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1.
Neurochem Res ; 44(3): 609-616, 2019 Mar.
Article in English | MEDLINE | ID: mdl-29353373

ABSTRACT

Maternal immune challenge has proved to induce moderate to severe behavioral disabilities in the offspring. Cognitive/behavioral deficits are supported by changes in synaptic plasticity in different brain areas. We have reported previously that prenatal exposure to bacterial LPS could induce inhibition of hippocampal long-term potentiation (LTP) in the CA1 area of the juvenile/adult male offspring associated with spatial learning inabilities. Nevertheless, deficits in plasticity could be observed at earlier stages as shown by the early loss of long-term depression (LTD) in immature animals. Moreover, aberrant forms of plasticity were also evidenced such as the transient occurrence of LTP instead of LTD in 15-25 day-old animals. This switch from LTD to LTP seemed to involve the activation of metabotropic glutamate receptor subtype 1 and 5 (mGlu1/5). We have thus investigated here whether the long-term depression elicited by the direct activation of these receptors (mGlu-LTD) with a selective agonist was also disturbed after prenatal stress. We find that in prenatally stressed rats, mGlu1/5 stimulation elicits long-term potentiation (mGlu-LTP) independently of N-methyl-D-aspartate receptors. Both mGlu5 and mGlu1 receptors are involved in this switch of plasticity. Moreover, this mGlu-LTP is still observed at later developmental stages than previously reported, i.e. after 25 day-old. In addition, increasing synaptic GABA with tiagabine tends to inhibit mGlu-LTP occurrence. By contrast, long-term depression induced with the activation of CB1 cannabinoid receptor is unaffected by prenatal stress. Therefore, prenatal stress drastically alters mGlu1/5-associated plasticity throughout development. MGlu-mediated plasticity is an interesting parameter to probe the long-lasting deficits reported in this model.


Subject(s)
Hippocampus/physiology , Long-Term Potentiation/physiology , Neuronal Plasticity/physiology , Receptors, Metabotropic Glutamate/immunology , Synaptic Transmission/physiology , Animals , Depression/immunology , Excitatory Amino Acid Antagonists/pharmacology , Female , Hippocampus/immunology , Long-Term Potentiation/immunology , Neuronal Plasticity/immunology , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/immunology , Synaptic Transmission/immunology
2.
ACS Chem Neurosci ; 8(8): 1724-1734, 2017 08 16.
Article in English | MEDLINE | ID: mdl-28511005

ABSTRACT

l-Theanine (or l-γ-N-ethyl-glutamine) is the major amino acid found in Camellia sinensis. It has received much attention because of its pleiotropic physiological and pharmacological activities leading to health benefits in humans, especially. We describe here a new, easy, efficient, and environmentally friendly chemical synthesis of l-theanine and l-γ-N-propyl-Gln and their corresponding d-isomers. l-Theanine, and its derivatives obtained so far, exhibited partial coagonistic action at N-methyl-d-aspartate (NMDA) receptors, with no detectable agonist effect at other glutamate receptors, on cultured hippocampal neurons. This activity was retained on NMDA receptors expressed in Xenopus oocytes. In addition, both GluN2A and GluN2B containing NMDA receptors were equally modulated by l-theanine. The stereochemical change from l-theanine to d-theanine along with the substitution of the ethyl for a propyl moiety in the γ-N position of l- and d-theanine significantly enhanced the biological efficacy, as measured on cultured hippocampal neurons. l-Theanine structure thus represents an interesting backbone to develop novel NMDA receptor modulators.


Subject(s)
Hippocampus/metabolism , Neurons/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Calcium/metabolism , Cells, Cultured , Excitatory Amino Acid Agonists/chemical synthesis , Excitatory Amino Acid Agonists/pharmacology , Glutamates/metabolism , Glutamic Acid/metabolism , Hippocampus/drug effects , Membrane Potentials/drug effects , Membrane Potentials/physiology , Mice , Neurons/drug effects , Oocytes , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/agonists , Xenopus , gamma-Aminobutyric Acid/metabolism
3.
Eur J Neurosci ; 42(8): 2568-76, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26153524

