell Line
• Disease Models, Animal
• ErbB Receptors/metabolism
• Female
• Host-Pathogen Interactions
• Humans
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Neutrophils/drug effects
• Neutrophils/metabolism
• Neutrophils/microbiology
• Receptors, Purinergic P2X7/metabolism
• Serine Endopeptidases/metabolism
• Signal Transduction
• Streptococcal Infections/drug therapy
• Streptococcal Infections/genetics
• Streptococcal Infections/metabolism
• Streptococcal Infections/microbiology
• Streptococcus pyogenes/enzymology
• Streptococcus pyogenes/genetics
• Streptococcus pyogenes/pathogenicity
• Substrate Specificity
• Mice

The ATP-gated P2X7 receptor is highly expressed in microglia and has been involved in diverse brain diseases. P2X7 effects were also described in neurons and astrocytes but its localisation and function in these cell types has been challenging to demonstrate in situ. BAC transgenic mouse lines have greatly advanced neuroscience research and two BAC-transgenic P2X7 reporter mouse models exist in which either a soluble EGFP (sEGFP) or an EGFP-tagged P2X7 receptor (P2X7-EGFP) is expressed under the control of a BAC-derived P2rx7 promoter. Here we evaluate both mouse models and find striking differences in both P2X expression levels and EGFP reporter expression patterns. Most remarkably, the sEGFP model overexpresses a P2X4 passenger gene and sEGFP shows clear neuronal localisation but appears to be absent in microglia. Preliminary functional analysis in a status epilepticus model suggests functional consequences of the observed P2X receptor overexpression. In summary, an aberrant EGFP reporter pattern and possible effects of P2X4 and/or P2X7 protein overexpression need to be considered when working with this model. We further discuss reasons for the observed differences and possible caveats in BAC transgenic approaches.

The purinergic P2X7 receptor (P2X7R) belongs to a family of trimeric ion channels that are gated by extracellular adenosine 5′-triphosphate (ATP). Several studies have pointed to a role of P2X7R-dependent signalling in Parkinson's disease (PD)-related neurodegeneration. The pathology of (PD) is characterized by the formation of insoluble alpha-synuclein (α-Syn) aggregates—Lewy bodies, but the mechanisms underlying α-Syn-induced dopaminergic cell death are still partially unclear. Our previous studies indicate that extracellular α-Syn directly interact with neuronal P2X7R and induces intracellular free calcium mobilization in neuronal cells. The main objective of this study was to examine the involvement of P2X7R receptor in α-Syn-induced mitochondrial dysfunction and cell death. We found that P2X7R stimulation is responsible for α-Syn-induced oxidative stress and activation of the molecular pathways of programmed cell death. Exogenous α-Syn treatment led to P2X7R-dependent decrease in mitochondrial membrane potential as well as elevation of mitochondrial ROS production resulting in breakdown of cellular energy production. Moreover, P2X7R-dependent deregulation of AMP-activated protein kinase as well as decrease in parkin protein level could be responsible for α-Syn-induced mitophagy impairment and accumulation of dysfunctional mitochondria. P2X7R might be putative pharmacological targets in molecular mechanism of extracellular α-Syn toxicity.

• -synuclein
• AMP-activated protein kinase
• P2X7 receptor
• mitochondria dysfunction
• parkin

• AMP-Activated Protein Kinases/metabolism
• Adenosine Triphosphate/chemistry
• Brain Neoplasms/metabolism
• Cell Line, Tumor
• Cell Survival
• Free Radicals
• Gene Expression Regulation, Neoplastic
• Humans
• Membrane Potential, Mitochondrial/drug effects
• Mitochondria/metabolism
• Mitochondria/pathology
• Mitophagy
• Neuroblastoma/metabolism
• Neurons/metabolism
• Oxidation-Reduction
• Oxidative Stress
• Receptors, Purinergic P2X7/metabolism
• Signal Transduction
• alpha-Synuclein/metabolism

• Adenosine triphosphate (ATP)
• Antagonist
• Nerve injury
• Neuropathic pain (NPP)
• P2X7 receptor (P2X7R)

