24 results on '"Illes, Peter"'
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2. Prefrontocortical Astrocytes Regulate Dominance Hierarchy in Male Mice.
- Author
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Tang Y, Yin HY, and Illes P
- Subjects
- Animals, Mice, Male, Behavior, Animal physiology, Astrocytes, Social Dominance
- Published
- 2024
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3. The anti-inflammatory astrocyte revealed: the role of the microbiome in shaping brain defences.
- Author
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Verkhratsky A, Illes P, Tang Y, and Semyanov A
- Subjects
- Anti-Inflammatory Agents, Brain, Astrocytes, Microbiota
- Published
- 2021
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4. Impaired ATP Release from Brain Astrocytes May be a Cause of Major Depression.
- Author
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Illes P, Rubini P, Yin H, and Tang Y
- Subjects
- Brain, Cells, Cultured, Humans, Adenosine Triphosphate, Astrocytes, Depressive Disorder, Major
- Published
- 2020
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5. Astroglia-Derived ATP Modulates CNS Neuronal Circuits.
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Illes P, Burnstock G, and Tang Y
- Subjects
- Animals, Exocytosis physiology, Humans, Neuronal Plasticity physiology, Signal Transduction, Adenosine Triphosphate physiology, Astrocytes physiology, Brain physiology, Neurons physiology, Spinal Cord physiology, Synaptic Transmission physiology
- Abstract
It is broadly recognized that ATP not only supports energy storage within cells but is also a transmitter/signaling molecule that serves intercellular communication. Whereas the fast (co)transmitter function of ATP in the peripheral nervous system has been convincingly documented, in the central nervous system (CNS) ATP appears to be primarily a slow transmitter/modulator. Data discussed in the present review suggest that the slow modulatory effects of ATP arise as a result of its vesicular/nonvesicular release from astrocytes. ATP acts together with other glial signaling molecules such as cytokines, chemokines, and free radicals to modulate neuronal circuits. Hence, astrocytes are positioned at the crossroads of the neuron-glia-neuron communication pathway., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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6. Astrocytic rather than neuronal P2X7 receptors modulate the function of the tri-synaptic network in the rodent hippocampus.
- Author
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Khan MT, Deussing J, Tang Y, and Illes P
- Subjects
- Action Potentials drug effects, Animals, Astrocytes drug effects, Brain metabolism, CA3 Region, Hippocampal metabolism, Dentate Gyrus metabolism, Dentate Gyrus physiology, Female, Glutamic Acid pharmacology, Hippocampus drug effects, Hippocampus metabolism, Interneurons metabolism, Male, Mice, Mice, Inbred C57BL, Neurons drug effects, Patch-Clamp Techniques methods, Presynaptic Terminals metabolism, Purinergic P2X Receptor Agonists pharmacology, Pyramidal Cells drug effects, Pyridines pharmacology, Receptors, GABA-A metabolism, Synapses metabolism, Synaptic Potentials, Tetrazoles pharmacology, Astrocytes metabolism, Receptors, Purinergic P2X7 metabolism
- Abstract
Whole-cell patch clamp recordings demonstrated that in the dentate gyrus (DG) as well as in the CA3 area of mouse hippocampal slices the prototypic P2X7 receptor (R) agonist dibenzoyl-ATP (Bz-ATP) induced inward current responses both in neurons and astrocytes. Whereas the selective P2X7R antagonist A438079 strongly inhibited both neuronal and astrocytic currents, a combination of ionotropic glutamate receptor (CNQX, AP-5) and GABA
A -R (gabazine) antagonists depressed the Bz-ATP-induced current responses in the DG (granule cells) and CA3 neurons only. It was concluded that Bz-ATP activated astrocytic P2X7Rs and thereby released glutamate and GABA to stimulate nearby neurons. The residual A438079-resistant current response of astrocytes was suggested to be due to the stimulation of P2XRs of the non-P2X7-type. Further, we searched for presynaptic P2X7Rs at the axon terminals of DG and CA3 pyramidal neurons innervating CA3 and CA1 cells, respectively. Bz-ATP potentiated the frequency of spontaneous postsynaptic currents (sPSCs) in CA1 but not CA3 pyramidal cells. However, the Bz-ATP effect in CA1 cells was inhibited by gabazine or the astrocytic toxin fluorocitrate suggesting stimulation of P2X7Rs at stratum radiatum astrocytes located near to interneurons and synapsing onto CA1 neurons. Our data suggest that functional P2X7Rs are missing at neurons in the tri-synaptic network of the rodent hippocampus, but are present at nearby astrocytes indirectly regulating network activity., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2019
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7. Neuronal P2X7 Receptors Revisited: Do They Really Exist?