ABSTRACT

Acute effects of ghrelin on excitatory synaptic transmission were evaluated on hippocampal CA1 synapses. Ghrelin triggered an enduring enhancement of synaptic transmission independently of NMDA receptor activation and probably via postsynaptic modifications. This ghrelin-mediated potentiation resulted from the activation of GHS-R1a receptors as it was mimicked by the selective agonist JMV1843 and blocked by the selective antagonist JMV2959. This potentiation also required the activation of PKA and ERK pathways to occur as it was inhibited by KT5720 and U0126, respectively. Moreover it most probably involved Ca(2+) influxes as both ghrelin and JMV1843 elicited intracellular Ca(2+) increases, which were dependent on the presence of extracellular Ca(2+) and mediated by L-type Ca(2+) channels opening. In addition, ghrelin potentiated AMPA receptor-mediated [Ca(2+) ]i increases while decreasing NMDA receptor-mediated ones. Thus the potentiation of synaptic transmission by GHS-R1a at hippocampal CA1 excitatory synapses probably results from postsynaptic mechanisms involving PKA and ERK activation, which are producing long-lasting enhancement of AMPA receptor-mediated responses.


Subject(s)
CA1 Region, Hippocampal/physiology , Cyclic AMP-Dependent Protein Kinases/metabolism , Ghrelin/metabolism , Long-Term Potentiation/physiology , MAP Kinase Signaling System/physiology , Synaptic Transmission/physiology , Animals , CA1 Region, Hippocampal/drug effects , Calcium/metabolism , Calcium Channels, L-Type/metabolism , Cells, Cultured , Central Nervous System Agents/administration & dosage , Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Ghrelin/administration & dosage , Long-Term Potentiation/drug effects , MAP Kinase Signaling System/drug effects , Male , Rats, Sprague-Dawley , Receptors, AMPA/metabolism , Receptors, Ghrelin/agonists , Receptors, Ghrelin/antagonists & inhibitors , Receptors, Ghrelin/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Synaptic Transmission/drug effects , Tissue Culture Techniques
4.
PLoS One ; 9(9): e106302, 2014.
Article in English | MEDLINE | ID: mdl-25184226

ABSTRACT

Maternal inflammation during pregnancy is associated with the later development of cognitive and behavioral impairment in the offspring, reminiscent of the traits of schizophrenia or autism spectrum disorders. Hippocampal long-term potentiation and long-term depression of glutamatergic synapses are respectively involved in memory formation and consolidation. In male rats, maternal inflammation with lipopolysaccharide (LPS) led to a premature loss of long-term depression, occurring between 12 and 25 postnatal days instead of after the first postnatal month, and aberrant occurrence of long-term potentiation. We hypothesized this would be related to GABAergic system impairment. Sprague Dawley rats received either LPS or isotonic saline ip on gestational day 19. Male offspring's hippocampus was studied between 12 and 25 postnatal days. Morphological and functional analyses demonstrated that prenatal LPS triggered a deficit of hippocampal GABAergic interneurons, associated with presynaptic GABAergic transmission deficiency in male offspring. Increasing ambient GABA by impairing GABA reuptake with tiagabine did not interact with the low frequency-induced long-term depression in control animals but fully prevented its impairment in male offspring of LPS-challenged dams. Tiagabine furthermore prevented the aberrant occurrence of paired-pulse triggered long-term potentiation in these rats. Deficiency in GABA seems to be central to the dysregulation of synaptic plasticity observed in juvenile in utero LPS-challenged rats. Modulating GABAergic tone may be a possible therapeutic strategy at this developmental stage.


Subject(s)
GABAergic Neurons/drug effects , Inflammation/drug therapy , Nipecotic Acids/administration & dosage , gamma-Aminobutyric Acid/metabolism , Animals , Child Development Disorders, Pervasive/drug therapy , Child Development Disorders, Pervasive/metabolism , Child Development Disorders, Pervasive/pathology , Female , Hippocampus/drug effects , Hippocampus/pathology , Humans , Inflammation/chemically induced , Inflammation/pathology , Lipopolysaccharides/toxicity , Male , Neuronal Plasticity , Pregnancy , Prenatal Exposure Delayed Effects , Rats , Schizophrenia/drug therapy , Schizophrenia/metabolism , Schizophrenia/pathology , Tiagabine , gamma-Aminobutyric Acid/drug effects
5.
Pediatr Res ; 73(6): 750-5, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23478644