• Adenosine Triphosphate/physiology
• Animals
• Brain/physiopathology
• Humans
• Inflammation/physiopathology
• Microglia/physiology
• Neuralgia/drug therapy
• Neuralgia/physiopathology
• Purinergic P2X Receptor Antagonists/administration & dosage
• Receptors, Purinergic P2X7/physiology
• Signal Transduction/drug effects

• Astrocyte
• Cell injury
• Oxidative stress
• Zinc

• Diabetic mellitus
• NOS neurons
• P2X7R
• Pannexin1
• Transmembrane pore

Neurogenesis is a persistent and essential feature of the adult mammalian hippocampus. Granular neurons generated from resident pools of stem or progenitor cells provide a mechanism for the formation and consolidation of new memories. Regulation of hippocampal neurogenesis is complex and multifaceted, and numerous signaling pathways converge to modulate cell proliferation, apoptosis, and clearance of cellular debris, as well as synaptic integration of newborn immature neurons. The expression of functional P2X7 receptors in the central nervous system has attracted much interest and the regulatory role of this purinergic receptor during adult neurogenesis has only recently begun to be explored. P2X7 receptors are exceptionally versatile: in their canonical role they act as adenosine triphosphate-gated calcium channels and facilitate calcium-signaling cascades exerting control over the cell via calcium-encoded sensory proteins and transcription factor activation. P2X7 also mediates transmembrane pore formation to regulate cytokine release and facilitate extracellular communication, and when persistently stimulated by high extracellular adenosine triphosphate levels large P2X7 pores form, which induce apoptotic cell death through cytosolic ion dysregulation. Lastly, as a scavenger receptor P2X7 directly facilitates phagocytosis of the cellular debris that arises during neurogenesis, as well as during some disease states. Understanding how P2X7 receptors regulate the physiology of stem and progenitor cells in the adult hippocampus is an important step towards developing useful therapeutic models for regenerative medicine. This review considers the relevant aspects of adult hippocampal neurogenesis and explores how P2X7 receptor activity may influence the molecular physiology of the hippocampus, and neural stem and progenitor cells.

• P2X7
• P2X7R
• SGZ
• adult neurogenesis
• calcium signaling
• hippocampus
• neural progenitor cells
• neural stem cells
• purinergic signaling

• Genotoxic stress
• Neuroprotection
• Oxidative stress
• P2X7 receptor
• P2Y(1)receptor
• P2Y(13)receptor

L-Lactate is a positive modulator of NMDAR-mediated signaling resulting in plasticity gene induction and memory consolidation. However, L-Lactate is also able to protect neurons against excito-toxic NMDAR activity, an indication of a mitigating action of L-Lactate on NMDA signaling. In this study, we provide experimental evidence that resolves this apparent paradox. Transient co-application of glutamate/glycine (1 μM/100 μM; 2 min) in primary cultures of mouse cortical neurons triggers a NMDA-dependent Ca²⁺ signal positively modulated by L-Lactate (10 mM) or DTT (1 mM) but decreased by Pyruvate (10 mM). This L-Lactate and DTT-induced potentiation is blocked by Ifenprodil (2 μM), a specific blocker of NMDARs containing NR2B sub-units. In contrast, co-application of glutamate/glycine (1 mM/100 μM; 2 min) elicits a NMDAR-dependent excitotoxic death in 49% of neurons. L-Lactate and Pyruvate significantly reduce this rate of cell death processes (respectively to 23% and 9%) while DTT has no effect (54% of neuronal death). This L-Lactate-induced neuroprotection is blocked by carbenoxolone and glibenclamide, respectively blockers of pannexins and K_ATP. In conclusion, our results show that L-Lactate is involved in two distinct and independent pathways defined as NMDAR-mediated potentiation pathway (or NADH pathway) and a neuroprotective pathway (or Pyruvate/ATP pathway), the prevalence of each one depending on the strength of the glutamatergic stimulus.

