Up-regulation of p2x2, p2x4 receptor and ischemic cell death: prevention by p2 antagonists

Cavaliere, Fabio; Florenzano, Fulvio; Amadio, Susanna; Fusco, Francesca R.; Viscomi, Maria Teresa; D’Ambrosi, Nadia; Vacca, Fabrizio; Sancesario, Giuseppe; Bernardi, Giorgio; Molinari, Marco; Volonté, Cinza

doi:10.1016/s0306-4522(03)00228-8

Cited by 151 publications

(116 citation statements)

References 55 publications

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“…Suramin or PPADS reduce neuronal death in primary neuron and brain slice cultures exposed to glucose deprivation or OGD (injury assessed ≥ 20 h) [44][45][46]; protection with low (PPADS, 5 µM) concentrations of has been reported in hippocampal slice cultures [47]. The current findings are the first to demonstrate that P2 antagonists can protect neurons during acute ischaemia, and that PPADS protects both neurons and astrocytes.…”

Section: Broad-spectrum P2 Antagonists Protect Neurons and Astrocytessupporting

confidence: 53%

Cooperation between NMDA-Type Glutamate and P2 Receptors for Neuroprotection during Stroke: Combining Astrocyte and Neuronal Protection

et al. 2018

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Excitotoxicity is the principle mechanism of acute injury during stroke. It is defined as the unregulated accumulation of excitatory neurotransmitters such as glutamate within the extracellular space, leading to over-activation of receptors, ionic disruption, cell swelling, cytotoxic Ca 2+ elevation and a feed-forward loop where membrane depolarisation evokes further neurotransmitter release. Glutamate-mediated excitotoxicity is well documented in neurons and oligodendrocytes but drugs targeting glutamate excitotoxicity have failed clinically which may be due to their inability to protect astrocytes. Astrocytes make up~50% of the brain volume and express high levels of P2 adenosine triphosphate (ATP)-receptors which have excitotoxic potential, suggesting that glutamate and ATP may mediate parallel excitotoxic cascades in neurons and astrocytes, respectively. Mono-cultures of astrocytes expressed an array of P2X and P2Y receptors can produce large rises in [Ca 2+ ]i; mono-cultured neurons showed lower levels of functional P2 receptors. Using high-density 1:1 neuron:astrocyte co-cultures, ischemia (modelled as oxygen-glucose deprivation: OGD) evoked a rise in extracellular ATP, while P2 blockers were highly protective of both cell types. GluR blockers were only protective of neurons. Neither astrocyte nor neuronal mono-cultures showed significant ATP release during OGD, showing that cell type interactions are required for ischemic release. P2 blockers were also protective in normal-density co-cultures, while low doses of combined P2/GluR blockers where highly protective. These results highlight the potential of combined P2/GluR block for protection of neurons and glia.

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Section: Broad-spectrum P2 Antagonists Protect Neurons and Astrocytessupporting

confidence: 53%

Cooperation between NMDA-Type Glutamate and P2 Receptors for Neuroprotection during Stroke: Combining Astrocyte and Neuronal Protection

et al. 2018

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“…For instance, early studies reported that P2X1 was strongly and transiently upregulated following ischemic insult in the hippocampus (Cavaliere et al, 2003), while P2X2 and P2X4 are upregulated in the dentate gyrus following oxygen and glucose deprivation in an organotypic hippocampal slice culture. Another study revealed an upregulation of P2X1 and P2X2 at the site of neurodegeneration following axotomy (Viscomi et al, 2004).…”