ABSTRACT

BACKGROUND: Prenatal infection is a major risk factor for the occurrence of neuropsychiatric disorders. These have been associated with hippocampal neuroanatomical and functional abnormalities. In the present study, we evaluated the occurrence of pyramidal cell disarray and reelin neuronal deficit in the hippocampus, and the protective role of N-acetyl-cysteine (NAC) in a rodent experimental model of prenatal immune challenge. METHODS: Sprague-Dawley rats received either 500 µg/kg of endotoxin (lipopolysaccharide, LPS) or 2 ml/kg of isotonic saline by i.p. injection on day 19 of gestation. After LPS injection, rats were or were not maintained on a preventive treatment of NAC (5 g/l in tap water), up to delivery. The pyramidal cell orientation and the number and type of reelin-expressing neurons were determined in male offspring. RESULTS: Prenatal LPS challenge led to permanent pyramidal cell disarray and to an early and transient decreased density of reelin-immunoreactive neurons. These disorders, more pronounced in the CA3 area, were prevented by NAC. CONCLUSION: Hippocampal cytoarchitectural alterations and reelin deficiency may be involved in the development of remote cognitive impairments in this model. The antioxidant NAC is an efficient neuroprotective drug that underlines the role of oxidative stress in prenatal infection and associated neurodevelopmental damage.


Subject(s)
Acetylcysteine/pharmacology , CA3 Region, Hippocampal/drug effects , Cell Adhesion Molecules, Neuronal/metabolism , Extracellular Matrix Proteins/metabolism , Maternal Exposure , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Pyramidal Cells/drug effects , Serine Endopeptidases/metabolism , Animals , CA3 Region, Hippocampal/cytology , Female , Male , Pregnancy , Rats , Rats, Sprague-Dawley , Reelin Protein
6.
Aging Cell ; 11(2): 336-44, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22230264

ABSTRACT

Oxidative stress (OS) resulting from an imbalance between antioxidant defenses and the intracellular accumulation of reactive oxygen species (ROS) contributes to age-related memory deficits. While impaired synaptic plasticity in neuronal networks is thought to underlie cognitive deficits during aging, whether this process is targeted by OS and what the mechanisms involved are still remain open questions. In this study, we investigated the age-related effects of the reducing agent N-acetyl-L-cysteine (L-NAC) on the activation of the N-methyl-D-aspartate receptor (NMDA-R) by its co-agonist D-serine, because alterations in this mechanism contribute greatly to synaptic plasticity deficits in aged animals. Long-term dietary supplementation with L-NAC prevented oxidative damage in the hippocampus of aged rats. Electrophysiological recordings in the CA1 of hippocampal slices indicated that NMDA-R-mediated synaptic potentials and theta-burst-induced long-term potentiation (LTP) were depressed in aged animals, deficits that could be reversed by exogenous D-serine. Chronic treatment with L-NAC, but not acute application of the reducing agent, restored potent D-serine-dependent NMDA-R activation and LTP induction in aged rats. In addition, it is also revealed that the age-related decrease in D-serine levels and in the expression of the synthesizing enzyme serine racemase, which underlies the decrease in NMDA-R activation by the amino acid, was rescued by long-term dietary treatment with L-NAC. Our results indicate that protecting redox status in aged animals could prevent injury to the cellular mechanisms underlying cognitive aging, in part by maintaining potent NMDA-R activation through the D-serine-dependent pathway.


Subject(s)
Aging , Hippocampus/metabolism , Neuronal Plasticity , Oxidative Stress , Receptors, N-Methyl-D-Aspartate/metabolism , Acetylcysteine/analogs & derivatives , Acetylcysteine/pharmacology , Animals , Lysine/analogs & derivatives , Lysine/pharmacology , Male , Neuronal Plasticity/drug effects , Rats , Rats, Wistar , Serine/metabolism
7.
Free Radic Biol Med ; 51(9): 1643-55, 2011 Nov 01.
Article in English | MEDLINE | ID: mdl-21843633