The P2X7 channel is involved in the pathogenesis of various CNS diseases. An increasing number of studies suggest its presence in neurons where its putative functions remain controversial for more than a decade. To resolve this issue and to provide a model for analysis of P2X7 functions, we generated P2X7 BAC transgenic mice that allow visualization of functional EGFP-tagged P2X7 receptors in vivo. Extensive characterization of these mice revealed dominant P2X7-EGFP protein expression in microglia, Bergmann glia, and oligodendrocytes, but not in neurons. These findings were further validated by microglia- and oligodendrocyte-specific P2X7 deletion and a novel P2X7-specific nanobody. In addition to the first quantitative analysis of P2X7 protein expression in the CNS, we show potential consequences of its overexpression in ischemic retina and post-traumatic cerebral cortex grey matter. This novel mouse model overcomes previous limitations in P2X7 research and will help to determine its physiological roles and contribution to diseases.

The human body relies on a molecule called ATP as an energy source and as a messenger. When cells die, for example if they are damaged or because of inflammation, they release large amounts of ATP into their environment. Their neighbors can detect the outpouring of ATP through specific receptors, the proteins that sit at the cell’s surface and can bind external agents.

Scientists believe that one of these ATP-binding receptors, P2X7, responds to high levels of ATP by triggering a cascade of reactions that results in inflammation and cell death. P2X7 also seems to play a role in several brain diseases such as epilepsia and Alzheimer’s, but the exact mechanisms are not known. In particular, how this receptor is involved in the death of neurons is unclear, and researchers still debate whether P2X7 is present in neurons and in other types of brain cells.

To answer this, Kaczmarek-Hájek, Zhang, Kopp et al. created genetically modified mice in which the P2X7 receptors carry a fluorescent dye. Powerful microscopes can pick up the light signal from the dye and help to reveal which cells have the receptors. These experiments show that neurons do not carry the protein; instead, P2X7 is present in certain brain cells that keep the neurons healthy. For example, it is found in the immune cells that ‘clean up’ the organ, and the cells that support and insulate neurons. Kaczmarek-Hájek et al. further provide preliminary data suggesting that, under certain conditions, if too many P2X7 receptors are present in these cells neuronal damage might be increased. It is therefore possible that the brain cells that carry P2X7 indirectly contribute to the death of neurons when large amounts of ATP are released.

The genetically engineered mouse designed for the experiments could be used in further studies to dissect the role that P2X7 plays in diseases of the nervous system. In particular, this mouse model might help to understand whether the receptor could become a drug target for neurodegenerative conditions.

• BAC transgene
• conditional knockout
• immunology
• inflammation
• mouse
• nanobody
• neuroscience
• purinergic P2X7 receptor

• NLRP3 inflammasomes
• STAT3
• astrocytes
• fluoxetine
• sleep deprivation

ATP can activate a variety of pathways through P2 purinoreceptors, leading to neuroprotection and pathology in the CNS. Among all P2X receptors, the P2X7 receptor (P2X7R) is a well-defined therapeutic target for inflammatory and neuropathic pain. Activation of P2X7R can generate reactive oxygen species (ROS) in macrophages and microglia. However, the role of ROS in P2X7R–induced pain remains unexplored. Here, we investigated the downstream effects of neuronal P2X7R activation in the spinal cord. We found that ATP induces ROS production in spinal cord dorsal horn neurons, an effect eliminated by ROS scavenger N-tert-butyl-α-phenylnitrone (PBN) and P2X7R antagonist A438079. A similar effect was observed with a P2X7R agonist, BzATP, and was attenuated by a NADPH oxidase inhibitor apocynin. Intrathecal administration of BzATP resulted in ROS production in the spinal cord and oxidative DNA damage in dorsal horn neurons. BzATP also induced robust biphasic spontaneous nociceptive behavior. Pre-treatment with A438079 abolished all BzATP-induced nociceptive behaviors, while ROS scavengers dose-dependently attenuated the secondary response. Here, we provide evidence that neuronal P2X7R activation leads to ROS production and subsequent nociceptive pain in mice. Together, the data indicate that P2X7R-induced ROS play a critical role in the P2X7R signaling pathway of the CNS.

Exposure of astrocytes to oxidative stress induces an increase of intracellular labile zinc and a decrease of functional expression of P2X7 receptorviaits translocation from the plasma membrane to the cytosol by altering the expression profile of P2X7 receptor and its splice variants, leading to a decrease of their engulfing activity.

• Epilepsy
• Feed-forward loop
• MicroRNA-22
• Purinergic P2X7 receptor
• Seizures
• Specificity protein 1 transcription factor