Section: The Role Of P2x Receptors In Neuroinflammationmentioning

confidence: 99%

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

et al. 2016

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a b s t r a c tThe principle functions of neuroinflammation are to limit tissue damage and promote tissue repair in response to pathogens or injury. While neuroinflammation has utility, pathophysiological inflammatory responses, to some extent, underlie almost all neuropathology. Understanding the mechanisms that control the three stages of inflammation (initiation, propagation and resolution) is therefore of critical importance for developing treatments for diseases of the central nervous system. The purinergic signaling system, involving adenosine, ATP and other purines, plus a host of P1 and P2 receptor subtypes, controls inflammatory responses in complex ways. Activation of the inflammasome, leading to release of pro-inflammatory cytokines, activation and migration of microglia and altered astroglial function are key regulators of the neuroinflammatory response. Here, we review the role of P1 and P2 receptors in mediating these processes and examine their contribution to disorders of the nervous system. Firstly, we give an overview of the concept of neuroinflammation. We then discuss the contribution of P2X, P2Y and P1 receptors to the underlying processes, including a discussion of cross-talk between these different pathways. Finally, we give an overview of the current understanding of purinergic contributions to neuroinflammation in the context of specific disorders of the central nervous system, with special emphasis on neuropsychiatric disorders, characterized by chronic low grade inflammation or maternal inflammation. An understanding of the important purinergic contribution to neuroinflammation underlying neuropathology is likely to be a necessary step towards the development of effective interventions.

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“…As shown in Figure 3A, these inhibitors added together did not significantly affect OGD-induced astrocyte V m depolarization nor the post-OGD hyperpolarization (n = 5, P > 0.1), indicating an insignificant contribution of astrocytic or neuronal glutamate ionotropic receptors and transporter activation to the OGDinduced astrocyte V m depolarization. Hippocampal astrocytes in vivo also express ionotropic purinergic P2X receptors (Kukley et al, 2001) that are upregulated in OGD conditions in hippocampal slice cultures (Cavaliere et al, 2003;Rundén-Pran et al, 2005). Although the level of the endogenous P2X agonist, ATP, can decrease very quickly in the first few minutes of ischemia (Nicholls and Attwell, 1990), it is possible that ATP could be released as a coneurotransmitter that modulates astrocyte V m via P2X receptors in the early phase of OGD.…”

Section: Activation Of Astrocytic Ionotropic Receptors and Transportementioning

confidence: 99%

Oxygen and Glucose Deprivation-Induced Changes in Astrocyte Membrane Potential and Their Underlying Mechanisms in Acute Rat Hippocampal Slices

Xie

Wang

Kimelberg

et al. 2007

J Cereb Blood Flow Metab

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Accumulating evidence indicates a significant astrocytic involvement in cerebral ischemia neuropathology, but little is known about the immediate astrocytic responses to ischemia insults in terms of electrophysiology and their pathologic implications. We show that astrocytes in acute rat hippocampal slices responded reversibly to more than 30 mins oxygen and glucose deprivation (OGD) treatment with depolarized membrane potentials (V m ) in whole-cell current clamp recording. This depolarization was multiphasic, showing an initial B11 mins small-amplitude depolarization plateau, followed by a 6-mins accelerated depolarization, and then a second plateau. Oxygen and glucose deprivation-induced astrocyte V m depolarization was only marginally inhibited, B10%, by inhibition of ionotropic glutamate, c-aminobutyric acid, purinergic receptors, and glutamate transporters presumed to be present on astrocytes in situ, suggesting increase in extracellular [K + ] was primarily responsible for the astrocytic V m change. The V m depolarization was five-fold greater when glycolysis was inhibited by iodoacetate in a short 8 mins OGD treatment, suggesting glycolytic ATP is critical in maintaining extracellular K + homeostasis in the early phase of OGD. Addition of oxidative metabolism inhibitors had much less effect. Cessation of OGD was always followed by a rapid and transient 9 mV astrocyte V m hyperpolarization relative to the control V m that was inhibited by ouabain, indicating a reactively enhanced Na + /K + -ATPase activity in post-OGD reperfusion. Altogether, hippocampal astrocytes appear to be electrophysiologically more resistant to acute ischemia insults as compared with neurons, and this should allow astrocytes to rescue endangered neurons in the face of acute ischemia insults via their various homeostatic functions.

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Up-regulation of p2x2, p2x4 receptor and ischemic cell death: prevention by p2 antagonists

Cited by 151 publications

References 55 publications

Cooperation between NMDA-Type Glutamate and P2 Receptors for Neuroprotection during Stroke: Combining Astrocyte and Neuronal Protection

Cooperation between NMDA-Type Glutamate and P2 Receptors for Neuroprotection during Stroke: Combining Astrocyte and Neuronal Protection

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

Oxygen and Glucose Deprivation-Induced Changes in Astrocyte Membrane Potential and Their Underlying Mechanisms in Acute Rat Hippocampal Slices

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