oalib
Search Results: 1 - 10 of 100 matches for " "
All listed articles are free for downloading (OA Articles)
Page 1 /100
Display every page Item
Activation of mGlu3 Receptors Stimulates the Production of GDNF in Striatal Neurons  [PDF]
Giuseppe Battaglia, Gemma Molinaro, Barbara Riozzi, Marianna Storto, Carla L. Busceti, Paola Spinsanti, Domenico Bucci, Valentina Di Liberto, Giuseppina Mudò, Corrado Corti, Mauro Corsi, Ferdinando Nicoletti, Natale Belluardo, Valeria Bruno
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006591
Abstract: Metabotropic glutamate (mGlu) receptors have been considered potential targets for the therapy of experimental parkinsonism. One hypothetical advantage associated with the use of mGlu receptor ligands is the lack of the adverse effects typically induced by ionotropic glutamate receptor antagonists, such as sedation, ataxia, and severe learning impairment. Low doses of the mGlu2/3 metabotropic glutamate receptor agonist, LY379268 (0.25–3 mg/kg, i.p.) increased glial cell line-derived neurotrophic factor (GDNF) mRNA and protein levels in the mouse brain, as assessed by in situ hybridization, real-time PCR, immunoblotting, and immunohistochemistry. This increase was prominent in the striatum, but was also observed in the cerebral cortex. GDNF mRNA levels peaked at 3 h and declined afterwards, whereas GDNF protein levels progressively increased from 24 to 72 h following LY379268 injection. The action of LY379268 was abrogated by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.), and was lost in mGlu3 receptor knockout mice, but not in mGlu2 receptor knockout mice. In pure cultures of striatal neurons, the increase in GDNF induced by LY379268 required the activation of the mitogen-activated protein kinase and phosphatidylinositol-3-kinase pathways, as shown by the use of specific inhibitors of the two pathways. Both in vivo and in vitro studies led to the conclusion that neurons were the only source of GDNF in response to mGlu3 receptor activation. Remarkably, acute or repeated injections of LY379268 at doses that enhanced striatal GDNF levels (0.25 or 3 mg/kg, i.p.) were highly protective against nigro-striatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri?dinein mice, as assessed by stereological counting of tyrosine hydroxylase-positive neurons in the pars compacta of the substantia nigra. We speculate that selective mGlu3 receptor agonists or enhancers are potential candidates as neuroprotective agents in Parkinson's disease, and their use might circumvent the limitations associated with the administration of exogenous GDNF.
Targeting Chronic Pain with Epigenetic Drugs: Focus on mGlu2 Receptors  [cached]
Santina Chiechio,Magda Zammataro,Robert W. Gereau IV,Agata Copani
Molecular and Cellular Pharmacology , 2009,
Abstract: Histone deacetylase (HDAC) enzymes regulate gene expression by affecting chromatin structure and/or the activity of transcription factors. We have recently demonstrated that histone deacetylase inhibitors (HDACIs) behave as epigenetic agents capable of inducing analgesia by up-regulating metabotropic glutamate type 2 (mGlu2) receptors. Specifically, the regulation of mGlu2 receptor expression appears to involve the acetylation of the NF-κB transcription factor. mGlu2 and mGlu3 receptors belong to class II metabotropic glutamate receptors. These receptors are coupled to Gi/o proteins and play an important role in mediating antinociception in a variety of inflammatory and chronic pain models. We have shown that the HDACI-mediated mGlu2 receptor up-regulation occurs in the dorsal horn of the spinal cord and in the dorsal root ganglia, supporting a predominant role for mGlu2 receptors as mediators of analgesia in experimental animal models of chronic pain. We suggest that drugs that increase the expression of mGlu2 receptors, such as HDACIs or acetylating drugs (e.g. L-acetylcarnitine), may be effective in patients with chronic pain that are refractory to conventional analgesics.