ABSTRACT

α-Tocopherol (α-TOH), a dietary component of vitamin E, is well known for its antioxidant capacity. Nevertheless, recent studies have pointed out non-anti-radical properties including cellular and genomic actions. Decreased levels of α-tocopherol in the brain are associated with neuronal dysfunctions ranging from mood disorders to neurodegeneration. All these behavioral effects of α-tocopherol deficiency probably do not rely simply on its anti-radical properties, but could also be reminiscent of a not-yet characterized neuromodulatory action. We have thus measured the direct actions of α-tocopherol and of its natural phosphate derivative, α-tocopheryl phosphate (α-TP), on synaptic transmission in rodent hippocampus. These compounds had opposite actions on both glutamatergic and GABAergic transmission: whereas α-TOH potentiated these transmissions, α-TP inhibited them. Interestingly, these effects were both mediated by cannabinoid receptors (CB1Rs), because they were blocked by the CB1R antagonist AM251. Although α-tocopherol and α-tocopheryl phosphate did not directly bind CB1R, both α-TP and CB1R agonists inhibited forskolin-evoked Erk1/2 phosphorylation in a nonadditive manner. Furthermore, both α-tocopherol and α-tocopheryl phosphate attenuated depolarization-induced suppression of excitation and CB1R agonist-mediated hypothermia. Therefore, we identify α-tocopherol as new lipid modulator of the cannabinoid system in the rodent hippocampus, i.e., a novel "non-anti-radical" action of vitamin E, which may have some preeminent impact in neuronal disorders associated with vitamin E deficiency.


Subject(s)
Antioxidants/pharmacology , Cannabinoids/metabolism , Hippocampus/drug effects , alpha-Tocopherol/analogs & derivatives , alpha-Tocopherol/pharmacology , Animals , Antioxidants/chemistry , Cannabinoid Receptor Agonists , Cells, Cultured , Hippocampus/cytology , Hippocampus/metabolism , Neurons/cytology , Neurons/drug effects , Neurons/metabolism , Rats , Receptors, Cannabinoid/metabolism , alpha-Tocopherol/chemistry
8.
Biol Psychiatry ; 70(10): 992-9, 2011 Nov 15.
Article in English | MEDLINE | ID: mdl-21377655

ABSTRACT

BACKGROUND: Maternal infection during pregnancy is a recognized risk factor for the occurrence of a broad spectrum of psychiatric and neurologic disorders, including schizophrenia, autism, and cerebral palsy. Prenatal exposure of rats to lipopolysaccharide (LPS) leads to impaired learning and psychotic-like behavior in mature offspring, together with an enduring modification of glutamatergic excitatory synaptic transmission. The question that arises is whether any alterations of excitatory transmission and plasticity occurred at early developmental stages after in utero LPS exposure. METHODS: Electrophysiological experiments were carried out on the CA1 area of hippocampal slices from prenatally LPS-exposed male offspring from 4 to 190 days old to study the developmental profiles of long-term depression (LTD) triggered by delivering 900 shocks either single- or paired-pulse (50-msec interval) at 1 Hz and the N-methyl-D-aspartate receptor (NMDAr) contribution to synaptic transmission. RESULTS: The age-dependent drop of LTD is accelerated in prenatally LPS-exposed animals, and LTD is transiently converted into a slow-onset long-term potentiation between 16 and 25 days old. This long-term potentiation depends on Group I metabotropic glutamate receptors and protein kinase A activations and is independent of NMDArs. Maternal LPS challenge also leads to a rapid developmental impairment of synaptic NMDArs. This was associated with a concomitant reduced expression of GluN1, without any detectable alteration in the developmental switch of NMDAr GluN2 subunits. CONCLUSIONS: Aberrant forms of synaptic plasticity can be detected at early developmental stages after prenatal LPS challenge concomitant with a clear hypo-functioning of the NMDAr in the hippocampus. This might result in later-occurring brain dysfunctions.


Subject(s)
CA1 Region, Hippocampal/physiopathology , Excitatory Postsynaptic Potentials/physiology , Long-Term Synaptic Depression/physiology , Prenatal Exposure Delayed Effects/pathology , Age Factors , Animals , Animals, Newborn , Biophysics , CA1 Region, Hippocampal/growth & development , CA1 Region, Hippocampal/pathology , Electric Stimulation , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Postsynaptic Potentials/drug effects , Female , Gene Expression Regulation, Developmental/drug effects , In Vitro Techniques , Long-Term Synaptic Depression/drug effects , Male , Patch-Clamp Techniques , Polysaccharides/pharmacology , Pregnancy , Pyridines/pharmacology , Rats , Receptors, N-Methyl-D-Aspartate/metabolism , Valine/analogs & derivatives , Valine/pharmacology
9.
Amino Acids ; 40(3): 913-22, 2011 Mar.
Article in English | MEDLINE | ID: mdl-20706748

