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Biomedical subjects

P Bezzi

Publications and source records attributed to P Bezzi.

At least 19 recordsLinked to original sources
PubMed2001

A neuron-glia signalling network in the active brain.

Glial cells are active partners of neurons in processing information and synaptic integration. They receive coded signals from synapses and elaborate modulatory responses. The active properties of glia, including long-range signalling and regulated transmitter release, are beginning to be elucidated. Recent insights suggest that the active brain should no longer be regarded as a circuitry of neuronal contacts, but as an integrated network of interactive neurons and glia.

Action Potentials↗
PubMed2001

CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity.

Astrocytes actively participate in synaptic integration by releasing transmitter (glutamate) via a calcium-regulated, exocytosis-like process. Here we show that this process follows activation of the receptor CXCR4 by the chemokine stromal cell-derived factor 1 (SDF-1). An extraordinary feature of the ensuing signaling cascade is the rapid extracellular release of tumor necrosis factor-alpha (TNFalpha). Autocrine/paracrine TNFalpha-dependent signaling leading to prostaglandin (PG) formation not only controls glutamate release and astrocyte communication, but also causes their derangement when activated microglia cooperate to dramatically enhance release of the cytokine in response to CXCR4 stimulation. We demonstrate that altered glial communication has direct neuropathological consequences and that agents interfering with CXCR4-dependent astrocyte-microglia signaling prevent neuronal apoptosis induced by the HIV-1 coat glycoprotein, gp120IIIB. Our results identify a new pathway for glia-glia and glia-neuron communication that is relevant to both normal brain function and neurodegenerative diseases.

Animals↗
PubMed2001

Synaptic transmission with the glia.

For decades, scientists thought that all of the missing secrets of brain function resided in neurons. However, a wave of new findings indicates that glial cells, formerly considered mere supporters and subordinate to neurons, participate actively in synaptic integration and processing of information in the brain.

Calcium Signaling↗
PubMed1999

Inhibitory effect of the neuroprotective agent idebenone on arachidonic acid metabolism in astrocytes.

Idebenone, a compound with protective efficacy against neurotoxicity both in in vitro and in in vivo models, exists in two different oxidative states: the ubiquinol-derivative (reduced idebenone) and the ubiquinone-derivative (oxidised idebenone). In the present study, we have observed that both the redox forms of idebenone have a dose-dependent inhibitory effect on the enzymatic metabolism of arachidonic acid in astroglial homogenates (IC50 reduced idebenone: 1.76 +/- 0.86 microM; IC50 oxidised idebenone: 16.65 +/- 3.48 microM), while in platelets, they are apparently less effective (IC50 reduced idebenone: 18.28 +/- 4.70 microM; IC50 oxidised idebenone: > 1 mM). We have also observed that the oxidised form preferentially inhibited cyclooxygenase vs. lipoxygenase metabolism (IC50 ratio lipoxygenase/cyclooxygenase: 3.22), while the reduced form did not discriminate between the two pathways (IC50 ratio lipoxygenase/cyclooxygenase: 1.38). In this respect, the inhibitory action of reduced idebenone resembled that of the antioxidant nordihydroguaiaretic acid, while oxidised idebenone behaved similarly as indomethacin and piroxicam--two typical anti-inflammatory agents. Our results suggest the existence of two distinct mechanisms of action for the two redox forms of idebenone and a preferential action of the drug on arachidonic acid metabolism in the central nervous system.

Animals↗
PubMed1999

The active role of astrocytes in synaptic transmission.

In the central nervous system, astrocytes form an intimately connected network with neurons, and their processes closely enwrap synapses. The critical role of these cells in metabolic and trophic support to neurons, ion buffering and clearance of neurotransmitters is well established. However, recent accumulating evidence suggests that astrocytes are active partners of neurons in additional and more complex functions. In particular, astrocytes express a repertoire of neurotransmitter receptors mirroring that of neighbouring synapses. Such receptors are stimulated during synaptic activity and start calcium signalling into the astrocyte network. Intracellular oscillations and intercellular calcium waves represent the astrocyte's own form of excitability, as they trigger release of transmitter (i.e. glutamate) via a novel process sensitive to blockers of exocytosis and involving cyclooxygenase eicosanoids. Astrocyte-released glutamate activates receptors on the surrounding neurons and modifies their electrical and intracellular calcium ([Ca2+]i) state. These exciting new findings reveal an active participation of astrocytes in synaptic transmission and the involvement of neuronastrocyte circuits in the processing of information in the brain.

Animals↗
PubMed1999

The highly integrated dialogue between neurons and astrocytes in brain function.

For decades neurons have been regarded as the only cells involved in the generation and control of brain signalling, while the surrounding glia was supposed to provide structural and metabolic support to neuronal function. However, based on a number of recent findings, a new view is emerging: astrocytes, the glial cells ensheathing synaptic specializations, are active and integrated participants of neurotransmission. Not only do astrocytes take up and remove synaptically released glutamate (the major excitatory neurotransmitter), thus ending its stimulatory action and preventing neuronal damage, but also and outstandingly, they are able to undergo rapid bidirectional communication with neurons, based on reciprocal glutamatergic signalling. Thus, release of glutamate from synaptic terminals, in addition to postsynaptic neurons, turns on the astrocytes nearby which respond by liberating the same neurotransmitter via a novel Ca(2+)-dependent mechanism and thereby signal back to neurons. The present review discusses the above findings and their important implications as well as additional evidence supporting the new concept of an integrated neuron-astrocyte communication in brain function.

Animals↗
PubMed1998

Prostaglandins stimulate calcium-dependent glutamate release in astrocytes.