The mGlu2/3 Receptor Agonists LY354740 and LY379268 Differentially Regulate Restraint-Stress-Induced Expression of c-Fos in Rat Cerebral Cortex  [PDF]
M. M. Menezes,M. A. Santini,M. J. Benvenga,G. J. Marek,K. M. Merchant,J. D. Mikkelsen,K. A. Svensson
Neuroscience Journal , 2013, DOI: 10.1155/2013/736439
Abstract: Metabotropic glutamate 2/3 (mGlu2/3) receptors have emerged as potential therapeutic targets due to the ability of mGlu2/3 receptor agonists to modulate excitatory transmission at specific synapses. LY354740 and LY379268 are selective and potent mGlu2/3 receptor agonists that show both anxiolytic- and antipsychotic-like effects in animal models. We compared the efficacy of LY354740 and LY379268 in attenuating restraint-stress-induced expression of the immediate early gene c-Fos in the rat prelimbic (PrL) and infralimbic (IL) cortex. LY354740 (10 and 30?mg/kg, i.p.) showed statistically significant and dose-related attenuation of stress-induced increase in c-Fos expression, in the rat cortex. By contrast, LY379268 had no effect on restraint-stress-induced c-Fos upregulation (0.3–10?mg/kg, i.p.). Because both compounds inhibit serotonin 2A receptor ( )-induced c-Fos expression, we hypothesize that LY354740 and LY379268 have different in vivo properties and that activation and restraint stress induce c-Fos through distinct mechanisms. 1. Introduction Preclinical and clinical studies indicate that modulation of glutamatergic activity in the brain may have therapeutic value for the treatment of schizophrenia and anxiety-related disorders [1, 2]. Glutamate acts through ligand-gated ion channels and G-protein-coupled metabotropic glutamate (mGlu) receptors. The mGlu receptors can be subdivided into three groups (Group I: mGlu1, 5; Group II: mGlu2, 3; Group III: mGlu4, 6, 7, 8) based on the sequence homology, signal transduction pathways, and pharmacology [3, 4]. Activation of presynaptic mGlu2 receptors with mGlu2/3 agonists negatively modulates the release of glutamate providing a feedback that prevents excessive glutamate release [5, 6]. Presynaptic mGlu2/3 receptors also regulate the release of other neurotransmitters [7], and postsynaptic mGlu2/3 receptors can regulate neuronal excitability via the modulation of ion channel functions [5]. The actions of multiple mGlu2/3 agonists and mGlu2 positive allosteric modulators (PAMs) have been explored in animal models predictive of antipsychotic and anxiolytic activity. Of these, the two orthosteric mGlu2/3 agonists, LY354740 and the structurally related compound LY379268, have been widely studied. LY354740 and LY379268 block PCP- and amphetamine-induced hyperlocomotion [8], two commonly used models of the positive symptoms of schizophrenia. Both compounds also show efficacy in alleviating cognitive deficits induced by PCP. For example, LY354740 improved the detrimental effects of PCP on the performance in a
Transcriptional regulation of metabotropic glutamate receptor 2/3 expression by the NF-κB pathway in primary dorsal root ganglia neurons: a possible mechanism for the analgesic effect of L-acetylcarnitine
Santina Chiechio, Agata Copani, Laura De Petris, Maria Elena P Morales, Ferdinando Nicoletti, Robert W Gereau
Molecular Pain , 2006, DOI: 10.1186/1744-8069-2-20
Abstract: Activation of group II metabotropic glutamate receptors (mGlu2 and mGlu3) induces antinociception in several pain models in rodents [1-5]. Consistent with these studies, we have shown that L-acetylcarnitine (LAC), a drug clinically effective in the treatment of neuropathic pain of various origins [6-9], up-regulates the expression of mGlu2 in the dorsal root ganglia (DRG) and in the dorsal horn (DH) of the spinal cord [10,11]. This has challenged the previous view that LAC increases pain thresholds and relieves neuropathic pain by enhancing brain acetylcholine synthesis [12] or by increasing the trophism of peripheral nerves [13,14]. Consistent with the "mGlu2 hypothesis of LAC-induced analgesia," the mGlu2/3 receptor antagonist, LY341495, prevents LAC-induced analgesia in rodents [10]. Interestingly, LAC selectively enhances the expression of mGlu2 receptors and has no effect on the expression of mGlu3 receptors [10,15], although these two receptor subtypes are highly homologous and share similar functions in the CNS [16]. This suggests that the expression of mGlu2 and mGlu3 is differentially regulated and that unraveling the nature of this difference may lead to the identification of new targets for the treatment