ABSTRACT

Five derivatives of 2-amino-adipic acid bearing a tetrazole-substituted in C5 position were synthesized. These compounds displayed selective antagonism towards N-methyl-D: -aspartate (NMDA) receptors compared with AMPA receptors, and they were devoid of any neurotoxicity. Among these five analogues, one exhibited a higher affinity for synaptic NMDA responses than the other four. Therefore, C5 tetrazole-substituted of 2-amino-adipic acid represent an interesting series of new NMDA receptor antagonists. This approach may be considered as a new strategy to develop ligands specifically targeted to synaptic or extra-synaptic NMDA receptors.


Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Tetrazoles/chemical synthesis , Tetrazoles/pharmacology , Adipates/chemistry , Enzyme Inhibitors/chemistry , Receptors, N-Methyl-D-Aspartate/metabolism , Structure-Activity Relationship , Tetrazoles/chemistry
10.
Mol Nutr Food Res ; 54(4): 496-505, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20087852

ABSTRACT

Pretreatment of cultured hippocampal neurons with a low concentration of alpha-tocopherol (alpha-TP), the major component of vitamin E, results in a long-lasting protection against oxidative damages, via genomic effects. This neuroprotection is associated with the attenuation of a calcium influx triggered by oxidative agents such as Fe(2+) ions. This Ca(2+) influx is supported by a TRP-like channel, also partly involved in capacitive calcium entry within neurons. Here, we evidence the contribution of TRPV1 channels in this mechanism. TRPV1 channels are activated by various agents including capsaicin, the pungent component of hot chili peppers and blocked by capsazepine (CPZ) or 5'-iodo-resiniferatoxin. Both TRPV1 inhibitors strongly reduced Fe(2+) ion-mediated toxicity and Ca(2+) influx, in the same way as to alpha-TP pretreatment. Moreover, CPZ also decreased capacitive calcium entry in hippocampal neurons. Finally, both CPZ and 5'-iodo-resiniferatoxin reduced spontaneous excitatory synaptic transmission; this depression of synaptic transmission being largely occluded in alpha-TP-pretreated neurons. In conclusion, in our experimental model, TRPV1 channels are involved in the Fe(2+) ion-induced neuronal death and a negative modulation of this channel activity by alpha-TP pretreatment may account, at least in part, for the long-lasting neuroprotection against oxidative stress.


Subject(s)
Hippocampus/cytology , Neurons/physiology , Neuroprotective Agents/pharmacology , Oxidative Stress/drug effects , TRPV Cation Channels/physiology , alpha-Tocopherol/pharmacology , Animals , Calcium/metabolism , Capsaicin/analogs & derivatives , Capsaicin/pharmacology , Cell Death/drug effects , Cell Death/physiology , Cells, Cultured , Diterpenes/pharmacology , Electric Conductivity , Ferrous Compounds/pharmacology , Glutamic Acid/metabolism , Hippocampus/embryology , Neurons/drug effects , Rats , Rats, Sprague-Dawley , Synaptic Transmission/drug effects , TRPV Cation Channels/antagonists & inhibitors , TRPV Cation Channels/drug effects
11.
Hippocampus ; 18(6): 602-9, 2008.
Article in English | MEDLINE | ID: mdl-18306297

ABSTRACT

Prenatal infection is a major stressful experience leading to enhanced susceptibility for mental illnesses in humans. We recently reported in rats, that oxidative stress and glutathione (GSH) shortage occurred in fetal male brain after lipopolysaccharide (LPS) to the dams and that these responses might be involved in the neurodevelopmental deficits observed in adolescent offspring. Furthermore, pretreatment with N-acetylcysteine (NAC) before LPS avoided both delayed synaptic plasticity and mnesic performance deficits. Since NAC is one of the few medications permitted in pregnant women, this study evaluated the ability of NAC to serve as a protective therapy even after the LPS challenge. Pregnant rats received a single ip injection of E. coli LPS, two days before delivery, and were given NAC in their tap water after the LPS. GSH was evaluated at the time of its expected drop in the hippocampus of male fetuses, whereas long-term potentiation (LTP) in the CA1 area of the hippocampus and spatial memory in the water-maze were recorded in 28-day-old male offspring. Post-treatment with NAC, four hours after the LPS challenge fully prevented the drop in the GSH hippocampal content. LTP, as well as spatial learning were completely protected. NAC administration at delivery also partially restored the LTP whereas post-treatment two days later was inefficient. Another set of dams were supplemented with alpha-tocopherol prior to LPS exposure, enhancing the alpha-tocopherol levels in fetal hippocampus. This treatment did not prevent the LPS-induced synaptic plasticity impairment. These results point to fetal hippocampal GSH as a major target of the detrimental effects of in utero LPS challenge. The therapeutic window of NAC extends up to birth, suggesting that this drug might be clinically useful even after an immuno-inflammatory episode.