- Author
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Illes P, Khan TM, and Rubini P
- Subjects
- Animals, Evidence-Based Medicine, Humans, Adenosine Triphosphate metabolism, Astrocytes metabolism, Models, Neurological, Nervous System Diseases metabolism, Neurons metabolism, Receptors, Purinergic P2X7 metabolism
- Abstract
P2X7 receptors (Rs) constitute a subclass of ATP-sensitive ionotropic receptors (P2X1-P2X7). P2X7Rs have many distinguishing features, mostly based on their long intracellular C terminus regulating trafficking to the cell membrane, protein-protein interactions, and post-translational modification. Their C-terminal tail is especially important in enabling the transition from the nonselective ion channel mode to a membrane pore allowing the passage of large molecules. There is an ongoing dispute on the existence of neuronal P2X7Rs with consequences for our knowledge on their involvement in neuroinflammation, aggravating stroke, temporal lobe epilepsy, neuropathic pain, and various neurodegenerative diseases. Whereas early results appeared to support the operation of P2X7Rs at neurons, more recently glial P2X7Rs are increasingly considered as indirect causes of neuronal effects. Specific tools for P2X7Rs are of limited value because of the poor selectivity of agonists, and the inherent failure of antibodies to differentiate between the large number of active and inactive splice variants, or gain-of-function and loss-of-function small nucleotide polymorphisms of the receptor. Unfortunately, the available P2RX7 knock-out mice generated by pharmaceutical companies possess certain splice variants, which evade inactivation. In view of the recently discovered bidirectional dialogue between astrocytes and neurons (and even microglia and neurons), we offer an alternative explanation for previous data, which assumedly support the existence of P2X7Rs at neurons. We think that the unbiased reader will follow our argumentation on astrocytic or microglial P2X7Rs being the primary targets of pathologically high extracellular ATP concentrations, although a neuronal localization of these receptors cannot be fully excluded either., Competing Interests: The authors declare no competing financial interests., (Copyright © 2017 the authors 0270-6474/17/377049-14$15.00/0.)
- Published
- 2017
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8. P2X7 receptor-sensitivity of astrocytes and neurons in the substantia gelatinosa of organotypic spinal cord slices of the mouse depends on the length of the culture period.
- Author
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Gao P, Ding X, Khan TM, Rong W, Franke H, and Illes P
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- Adenosine Triphosphate analogs & derivatives, Adenosine Triphosphate pharmacology, Animals, Astrocytes drug effects, Excitatory Postsynaptic Potentials drug effects, Excitatory Postsynaptic Potentials physiology, Membrane Potentials drug effects, Mice, Inbred C57BL, Neurons drug effects, Neurons metabolism, Posterior Horn Cells drug effects, Spinal Cord drug effects, Spinal Cord metabolism, Substantia Gelatinosa drug effects, Astrocytes metabolism, Receptors, Purinergic P2X7 metabolism, Substantia Gelatinosa metabolism
- Abstract
The whole-cell patch-clamp technique was used to record current responses to AMPA, N-methyl-d-aspartate (NMDA), muscimol and dibenzoyl-ATP (Bz-ATP) in superficial (reactive/gliotic) substantia gelatinosa (SG) astrocytes and neurons of spinal cord slices kept for different periods of time in organotypic culture. Currents induced by AMPA, NMDA and muscimol confirmed the existence of their specific receptors in 2-week-old neurons; astrocytes cultured for the same period of time responded to AMPA and muscimol, but not to NMDA. AMPA had a larger effect on 2-week-old astrocytes than on the 1-week-old ones, in spite of a similar sensitivity of the age-matched neurons to this amino acid. The effect of the prototypic P2X7 receptor agonist Bz-ATP on superficial astrocytes and neurons depended on the drug concentration applied and increased in parallel with the lengthening of the culture period. The amplitudes of Bz-ATP currents of deep (resting) astrocytes were age-independent. Neurons located in deep layers exhibited after 1week of culturing much larger Bz-ATP currents than the superficial ones of the same age. In conclusion, whereas resting astrocytes had culture period-independent P2X7 receptor-sensitivity, reactive/gliotic astrocytes exhibited P2X7 receptor-sensitivity increasing in parallel with the prolongation of the time spent in culture. The results with Bz-ATP agree with the facilitation of AMPA-induced currents in reactive astrocytes during development, and with the hypothesis that extracellular ATP is an ontogenetically early transmitter/signaling molecule in the CNS., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2017
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9. Astrocyte-neuron interaction in the substantia gelatinosa of the spinal cord dorsal horn via P2X7 receptor-mediated release of glutamate and reactive oxygen species.