of neuropathic pain.Analysis of the 5'-region upstream of the coding sequence of the human GRM2 gene (encoding mGlu2) [GenBank: AB045011], using the Transcription Factor Binding Sites Database TRANSFACT and TFSEARCH, revealed the presence of many potential regulatory elements for transcription factors of the NF-κB family, including p50 and p65/Rel-A, and for the coactivator p300. In contrast, only one binding site for the NF-κB family protein, c-Rel, and no binding sites for p65/RelA and p300 have been described in the putative promoter region of the human GRM3 gene encoding mGlu3 [17]. Hence, we focused on the NF-κB pathway in the search for mechanisms that account for the selective effect of LAC on mGlu2 expression.NF-κB consists of transcription factor
N-Acetyl-cysteine causes analgesia by reinforcing the endogenous activation of type-2 metabotropic glutamate receptors  [cached]
Bernabucci Matteo,Notartomaso Serena,Zappulla Cristina,Fazio Francesco
Molecular Pain , 2012, DOI: 10.1186/1744-8069-8-77
Abstract: Background Pharmacological activation of type-2 metabotropic glutamate receptors (mGlu2 receptors) causes analgesia in experimental models of inflammatory and neuropathic pain. Presynaptic mGlu2 receptors are activated by the glutamate released from astrocytes by means of the cystine/glutamate antiporter (System xc- or Sxc-). We examined the analgesic activity of the Sxc- activator, N-acetyl-cysteine (NAC), in mice developing inflammatory or neuropathic pain. Results A single injection of NAC (100 mg/kg, i.p.) reduced nocifensive behavior in the second phase of the formalin test. NAC-induced analgesia was abrogated by the Sxc- inhibitor, sulphasalazine (8 mg/kg, i.p.) or by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.). NAC still caused analgesia in mGlu3 / mice, but was inactive in mGlu2 / mice. In wild-type mice, NAC retained the analgesic activity in the formalin test when injected daily for 7 days, indicating the lack of tolerance. Both single and repeated injections of NAC also caused analgesia in the complete Freund’s adjuvant (CFA) model of chronic inflammatory pain, and, again, analgesia was abolished by LY341495. Data obtained in mice developing neuropathic pain in response to chronic constriction injury (CCI) of the sciatic nerve were divergent. In this model, a single injection of NAC caused analgesia that was reversed by LY341495, whereas repeated injections of NAC were ineffective. Thus, tolerance to NAC-induced analgesia developed in the CCI model, but not in models of inflammatory pain. The CFA and CCI models differed with respect to the expression levels of xCT (the catalytic subunit of Sxc-) and activator of G-protein signaling type-3 (AGS3) in the dorsal portion of the lumbar spinal cord. CFA-treated mice showed no change in either protein, whereas CCI mice showed an ipislateral reduction in xCT levels and a bilateral increase in AGS3 levels in the spinal cord. Conclusions These data demonstrate that pharmacological activation of Sxc- causes analgesia by reinforcing the endogenous activation of mGlu2 receptors. NAC has an excellent profile of safety and tolerability when clinically used as a mucolytic agent or in the management of acetaminophen overdose. Thus, our data encourage the use of NAC for the experimental treatment of inflammatory pain in humans.
Effects of LY354740, a Selective Agonist for Glutamate Metabotropic Receptors of Group II, on Aggressive Behaviour in Mice  [PDF]
Vanessa De Castro,Mercedes Martín-López,José Francisco Navarro
Universitas Psychologica , 2010,
Abstract: Recent studies have demonstrated that glutamate metabotropic receptorsmGlu1 and mGlu5 are involved in the regulation of aggressive behaviour.This study examines the effect of the administration of LY354740 (4-16 mg/kg i.p.), a selective group II metabotropic receptors agonist (mGlu2/3),using an isolation-induced aggression model. Individually housed mice were exposed to anosmic opponents 30 min after drug administration. Ten min of diadic interactions were staged between a singly housed and an anosmic mouse in a neutral area. The encounters were videotaped and the accumulatedtime allocated by subjects to ten broad behavioural categories wasestimated using an ethologically based analysis. LY354740 (12 and 16 mg/kg) significantly reduced offensive behaviours, without affecting immobility, as compared with the control group. These results suggestan implication of mGlu group II receptors in the modulationof aggression.