Subject(s)
Acetylcysteine/administration & dosage , Endotoxemia/drug therapy , Long-Term Potentiation , Maternal Exposure , Memory Disorders/prevention & control , Neuroprotective Agents/administration & dosage , Pregnancy Complications/drug therapy , Prenatal Exposure Delayed Effects/prevention & control , Acetylcysteine/pharmacology , Acetylcysteine/therapeutic use , Animals , Antioxidants/administration & dosage , Antioxidants/pharmacology , Antioxidants/therapeutic use , Drug Administration Schedule , Drug Evaluation, Preclinical , Endotoxemia/immunology , Endotoxemia/physiopathology , Female , Glutathione/analysis , Glutathione/deficiency , Hippocampus/chemistry , Hippocampus/embryology , Hippocampus/pathology , Lipopolysaccharides/toxicity , Long-Term Potentiation/drug effects , Long-Term Potentiation/physiology , Male , Maze Learning/drug effects , Maze Learning/physiology , Memory Disorders/etiology , Memory Disorders/physiopathology , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Pregnancy , Pregnancy Complications/immunology , Prenatal Exposure Delayed Effects/physiopathology , Rats , Rats, Sprague-Dawley , alpha-Tocopherol/administration & dosage , alpha-Tocopherol/analysis , alpha-Tocopherol/therapeutic use
12.
Curr Drug Targets ; 8(5): 651-81, 2007 May.
Article in English | MEDLINE | ID: mdl-17504108

ABSTRACT

L-glutamate (Glu), the main excitatory amino acid neurotransmitter in the mammalian central nervous system, is involved in many physiological functions, including learning and memory, but also in toxic phenomena occurring in numerous degenerative or neurological diseases. These functions mainly result from its interaction with Glu receptors (GluRs). The broad spectrum of roles played by glutamate derived from the large number of membrane receptors, which are currently classified in two main categories, ionotropic (iGluRs) and metabotropic (mGluRs) receptors. The iGluRs are ion channels, permeant to Na(+) (Ca(2+)) while the mGluRs belongs to the superfamily of G-protein coupled receptors (GPCRs). Despite continuous efforts over more than two decades, the use of iGluR agonists or antagonists to improve or inhibit excitatory transmission in pathological states still remains a major challenge, though the discovery and development of recent molecules may prove it worthwhile. This probably results form the vital role of fast excitatory transmission in many fundamental physiological functions. Since the discovery of mGluRs, hope has emerged. Indeed, mGluRs are mainly involved in the regulation of fast excitatory transmission. Consequently, it was logically thought that modulating mGluRs with agonists or antagonists might lead to more subtle regulation of fast excitatory transmission than by directly blocking iGluRs. As a result of intensive investigation, new drugs permitting to discriminate between these receptors have emerged. Moreover, a new class of molecules acting as negative or positive allosteric modulators or mGluRs is now available and appears to be promising. In the following, we will review the classification of mGluRs and the functions in which mGluRs are involved. We will focus on their potential as therapeutic targets for improving numerous physiological functions and for different neurodegenerative and neuropsychiatric disorders, which are related to malfunction of Glu signaling in human beings.