- Author
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Ficker C, Rozmer K, Kató E, Andó RD, Schumann L, Krügel U, Franke H, Sperlágh B, Riedel T, and Illes P
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- Animals, Astrocytes drug effects, CA1 Region, Hippocampal drug effects, CA1 Region, Hippocampal metabolism, Glutamic Acid metabolism, Humans, Hydrogen Peroxide metabolism, Immunohistochemistry, Mice, Transgenic, Microelectrodes, Microglia metabolism, Neurons drug effects, Patch-Clamp Techniques, Rats, Wistar, Reactive Oxygen Species metabolism, Receptors, AMPA metabolism, Receptors, N-Methyl-D-Aspartate metabolism, Spinal Cord Dorsal Horn drug effects, Substantia Gelatinosa drug effects, Tissue Culture Techniques, gamma-Aminobutyric Acid metabolism, Astrocytes metabolism, Neurons metabolism, Receptors, Purinergic P2X7 metabolism, Spinal Cord Dorsal Horn metabolism, Substantia Gelatinosa metabolism
- Abstract
The substantia gelatinosa (SG) of the spinal cord processes incoming painful information to ascending projection neurons. Whole-cell patch clamp recordings from SG spinal cord slices documented that in a low Ca(2+) /no Mg(2+) (low X(2+) ) external medium adenosine triphosphate (ATP)/dibenzoyl-ATP, Bz-ATP) caused inward current responses, much larger in amplitude than those recorded in a normal X(2+) -containing bath medium. The effect of Bz-ATP was antagonized by the selective P2X7 receptor antagonist A-438079. Neuronal, but not astrocytic Bz-ATP currents were strongly inhibited by a combination of the ionotropic glutamate receptor antagonists AP-5 and CNQX. In fact, all neurons and some astrocytes responded to NMDA, AMPA, and muscimol with inward current, demonstrating the presence of the respective receptors. The reactive oxygen species H2 O2 potentiated the effect of Bz-ATP at neurons but not at astrocytes. Hippocampal CA1 neurons exhibited a behavior similar to, but not identical with SG neurons. Although a combination of AP-5 and CNQX almost abolished the effect of Bz-ATP, H2 O2 was inactive. A Bz-ATP-dependent and A-438079-antagonizable reactive oxygen species production in SG slices was proven by a microelectrode biosensor. Immunohistochemical investigations showed the colocalization of P2X7-immunoreactivity with microglial (Iba1), but not astrocytic (GFAP, S100β) or neuronal (MAP2) markers in the SG. It is concluded that SG astrocytes possess P2X7 receptors; their activation leads to the release of glutamate, which via NMDA- and AMPA receptor stimulation induces cationic current in the neighboring neurons. P2X7 receptors have a very low density under resting conditions but become functionally upregulated under pathological conditions., (© 2014 Wiley Periodicals, Inc.)
- Published
- 2014
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10. Functional P2X7 receptors at cultured hippocampal astrocytes but not neurons.
- Author
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Rubini P, Pagel G, Mehri S, Marquardt P, Riedel T, and Illes P
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- Animals, Animals, Newborn, Cells, Cultured, Membrane Potentials physiology, Rats, Rats, Wistar, Astrocytes physiology, Hippocampus cytology, Hippocampus physiology, Neurons physiology, Receptors, Purinergic P2X7 physiology
- Abstract
P2X7 receptors have been suggested to be located both on neurons and astrocytes of the central and peripheral nervous systems. In the present Ca(2+)-imaging and patch-clamp study, we reinvestigated these findings on mixed neuronal-astrocytic cell cultures prepared from embryonic or newborn rat hippocampi. We found in a Mg(2+)-free bath medium that the prototypic P2X7 receptor agonist dibenzoyl-adenosine triphosphate (Bz-ATP) increased the intracellular Ca(2+) concentration ([Ca(2+)]i) both in the neuronal cell bodies and in their axo-dendritic processes only to a very minor extent. However, Bz-ATP produced marked [Ca(2+)]i transients in the neuronal processes, when they grew above a glial carpet, which was uniformly sensitive to Bz-ATP. These glial signals might be misinterpreted as neuronal responses because of the poor focal discrimination by a fluorescent microscope. Most astrocytes had a polygonal shape without clearly circumscribable boundaries, but a subgroup of them had neuron-like appearance. The cellular processes of this astrocytic subgroup, just as their cell somata and their polygonal counterparts, appeared to possess a high density of functional P2X7 receptors. In contrast to astrocytes, in a low Ca(2+)/no Mg(2+)-containing bath medium, hippocampal neurons failed to respond to Bz-ATP with membrane currents. In addition, neither the amplitude nor the frequency of spontaneous excitatory postsynaptic currents, representing the quantal release of glutamate, was modified by Bz-ATP. We conclude that cultured hippocampal neurons, in contrast to astrocytes, possess P2X7 receptors, if at all, only at a low density.
- Published
- 2014
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11. Anoxic depolarization of hippocampal astrocytes: possible modulation by P2X7 receptors.
