Bezzi, P. et al. Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391, 281-285
Institute of Pharmacological Sciences, University of Milan, Italy. Nature
(Impact Factor: 41.46).
02/1998; 391(6664):281-5. DOI: 10.1038/34651
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.
Available from: Daniela Rossi
- "However, subsequent studies in situ rather indicated that the gap junctional communication between astrocytic and neuronal networks occurs at the early stages of neural development and lessens with the progression of differentiation (Alvarez-Maubecin et al., 2000; Bittman et al., 2002). It was therefore proposed that astrocytic Ca 2+ waves can affect the calcium concentration of the neighboring neurons by Ca 2+ -dependent release of various chemical transmitters , which can activate neuronal ionotropic and metabotropic receptors (Bezzi et al., 1998, 2001, 2004; Henneberger et al., 2010; Jourdain et al., 2007; Lalo et al., 2014; Mothet et al., 2005; Panatier et al., 2006; Parpura et al., 1994; Pascual et al., 2005; Santello et al., 2011; Slezak et al., 2012). Because a single astrocyte can contact thousands of synapses and hundreds of dendrites (Bushong et al., 2002; Halassa et al., 2007), one may hypothesize that the astrocytic networks can activate multiple neurons via the discharge of chemical transmitters. "
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ABSTRACT: Recent breakthroughs in neuroscience have led to the awareness that we should revise our traditional mode of thinking and studying the CNS, i.e. by isolating the privileged network of "intelligent" synaptic contacts. We may instead need to contemplate all the variegate communications occurring between the different neural cell types, and centrally involving the astrocytes. Basically, it appears that a single astrocyte should be considered as a core that receives and integrates information from thousands of synapses, other glial cells and the blood vessels. In turn, it generates complex outputs that control the neural circuitry and coordinate it with the local microcirculation. Astrocytes thus emerge as the possible fulcrum of the functional homeostasis of the healthy CNS. Yet, evidence indicates that the bridging properties of the astrocytes can change in parallel with, or as a result of, the morphological, biochemical and functional alterations these cells undergo upon injury or disease. As a consequence, they have the potential to transform from supportive friends and interactive partners for neurons into noxious foes. In this review, we summarize the currently available knowledge on the contribution of astrocytes to the functioning of the CNS and what goes wrong in various pathological conditions, with a particular focus on amyotrophic lateral sclerosis, Alzheimer's disease and ischemia. The observations described convincingly demonstrate that the development and progression of several neurological disorders involve the de-regulation of a finely tuned interplay between multiple cell populations. Thus, it seems that a better understanding of the mechanisms governing the integrated communication and detrimental responses of the astrocytes as well as their impact towards the homeostasis and performance of the CNS is fundamental to open novel therapeutic perspectives.
Copyright © 2015. Published by Elsevier Ltd.
Available from: Zhidong Liu
- "Since Benveniste demonstrated that ischemic injury evoked release of glutamic acid (Glu) and aspartic acid (Asp) from the rat hippocampus (Benveniste et al., 1984), the changes of amino acids during cerebral ischemia–reperfusion have been of much research interests. Asp and Glu are released excessively from neurons and astrocytes after ischemic injury (Benveniste et al., 1984; Bezzi et al., 1998; Drejer et al., 1985; Katchman and Hershkowitz, 1993), which might contribute to the progressive neural injury. Glycine (Gly), Taurine (Tau) and g-aminobutyric acid (GABA) are inhibitory amino acids (IAA), which can inhibit the excess-activity of nerve cell caused by excitatory amino acids (EAA) (Shah et al., 2002). "
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ABSTRACT: Baicalin has many pharmacological activities, including neuroprotective function against ischemia and neurodegeneration. In our previous study, we found that Baicalin-loaded PEGylated cationic solid lipid nanoparticles modified by OX26 antibody (OX26-PEG-CSLN) might be a promising carrier to deliver drugs across the blood-brain barrier for the treatment of brain diseases. So, the aim of this present study was to further elucidate the mechanisms of OX26-PEG-CSLN cerebral ischemia protection by monitoring the changes of extracellular amino acids. In addition, we investigated the effect of OX26-PEG-CSLN on the excitotoxic neuronal injury as well as the pharmacokinetic profiles of baicalin in cerebrospinal fluid during ischemia-reperfusion period. The cerebrospinal fluid was collected by a microdialysis technique and divided into two parts-one part for pharmacokinetic study of baicalin using LC-MS/MS method and the other for pharmacodynamic study which was done by pre-column derivatization of the amino acids and analysis using a high-performance liquid chromatography with fluorescence detector (HPLC-FLD). The pharmacokinetic study showed that the AUC value of OX26-PEG-CSLN was 5.69-fold higher than that of the baicalin solution (Sol) (P < 0.05) and the Cmax value of OX26-PEG-CSLN was 6.84-fold higher than that of the Sol (P < 0.05). Moreover, the extracellular levels of glutamate (Glu), aspartic acid (Asp), glycine (Gly), taurine (Tau) and γ-aminobutyric acid (GABA) were measured for monitoring the imbalance of amino acids caused by ischemia and reperfusion. The excitotoxic index (EI) was also calculated for evaluating the imbalance between excitatory amino acid and inhibitory amino acid. The pharmacodynamic study showed that OX26-PEG-CSLN had stronger effect than Sol in reducing the content of aspartic, glutamic acid and increasing the concentrations of glycine, taurine and γ-aminobutyric acid during ischemia-reperfusion period. In conclusion, OX26-PEG-CSLN improved uptake of baicalin across the BBB into the brain, and elevated bioavailability of baicalin in cerebral spinal fluid of rats under the cerebral ischemia-reperfusion injury. OX26-PEG-CSLN had much higher protection effect against cerebral ischemia injury than Sol by relieving the excitotoxic neuronal injury via regulating amino acid levels in cerebral spinal fluid.
Copyright © 2015. Published by Elsevier B.V.
Available from: Thimmasettappa Thippeswamy
- "In addition to NOX, the cyclooxygenase-2 (COX-2) enzymes have been found to upregulate ROS levels via the production of prostaglandins (specifically, F 2 and H) . In an in vitro model of rat cortex, it has been shown that the prostaglandins stimulate astrocytes to produce proinflammatory cytokines, which initiated neuronal death . COX-2 is also responsible for a number of inflammatory responses in tissues involving neutrophils of the immune system . "
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ABSTRACT: An insult to the brain (such as the first seizure) causes excitotoxicity, neuroinflammation, and production of reactive oxygen/nitrogen species (ROS/RNS). ROS and RNS produced during status epilepticus (SE) overwhelm the mitochondrial natural antioxidant defense mechanism. This leads to mitochondrial dysfunction and damage to the mitochondrial DNA. This in turn affects synthesis of various enzyme complexes that are involved in electron transport chain. Resultant effects that occur during epileptogenesis include lipid peroxidation, reactive gliosis, hippocampal neurodegeneration, reorganization of neural networks, and hypersynchronicity. These factors predispose the brain to spontaneous recurrent seizures (SRS), which ultimately establish into temporal lobe epilepsy (TLE). This review discusses some of these issues. Though antiepileptic drugs (AEDs) are beneficial to control/suppress seizures, their long term usage has been shown to increase ROS/RNS in animal models and human patients. In established TLE, ROS/RNS are shown to be harmful as they can increase the susceptibility to SRS. Further, in this paper, we review briefly the data from animal models and human TLE patients on the adverse effects of antiepileptic medications and the plausible ameliorating effects of antioxidants as an adjunct therapy.
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