Astrocytes in the brain form an intimately associated network with neurons. They respond to neuronal activity and synaptically released glutamate by raising intracellular calcium concentration ([Ca2+]i), which could represent the start of back-signalling to neurons. Here we show that coactivation of the AMPA/kainate and metabotropic glutamate receptors (mGluRs) on astrocytes stimulates these cells to release glutamate through a Ca2+-dependent process mediated by prostaglandins. Pharmacological inhibition of prostaglandin synthesis prevents glutamate release, whereas application of prostaglandins (in particular PGE2) mimics and occludes the releasing action of GluR agonists. PGE2 promotes Ca2+-dependent glutamate release from cultured astrocytes and also from acute brain slices under conditions that suppress neuronal exocytotic release. When applied to the CA1 hippocampal region, PGE2 induces increases in [Ca2+]i both in astrocytes and in neurons. The [Ca2+]i increase in neurons is mediated by glutamate released from astrocytes, because it is abolished by GluR antagonists. Our results reveal a new pathway of regulated transmitter release from astrocytes and outline the existence of an integrated glutamatergic cross-talk between neurons and astrocytes in situ that may play critical roles in synaptic plasticity and in neurotoxicity.

Animals↗
PubMed1997

HIV-1 gp120 glycoprotein affects the astrocyte control of extracellular glutamate by both inhibiting the uptake and stimulating the release of the amino acid.

The mechanisms of HIV-1 neurotoxicity remain still undefined although the induction of signalling events and a modest inhibition of glutamate uptake induced by the envelope glycoprotein, gp120, have called attention to astrocytes. Here we demonstrate that the levels at which the viral glycoprotein affects glutamate homeostasis of astrocyte cultures are at least two: not only the inhibition of uptake, due to an effect at site(s) away from the transporters of the amino acid but also a slow stimulation of release. The combination of these two events accounts for a considerable steady increase of the extracellular concentration of the excitatory amino acid which could play an important role in the neurotoxicity often observed in AIDS patients.

Animals↗
PubMed1996

The competitive transport inhibitor L-trans-pyrrolidine-2, 4-dicarboxylate triggers excitotoxicity in rat cortical neuron-astrocyte co-cultures via glutamate release rather than uptake inhibition.

We studied the early and late effects of L-trans-pyrrolidine-2,4-dicarboxylate (PDC), a competitive inhibitor of glutamate uptake with low affinity for glutamate receptors, in co-cultures of rat cortical neurons and glia expressing spontaneous excitatory amino acid (EAA) neurotransmission. At 100 or 200 microM, PDC induced different patterns of electrical changes: 100 microM prolonged tetrodotoxin-sensitive excitation triggered by synaptic glutamate release; 200 microM produced sustained, tetrodotoxin-insensitive and EAA-mediated neuronal depolarization, overwhelming synaptic activity. At 200 microM, but not at 100 microM, PDC caused rapid elevation of the glutamate concentration ([Glu]o) in the culture medium, resulting in NMDA receptor-mediated excitotoxic death of neurons 24 h later. The increase in [Glu]o was largely insensitive to tetrodotoxin, independent of extracellular Ca2+, and present also in astrocyte-pure cultures. By the use of glutamate transporters functionally reconstituted in liposomes, we showed directly that PDC activates carrier-mediated release of glutamate via heteroexchange. Glutamate release and delayed neurotoxicity in our cultures were suppressed if PDC was applied in a Na(+)-free medium containing Li+. However, replacement of Na+ with choline instead of Li+ did not result in an identical effect, suggesting that Li+ does not act simply as an external Na+ substitute. In conclusion, our data indicate that alteration of glutamate transport by PDC has excitotoxic consequences and that active release of glutamate rather than just uptake inhibition is responsible for the generation of neuronal injury.

Animals↗
PubMed1995

[Ca2+] modulates the ratio between cycloxygenase and lipoxygenase metabolism of arachidonic acid in homogenates of hippocampal astroglial cultures.

While studying the enzymatic processing of arachidonic acid (AA) to eicosanoids in homogenates of hippocampal astrocytes, we observed that all the HPLC peaks corresponding to AA metabolites displayed significantly different levels depending on the presence or not of free Ca2+ in the incubation medium. A specific pattern was noticed, i.e. lipoxygenase (LOX) derivatives, in particular 12-hydroxyeicosatetraenoic acid (12-HETE), showed higher levels in medium containing 1 mM Ca2+, while cycloxygenase (COX) products including prostaglandins (PG) F2 alpha, E2 and D2 and 12-hydroxyhepatadecatrienoic acid (12-HHT), were higher in Ca(2+)-free medium. COX metabolism exceeded LOX metabolism by threefold in Ca(2+)-free medium, while it was only 60% of it in 1 mM Ca2+. The total amount of AA processed under the two conditions was identical. These data suggest that free [Ca2+] influences the pattern of AA metabolites formed in hippocampal astrocytes, with possible important implications in view of the distinct roles played by COX and LOX eicosanoids in synaptic transmission and neurotoxicity in this area.

Animals↗
PubMed1977

[A case of primary hyperparathyroidism sustained by parathyroid adenocarcinomatosis].

Primary hyperparathyroidism may at times be associated with carcinoma of the parathyroids. A personal case of primary hyperparathyroidism was operated on by total thyro-parathyroidectomy. The histological picture presented atypical cell patterns and infiltrations of the thyroid capsule, together with adenomatuous parathyroid formations suggesting the possibility of a malignant transformation of initially benign process. Given the benign clinical course, it is possible that when subjected to radical, timely measures, even atypical parathyroid processes may be cured completely.

Adenocarcinoma↗