- Author
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Leichsenring A, Riedel T, Qin Y, Rubini P, and Illes P
- Subjects
- 2-Amino-5-phosphonovalerate pharmacology, Adenosine Triphosphate metabolism, Animals, Astrocytes drug effects, CA1 Region, Hippocampal cytology, CA1 Region, Hippocampal drug effects, CA1 Region, Hippocampal physiology, Excitatory Amino Acid Antagonists pharmacology, Glutamates metabolism, Hippocampus cytology, Hippocampus drug effects, In Vitro Techniques, Ion Channels drug effects, Neurons drug effects, Patch-Clamp Techniques, Purinergic P2X Receptor Antagonists pharmacology, Purinergic P2Y Receptor Agonists pharmacology, Pyridines pharmacology, Pyridoxal Phosphate analogs & derivatives, Pyridoxal Phosphate pharmacology, Rats, Rats, Wistar, Receptors, N-Methyl-D-Aspartate antagonists & inhibitors, Tetrazoles pharmacology, Tetrodotoxin pharmacology, Astrocytes physiology, Cell Hypoxia physiology, Hippocampus physiology, Receptors, Purinergic P2X7 drug effects
- Abstract
Current responses from CA1 neurons and stratum oriens astrocytes were recorded from hippocampal brain slices by means of the whole-cell patch-clamp technique. Anoxic depolarization (AD) was induced by an oxygen/glucose-deprived (OGD) medium also containing sodium iodoacetate and antimycin, in order to block glycolysis and oxidative phosphorylation, respectively. Anoxic depolarization has been reported to be due to the sudden increase of the extracellular K(+) concentration and the accompanying explosive rise in glutamate concentration. We asked ourselves whether the release of ATP activating P2X7 receptors is also involved in the AD. Although, the AD was evoked in absolute synchrony in neurons and astrocytes, and the NMDA receptor antagonistic AP-5 depressed these responses, neither the non-selective P2 receptor antagonist PPADS, nor the highly selective P2X7 receptor antagonist A438079 interfered with the AD or its delay time in neurons/astrocytes after inducing chemical hypoxia. However, A438079, but not PPADS increased in astrocytes the slow inward current observed in a hypoxic medium. It is concluded that ATP co-released with glutamate by hypoxic stimulation has only a minor function in the present brain slice system., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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12. P2X receptors and their roles in astroglia in the central and peripheral nervous system.
- Author
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Illes P, Verkhratsky A, Burnstock G, and Franke H
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- Animals, Cell Communication physiology, Cell Proliferation, Homeostasis physiology, Humans, Models, Neurological, Neurons physiology, Pain Perception physiology, Signal Transduction physiology, Synaptic Transmission physiology, Astrocytes physiology, Central Nervous System physiology, Peripheral Nervous System physiology, Receptors, Purinergic P2X physiology
- Abstract
Astrocytes are a class of neural cells that control homeostasis at all levels of the central and peripheral nervous system. There is a bidirectional neuron-glia interaction via a number of extracellular signaling molecules, glutamate and ATP being the most widespread. ATP activates ionotropic P2X and metabotropic P2Y receptors, which operate in both neurons and astrocytes. Morphological, biochemical, and functional evidence indicates the expression of astroglial P2X(1/5) heteromeric and P2X(7) homomeric receptors, which mediate physiological and pathophysiological responses. Activation of P2X(1/5) receptors triggers rapid increase of intracellular Na(+) that initiates immediate cellular reactions, such as the depression of the glutamate transporter to keep high glutamate concentrations in the synaptic cleft, the activation of the local lactate shuttle to supply energy substrate to pre- and postsynaptic neuronal structures, and the reversal of the Na(+)/Ca(2+) exchange resulting in additional Ca(2+) entry. The consequences of P2X(7) receptor activation are mostly but not exclusively mediated by the entry of Ca(2+) and result in reorganization of the cytoskeleton, inflammation, apoptosis/necrosis, and proliferation, usually at a prolonged time scale. Thus, astroglia detect by P2X(1/5) and P2X(7) receptors both physiological concentrations of ATP secreted from presynaptic nerve terminals and also much higher concentrations of ATP attained under pathological conditions.
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- 2012
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13. Pathophysiology of astroglial purinergic signalling.
- Author
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Franke H, Verkhratsky A, Burnstock G, and Illes P
- Subjects
- Adenosine Triphosphate physiology, Animals, Astrocytes drug effects, Astrocytes pathology, Brain physiology, Brain Neoplasms pathology, Brain Neoplasms physiopathology, Humans, Neurotoxicity Syndromes pathology, Neurotoxicity Syndromes physiopathology, Receptors, Purinergic drug effects, Signal Transduction drug effects, Substance-Related Disorders pathology, Substance-Related Disorders physiopathology, Astrocytes physiology, Central Nervous System Diseases physiopathology, Receptors, Purinergic physiology, Signal Transduction physiology
- Abstract
Astrocytes are fundamental for central nervous system (CNS) physiology and are the fulcrum of neurological diseases. Astroglial cells control development of the nervous system, regulate synaptogenesis, maturation, maintenance and plasticity of synapses and are central for nervous system homeostasis. Astroglial reactions determine progression and outcome of many neuropathologies and are critical for regeneration and remodelling of neural circuits following trauma, stroke, ischaemia or neurodegenerative disorders. They secrete multiple neurotransmitters and neurohormones to communicate with neurones, microglia and the vascular walls of capillaries. Signalling through release of ATP is the most widespread mean of communication between astrocytes and other types of neural cells. ATP serves as a fast excitatory neurotransmitter and has pronounced long-term (trophic) roles in cell proliferation, growth, and development. During pathology, ATP is released from damaged cells and acts both as a cytotoxic factor and a proinflammatory mediator, being a universal "danger" signal. In this review, we summarise contemporary knowledge on the role of purinergic receptors (P2Rs) in a variety of diseases in relation to changes of astrocytic functions and nucleotide signalling. We have focussed on the role of the ionotropic P2X and metabotropic P2YRs working alone or in concert to modify the release of neurotransmitters, to activate signalling cascades and to change the expression levels of ion channels and protein kinases. All these effects are of great importance for the initiation, progression and maintenance of astrogliosis-the conserved and ubiquitous glial defensive reaction to CNS pathologies. We highlighted specific aspects of reactive astrogliosis, especially with respect to the involvement of the P2X(7) and P2Y(1)R subtypes. Reactive astrogliosis exerts both beneficial and detrimental effects in a context-specific manner determined by distinct molecular signalling cascades. Understanding the role of purinergic signalling in astrocytes is critical to identifying new therapeutic principles to treat acute and chronic neurological diseases.