Subject(s)
Drug Delivery Systems/methods , Excitatory Amino Acid Agents/pharmacology , Receptors, Metabotropic Glutamate/agonists , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , Drug Delivery Systems/trends , Excitatory Amino Acid Agents/metabolism , Excitatory Amino Acid Agents/therapeutic use , Humans , Receptors, Metabotropic Glutamate/metabolism
13.
Free Radic Biol Med ; 42(8): 1231-45, 2007 Apr 15.
Article in English | MEDLINE | ID: mdl-17382204

ABSTRACT

Prenatal infection is a major risk responsible for the occurrence of psychiatric conditions in infants. Mimicking maternal infection by exposing pregnant rodents to bacterial endotoxin lipopolysaccharide (LPS) also leads to major brain disorders in the offspring. The mechanisms of LPS action remain, however, unknown. Here, we show that LPS injection during pregnancy in rats, 2 days before delivery, triggered an oxidative stress in the hippocampus of male fetuses, evidenced by a rapid rise in protein carbonylation and by decreases in alpha-tocopherol levels and in the ratio of reduced/oxidized forms of glutathione (GSH/GSSG). Neither protein carbonylation increase nor decreases in alpha-tocopherol levels and GSH/GSSG ratio were observed in female fetuses. NMDA synaptic currents and long-term potentiation in CA1, as well as spatial recognition in the water maze, were also impaired in male but not in female 28-day-old offspring. Pretreatment with the antioxidant N-acetylcysteine prevented the LPS-induced changes in the biochemical markers of oxidative stress in male fetuses, and the delayed detrimental effects in male 28-day-old offspring, completely restoring both long-term potentiation in the hippocampus and spatial recognition performance. Oxidative stress in the hippocampus of male fetuses may thus participate in the neurodevelopmental damage induced by a prenatal LPS challenge.


Subject(s)
Brain/embryology , Infections/embryology , Oxidative Stress , Animals , Brain Diseases/chemically induced , Brain Diseases/embryology , Brain Diseases/etiology , Chromatography, High Pressure Liquid , Female , Glutathione/metabolism , Glutathione Disulfide/metabolism , Hippocampus/embryology , Hippocampus/physiopathology , Lipopolysaccharides/toxicity , Patch-Clamp Techniques , Pregnancy , Rats , Rats, Sprague-Dawley , alpha-Tocopherol/metabolism
14.
Free Radic Biol Med ; 39(8): 1009-20, 2005 Oct 15.
Article in English | MEDLINE | ID: mdl-16198228

ABSTRACT

Neuroprotection exerted by alpha-tocopherol against oxidative stress was investigated in cultured rat hippocampal neurons. In addition to its direct action as a radical scavenger revealed at concentrations above 10 microM, a transient application of 1 microM alpha-tocopherol phosphate (alpha-TP) to neurons induced a complete delayed long-lasting protection against oxidative insult elicited by exposure to Fe2+ ions, but not against excitotoxicity. A minimal 16-h application of alpha-TP was required to observe the protection against subsequent oxidative stress. This delayed protection could last up to a week after the application of alpha-TP, even when medium was changed after the alpha-TP treatment. Cycloheximide, added either 2 h before or together with alpha-TP, prevented the delayed neuroprotection, but not the acute. However, cycloheximide applied after the 16-h alpha-TP pretreatment did not alter the delayed neuroprotection. Neither Trolox, a cell-permeant analogue of alpha-tocopherol, nor other antioxidants, such as epigallocatechin-gallate and N-acetyl-L-cysteine, elicited a similar long-lasting protection. Only tert-butylhydroquinone could mimic the alpha-TP effect. Depletion of glutathione (GSH) by L-buthionine sulfoximine did not affect the delayed alpha-TP protection. Thus, in addition to its acute anti-radical action, alpha-TP induces a long-lasting protection of neurons against oxidative damage, via a genomic action on antioxidant defenses apparently unrelated to GSH biosynthesis.


Subject(s)
Free Radical Scavengers/pharmacology , Hippocampus/drug effects , Neurons/drug effects , Oxidative Stress/drug effects , alpha-Tocopherol/pharmacology , Animals , Cells, Cultured , Cycloheximide/toxicity , Genome/drug effects , Glutathione/deficiency , Hippocampus/cytology , Iron/toxicity , Oxidative Stress/genetics , Protein Synthesis Inhibitors/toxicity , Rats
15.
J Neurosci Res ; 75(1): 125-32, 2004 Jan 01.
Article in English | MEDLINE | ID: mdl-14689455