- Published
- 2012
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14. Rodent cortical astroglia express in situ functional P2X7 receptors sensing pathologically high ATP concentrations.
- Author
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Oliveira JF, Riedel T, Leichsenring A, Heine C, Franke H, Krügel U, Nörenberg W, and Illes P
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- Animals, Brain Chemistry, Fluorescent Antibody Technique, Membrane Potentials physiology, Mice, Mice, Knockout, Microscopy, Confocal, Organ Culture Techniques, Patch-Clamp Techniques, Rats, Rats, Wistar, Adenosine Triphosphate metabolism, Astrocytes metabolism, Cerebral Cortex physiology, Receptors, Purinergic P2X7 metabolism
- Abstract
ATP is an important neuronal and astroglial signaling molecule in the brain. In the present study, brain slices were prepared from the prefrontal cortex (PFC) of Wistar rats and 2 lines of mice. P2X₇ receptor immunoreactivity was colocalized with astro- and microglial but not neuronal markers. Whole-cell patch-clamp recordings showed that, in astroglial cells, dibenzoyl-ATP (BzATP) and ATP caused inward currents, near the resting membrane potential. The inactivity of α,β-methylene ATP, as well as the potency increases of BzATP and ATP in a low divalent cation (X²(+))-containing superfusion medium suggested the involvement of P2X₇ receptors. This idea was corroborated by the inhibition of these current responses by PPADS, Brilliant Blue G, A 438079, and calmidazolium. Ivermectin, trinitrophenyl-adenosine-5'-triphosphate, and cyclopentyl-dipropylxanthine did not alter the agonist effects. The reversal potential of BzATP was near 0 mV, indicating the opening of cationic receptor channels. In a low X²(+) superfusion medium, ATP-induced current responses in PFC astroglial cells of wild-type mice but not of the P2X₇ knockouts. Hence, cortical astroglia of rats and mice possess functional P2X₇ receptors. These receptors may participate in necrotic/apoptotic or proliferative reactions after stimulation by large quantities of ATP released by central nervous system injury.
- Published
- 2011
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15. P2 receptors and neuronal injury.
- Author
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Franke H, Krügel U, and Illes P
- Subjects
- Animals, Apoptosis, Humans, Signal Transduction, Adenosine Triphosphate metabolism, Astrocytes metabolism, Brain physiopathology, Brain Diseases physiopathology, Nerve Regeneration physiology, Neuronal Plasticity, Neurons metabolism, Receptors, Purinergic P2 metabolism
- Abstract
Extracellular adenosine 5'-triphosphate (ATP) was proposed to be an activity-dependent signaling molecule that regulates glia-glia and glia-neuron communications. ATP is a neurotransmitter of its own right and, in addition, a cotransmitter of other classical transmitters such as glutamate or GABA. The effects of ATP are mediated by two receptor families belonging either to the P2X (ligand-gated cationic channels) or P2Y (G protein-coupled receptors) types. P2X receptors are responsible for rapid synaptic responses, whereas P2Y receptors mediate slow synaptic responses and other types of purinergic signaling involved in neuronal damage/regeneration. ATP may act at pre- and postsynaptic sites and therefore, it may participate in the phenomena of long-term potentiation and long-term depression of excitatory synaptic transmission. The release of ATP into the extracellular space, e.g., by exocytosis, membrane transporters, and connexin hemichannels, is a widespread physiological process. However, ATP may also leave cells through their plasma membrane damaged by inflammation, ischemia, and mechanical injury. Functional responses to the activation of multiple P2 receptors were found in neurons and glial cells under normal and pathophysiological conditions. P2 receptor-activation could either be a cause or a consequence of neuronal cell death/glial activation and may be related to detrimental and/or beneficial effects. The present review aims at demonstrating that purinergic mechanisms correlate with the etiopathology of brain insults, especially because of the massive extracellular release of ATP, adenosine, and other neurotransmitters after brain injury. We will focus in this review on the most important P2 receptor-mediated neurodegenerative and neuroprotective processes and their beneficial modulation by possible therapeutic manipulations.