ABSTRACT

Prenatal infection constitutes an important risk factor for brain injury, in both premature and full-term infants. Unfortunately, as the mechanisms involved are far from understood, no therapeutic strategy emerges to prevent the damage. We tested the hypothesis that administration of lipopolysaccharide (LPS) to gravid female rats enhanced glutamate-induced oxidative stress in brain of pups. A microdialysis probe was implanted into the striatum of 14-day-old animals and the release of hydroxyl radicals (.OH) in the perfusion medium was evaluated. Glutamate promoted a delayed.OH release in the offspring of dams given LPS, contrasting with the.OH decreases observed in control animals. A similar response occurred after infusion of (R,S)-3,5-dihydroxyphenylglycine (DHPG), a Group I metabotropic glutamate receptor (mGluR) agonist. This response was not consecutive to a remote activation of N-methyl-D-aspartate (NMDA) receptors, as it was unaffected by an NMDA receptor antagonist. Furthermore, the response to NMDA itself decreased in the offspring of dams given LPS. Massive amounts of DHPG, however, likely internalizing the mGlu receptor, still blunted the response to NMDA, as in controls. No quantitative variation occurred in mGluR1, mGluR5, or the NR1 subunit of the NMDA receptor between controls and neonates born from LPS-treated dams. Direct LPS injection into age-matched pups, by contrast, affected the response to neither glutamate nor DHPG. These results confirm that normally during perinatal development, the brain is protected from any oxidative stress resulting from excess glutamate, and the results support the hypothesis that maternal infection before delivery may lead to critical brain damage via the release of toxic free radicals.


Subject(s)
Brain/metabolism , Fetal Diseases/metabolism , Glutamic Acid/metabolism , Hydroxyl Radical/metabolism , Methoxyhydroxyphenylglycol/analogs & derivatives , Prenatal Exposure Delayed Effects , 2,3-Diketogulonic Acid/metabolism , Aging , Animals , Animals, Newborn , Brain/drug effects , Cell Membrane/drug effects , Cell Membrane/metabolism , Chromatography, High Pressure Liquid/methods , Cyclohexanes/pharmacology , Cyclohexenes , Female , Functional Laterality , Lipopolysaccharides/toxicity , Male , Methoxyhydroxyphenylglycol/pharmacology , Neuroprotective Agents/pharmacology , Oxidative Stress , Piperidines/pharmacology , Pregnancy , Rats , Rats, Wistar , Receptors, Metabotropic Glutamate/metabolism , Subcellular Fractions/drug effects , Subcellular Fractions/metabolism , Time Factors
16.
Brain Res Bull ; 61(4): 453-7, 2003 Aug 30.
Article in English | MEDLINE | ID: mdl-12909289

ABSTRACT

Disruption of glutamate homeostasis frequently leads to oxidative stress and to the release of hydroxyl radicals (radical OH). Here, we investigated, via a microdialysis approach, the possible involvement of metabotropic glutamate receptors in the glutamate-induced release of hydroxyl radicals in adult rat striatum. Glutamate was applied at low amount, resulting in a moderate release that was not inhibited by dizocilpine (MK-801), a specific NMDA receptor antagonist. (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG), a broad spectrum metabotropic antagonist, that does not exert any effect on the basal release of radical OH suppressed their response to glutamate. (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD), a non-selective metabotropic glutamate receptors agonist, promoted an radical OH release almost similar to that observed after glutamate, which was similarly impaired by co-infusion with MCPG. By contrast, infusion of (RS)-3,5-dihydroxyphenylglycine (DHPG), a more specific group I metabotropic glutamate receptors agonist, did not result in any appreciable radical OH response. Thus, beside NMDA receptors, some metabotropic glutamate receptors may also be involved in the glutamate-induced release of hydroxyl radicals.


Subject(s)
Corpus Striatum/metabolism , Cycloleucine/analogs & derivatives , Hydroxyl Radical/metabolism , Methoxyhydroxyphenylglycol/analogs & derivatives , Receptors, Metabotropic Glutamate/metabolism , Analysis of Variance , Animals , Corpus Striatum/drug effects , Cycloleucine/pharmacology , Dizocilpine Maleate/pharmacology , Drug Interactions , Excitatory Amino Acid Antagonists/pharmacology , Glutamic Acid/pharmacology , Glycine/analogs & derivatives , Glycine/pharmacology , Male , Methoxyhydroxyphenylglycol/pharmacology , Rats , Rats, Wistar , Receptors, Metabotropic Glutamate/agonists , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Time Factors
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