- Published
- 2006
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16. Spatial and temporal aspects of Ca2+ signaling mediated by P2Y receptors in cultured rat hippocampal astrocytes.
- Author
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Koizumi S, Saito Y, Nakazawa K, Nakajima K, Sawada JI, Kohsaka S, Illes P, and Inoue K
- Subjects
- Adenosine Triphosphate pharmacology, Animals, Calcium physiology, Calcium Channel Blockers pharmacology, Cations, Divalent pharmacology, Cells, Cultured, Dose-Response Relationship, Drug, Enzyme Inhibitors pharmacology, Hippocampus cytology, Indoles pharmacology, Inositol 1,4,5-Trisphosphate pharmacology, Microscopy, Confocal, Nicardipine pharmacology, Rats, Rats, Wistar, Uridine Triphosphate pharmacology, Astrocytes drug effects, Calcium Signaling drug effects, Hippocampus drug effects, Receptors, Purinergic drug effects
- Abstract
ATP produces a variety of Ca2+ responses in astrocytes. To address the complex spatio-temporal Ca2+ signals, we analyzed the ATP-evoked increase in intracellular Ca2+ concentration ([Ca2+]i) in cultured rat hippocampal astrocytes using fura-2 or fluo-3 based Ca2+ imaging techniques. ATP at less than 10 nM produced elementary Ca2+ release event "puffs" in a manner independent of extracellular Ca2+. Stimulation with higher ATP concentrations (3 or 10 micro M) resulted in global Ca2+ responses such as intercellular Ca2+ wave. These Ca2+ responses were mainly mediated by metabotropic P2Y receptors. ATP acting on both P2Y1 and P2Y2 receptors produced a transient Ca2+ release by inositol 1,4,5-trisphosphate (InsP3). When cells were stimulated with ATP much longer, the transient [Ca2+]i elevation was followed by sustained Ca2+ entry from the extracellular space. This sustained rise in [Ca2+]i was inhibited by Zn2+ (<10 micro M), an inhibitor of capacitative Ca2+ entry (CCE). CCE induced by cyclopiazonic acid or thapsigargin and Ca2+ entry evoked by ATP share the same pharmacological profile in astrocytes. Taken together, the hierarchical Ca2+ responses to ATP were observed in hippocampal astrocytes, i.e., puffs, global Ca2+ release by InsP3, and CCE in response to depletion of InsP3-sensitive Ca2+ stores. It should be noted that these Ca2+ signals and their modulation by Zn2+ could occur in the hippocampus in situ since both ATP and Zn2+ are rich in the hippocampus and could be released by excitatory stimulation.
- Published
- 2002
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17. Astrocytes in human central nervous system diseases: a frontier for new therapies.
- Author
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Verkhratsky, Alexei, Butt, Arthur, Li, Baoman, Illes, Peter, Zorec, Robert, Semyanov, Alexey, Tang, Yong, and Sofroniew, Michael
- Subjects
Humans ,Astrocytes ,Central Nervous System Diseases ,Homeostasis ,Stroke - Abstract
Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence of the central nervous system (CNS). Astroglia contribute to the pathophysiology of all neurological and neuropsychiatric disorders in ways that can be either beneficial or detrimental to disorder outcome. Pathophysiological changes in astroglia can be primary or secondary and can result in gain or loss of functions. Astroglia respond to external, non-cell autonomous signals associated with any form of CNS pathology by undergoing complex and variable changes in their structure, molecular expression, and function. In addition, internally driven, cell autonomous changes of astroglial innate properties can lead to CNS pathologies. Astroglial pathophysiology is complex, with different pathophysiological cell states and cell phenotypes that are context-specific and vary with disorder, disorder-stage, comorbidities, age, and sex. Here, we classify astroglial pathophysiology into (i) reactive astrogliosis, (ii) astroglial atrophy with loss of function, (iii) astroglial degeneration and death, and (iv) astrocytopathies characterised by aberrant forms that drive disease. We review astroglial pathophysiology across the spectrum of human CNS diseases and disorders, including neurotrauma, stroke, neuroinfection, autoimmune attack and epilepsy, as well as neurodevelopmental, neurodegenerative, metabolic and neuropsychiatric disorders. Characterising cellular and molecular mechanisms of astroglial pathophysiology represents a new frontier to identify novel therapeutic strategies.
- Published
- 2023
18. Astrocyte activation in hindlimb somatosensory cortex contributes to electroacupuncture analgesia in acid-induced pain.
- Author
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Qing Ye, Jie Li, Wen-Jing Ren, Ying Zhang, Tao Wang, Rubini, Patrizia, Hai-Yan Yin, Illes, Peter, and Yong Tang
- Subjects
SOMATOSENSORY cortex ,ELECTROACUPUNCTURE ,HINDLIMB ,ANALGESIA ,PAIN management ,EXPERIMENTAL arthritis - Abstract
Background: Several studies have confirmed the direct relationship between extracellular acidification and the occurrence of pain. As an effective pain management approach, the mechanism of electroacupuncture (EA) treatment of acidification-induced pain is not fully understood. The purpose of this study was to assess the analgesic effect of EA in this type of pain and to explore the underlying mechanism(s). Methods: We used plantar injection of the acidified phosphate-buffered saline (PBS; pH 6.0) to trigger thermal hyperalgesia in male Sprague--Dawley (SD) rats aged 6-8 weeks. The value of thermal withdrawal latency (TWL) was quantified after applying EA stimulation to the ST36 acupoint and/or chemogenetic control of astrocytes in the hindlimb somatosensory cortex. Results: Both EA and chemogenetic astrocyte activation suppressed the acidinduced thermal hyperalgesia in the rat paw, whereas inhibition of astrocyte activation did not influence the hyperalgesia. At the same time, EA-induced analgesia was blocked by chemogenetic inhibition of astrocytes. Conclusion: The present results suggest that EA-activated astrocytes in the hindlimb somatosensory cortex exert an analgesic effect on acid-induced pain, although these astrocytes might only moderately regulate acid-induced pain in the absence of EA. Our results imply a novel mode of action of astrocytes involved in EA analgesia. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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19. Astrocytic and Oligodendrocytic P2X7 Receptors Determine Neuronal Functions in the CNS
- Author
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Zhao, Ya-Fei, Tang, Yong, and Illes, Peter
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Cellular and Molecular Neuroscience ,signaling molecules ,astrocytes ,oligodendrocytes ,neurons ,Review ,ddc:610 ,Molecular Biology ,P2X7 receptors ,P2X7 receptors, astrocytes, oligodendrocytes, neurons, signaling molecules ,Neuroscience - Abstract
P2X7 receptors are members of the ATP-gated cationic channel family with a preferential localization at the microglial cells, the resident macrophages of the brain. However, these receptors are also present at neuroglia (astrocytes, oligodendrocytes) although at a considerably lower density. They mediate necrosis/apoptosis by the release of pro-inflammatory cytokines/chemokines, reactive oxygen species (ROS) as well as the excitotoxic (glio)transmitters glutamate and ATP. Besides mediating cell damage i.e., superimposed upon chronic neurodegenerative processes in Alzheimer’s Disease, Parkinson’s Disease, multiple sclerosis, and amyotrophic lateral sclerosis, they may also participate in neuroglial signaling to neurons under conditions of high ATP concentrations during any other form of neuroinflammation/neurodegeneration. It is a pertinent open question whether P2X7Rs are localized on neurons, or whether only neuroglia/microglia possess this receptor-type causing indirect effects by releasing the above-mentioned signaling molecules. We suggest as based on molecular biology and functional evidence that neurons are devoid of P2X7Rs although the existence of neuronal P2X7Rs cannot be excluded with absolute certainty.
- Published
- 2021
20. ATP indirectly stimulates hippocampal CA1 and CA3 pyramidal neurons via the activation of neighboring P2X7 receptor-bearing astrocytes and NG2 glial cells, respectively.
- Author
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Ying Zhang, Hai-Yan Yin, Rubini, Patrizia, Illes, Peter, and Yong Tang
- Abstract
There is ongoing dispute on the question whether CNS neurons possess ATP-sensitive P2X7 receptors (Rs) or whether only non-neuronal cells bear this receptor-type and indirectly signal to the neighboring neurons. We genetically deleted P2X7Rs specifically in astrocytes, oligodendrocytes and microglia, and then recorded current responses in neurons to the prototypic agonist of this receptor, dibenzoyl-ATP (Bz-ATP). These experiments were made in brain slice preparations taken from the indicated variants of the P2X7R KO animals. In hippocampal CA3, but not CA1 pyramidal neurons, the deletion of oligodendrocytic (NG2 glial) P2X7Rs abolished the Bz-ATP-induced current responses. In contrast to the Bz-ATP-induced currents in CA3 pyramidal neurons, current amplitudes evoked by the ionotropic glutamate/GABA
A R agonists AMPA/muscimol were not inhibited at all. Whereas in the CA3 area NG2 glia appeared to mediate the P2X7R-mediated stimulation of pyramidal neurons, in the CA1 area, astrocytic P2X7Rs had a somewhat similar effect. This was shown by recording the frequencies and amplitudes of spontaneous excitatory currents (sPSCs) in brain slice preparations. Bz-ATP increased the sPSC frequency in CA1, but not CA3 pyramidal neurons without altering the amplitude, indicating a P2X7R-mediated increase of the neuronal input. Microinjection of the selective astrocytic toxin L-α-aminoadipate into both hippocampi, or the in vitro application of the GABAA R antagonistic gabazine, completely blocked the frequency increases of sPSCs. Hence, CA1 and CA3 pyramidal neurons of the mouse did not possess P2X7Rs, but were indirectly modulated by astrocytic and oligodendrocytic P2X7Rs, respectively. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
21. Nucleotide signaling in astrogliosis.
- Author
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Franke, Heike and Illes, Peter
- Subjects
- *
ASTROCYTES , *NUCLEOTIDES , *CELLULAR signal transduction , *CENTRAL nervous system injuries , *ADENOSINE triphosphate , *EXTRACELLULAR enzymes , *PURINERGIC receptors - Abstract
Highlights: [•] ATP is released by various mechanisms following acute and chronic damage to the central nervous system. [•] Extracellular ATP activates P2X and P2Y receptors at astrocytes. [•] Activation of astrocytic P2X and P2Y receptors induced astrogliosis. [Copyright &y& Elsevier]
- Published
- 2014
- Full Text
- View/download PDF
22. High, in Contrast to Low Levels of Acute Stress Induce Depressive-like Behavior by Involving Astrocytic, in Addition to Microglial P2X7 Receptors in the Rodent Hippocampus.
- Author
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Zhao, Ya-Fei, Ren, Wen-Jing, Zhang, Ying, He, Jin-Rong, Yin, Hai-Yan, Liao, Yang, Rubini, Patrizia, Deussing, Jan M., Verkhratsky, Alexei, Yuan, Zeng-Qiang, Illes, Peter, and Tang, Yong
- Subjects
MICROGLIA ,MENTAL depression ,RODENTS ,CENTRAL nervous system ,HIPPOCAMPUS (Brain) ,RATS ,ASTROCYTES ,MURIDAE - Abstract
Extracellular adenosine 5′-triphosphate (ATP) in the brain is suggested to be an etiological factor of major depressive disorder (MDD). It has been assumed that stress-released ATP stimulates P2X7 receptors (Rs) at the microglia, thereby causing neuroinflammation; however, other central nervous system (CNS) cell types such as astrocytes also possess P2X7Rs. In order to elucidate the possible involvement of the MDD-relevant hippocampal astrocytes in the development of a depressive-like state, we used various behavioral tests (tail suspension test [TST], forced swim test [FST], restraint stress, inescapable foot shock, unpredictable chronic mild stress [UCMS]), as well as fluorescence immunohistochemistry, and patch-clamp electrophysiology in wild-type (WT) and genetically manipulated rodents. The TST and FST resulted in learned helplessness manifested as a prolongation of the immobility time, while inescapable foot shock caused lower sucrose consumption as a sign of anhedonia. We confirmed the participation of P2X7Rs in the development of the depressive-like behaviors in all forms of acute (TST, FST, foot shock) and chronic stress (UCMS) in the rodent models used. Further, pharmacological agonists and antagonists acted in a different manner in rats and mice due to their diverse potencies at the respective receptor orthologs. In hippocampal slices of mice and rats, only foot shock increased the current responses to locally applied dibenzoyl-ATP (Bz-ATP) in CA1 astrocytes; in contrast, TST and restraint depressed these responses. Following stressful stimuli, immunohistochemistry demonstrated an increased co-localization of P2X7Rs with a microglial marker, but no change in co-localization with an astroglial marker. Pharmacological damage to the microglia and astroglia has proven the significance of the microglia for mediating all types of depression-like behavioral reactions, while the astroglia participated only in reactions induced by strong stressors, such as foot shock. Because, in addition to acute stressors, their chronic counterparts induce a depressive-like state in rodents via P2X7R activation, we suggest that our data may have relevance for the etiology of MDD in humans. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
23. Purinergic Signaling in Brain Physiology
- Author
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Glaser, Talita, Ulrich, Henning, Ulrich, Henning, editor, Illes, Peter, editor, and Glaser, Talita, editor
- Published
- 2023
- Full Text
- View/download PDF
24. Adenosine receptor signaling in the brain immune system
- Author
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Haskó, György, Pacher, Pál, Sylvester Vizi, E., and Illes, Peter
- Subjects
- *
BRAIN , *IMMUNE system , *ASTROCYTES , *MICROGLIA , *ADENOSINES - Abstract
The brain immune system, which consists mainly of astrocytes, microglia and infiltrating immune cells, is quiescent normally, but it is activated in response to pathophysiological events such as ischemia, trauma, inflammation and infection. Adenosine is an endogenous purine nucleoside that is generated at sites that are subjected to these ‘stressful’ conditions. Adenosine interacts with specific G-protein-coupled receptors on astrocytes, microglia and infiltrating immune cells to regulate the function of the immune system in the brain. Although many of the effects of adenosine on immune-competent cells in the brain protect neuronal integrity, adenosine might also aggravate neuronal injury by promoting inflammatory processes. A more complete understanding of adenosine receptor function in the brain immune system should help develop novel therapeutic ways to treat brain disorders that are associated with a dysfunctional immune response. [Copyright &y& Elsevier]
- Published
- 2005
- Full Text
- View/download PDF
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