Main Factors to Restrain the Development of Library and Their Countermeasures  [cached]
Qian Jiang,Yonghong Zhang
International Education Studies , 2011, DOI: 10.5539/ies.v4n2p54
Abstract: From many aspects such as the resource construction, the talent group, and the mechanism and system, main factors to restrain the development of college library are analyzed, and corresponding countermeasures are proposed in this article.
Metabotropic glutamate receptors inhibit microglial glutamate release  [cached]
Stephen M McMullan,Bounleut Phanavanh,Gary Guo Li,Steven W Barger
ASN Neuro , 2012, DOI: 10.1042/an20120044
Abstract: Pro-inflammatory stimuli evoke an export of glutamate from microglia that is sufficient to contribute to excitotoxicity in neighbouring neurons. Since microglia also express various glutamate receptors themselves, we were interested in the potential feedback of glutamate on this system. Several agonists of mGluRs (metabotropic glutamate receptors) were applied to primary rat microglia, and the export of glutamate into their culture medium was evoked by LPS (lipopolysaccharide). Agonists of group-II and -III mGluR ACPD [(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid] and L-AP4 [L-(+)-2-amino-4-phosphonobutyric acid] were both capable of completely blocking the glutamate export without interfering with the production of NO (nitric oxide); the group-I agonist tADA (trans-azetidine-2,4-dicarboxylic acid) was ineffective. Consistent with the possibility of feedback, inhibition of mGluR by MSPG [(R,S)-α-2-methyl-4sulfonophenylglycine] potentiated glutamate export. As the group-II and -III mGluR are coupled to Gαi-containing G-proteins and the inhibition of adenylate cyclase, we explored the role of cAMP in this effect. Inhibition of cAMP-dependent protein kinase [also known as protein kinase A (PKA)] by H89 mimicked the effect of ACPD, and the mGluR agonist had its actions reversed by artificially sustaining cAMP through the PDE (phosphodiesterase) inhibitor IBMX (isobutylmethylxanthine) or the cAMP mimetic dbcAMP (dibutyryl cAMP). These data indicate that mGluR activation attenuates a potentially neurotoxic export of glutamate from activated microglia and implicate cAMP as a contributor to this aspect of microglial action.
Metabotropic Glutamate Receptors for Parkinson's Disease Therapy  [PDF]
Fabrizio Gasparini,Thérèse Di Paolo,Baltazar Gomez-Mancilla
Parkinson's Disease , 2013, DOI: 10.1155/2013/196028
Abstract: Excessive glutamatergic signalling within the basal ganglia is implicated in the progression of Parkinson’s disease (PD) and inthe emergence of dyskinesia associated with long-term treatment with L-DOPA. There is considerable research focus on the discovery and development of compounds that modulate glutamatergic signalling via glutamate receptors, as treatments for PD and L-DOPA-induced dyskinesia (LID). Although initial preclinical studies with ionotropic glutamate receptor antagonists showed antiparkinsonian and antidyskinetic activity, their clinical use was limited due to psychiatric adverse effects, with the exception of amantadine, a weak N-methyl-d-aspartate (NMDA) antagonist, currently used to reduce dyskinesia in PD patients. Metabotropic receptor (mGlu receptor) modulators were considered to have a more favourable side-effect profile, and several agents have been studied in preclinical models of PD. The most promising results have been seen clinically with selective antagonists of mGlu5 receptor and preclinically with selective positive allosteric modulators of mGlu4 receptor. The growing understanding of glutamate receptor crosstalk also raises the possibility of more precise modulation of glutamatergic transmission, which may lead to the development of more effective agents for PD. 1. Introduction Parkinson’s disease (PD) is a chronic progressive neurodegenerative disorder of the central nervous system (CNS), characterised by a gradual loss of dopaminergic neurotransmission. Cardinal symptoms of PD include tremor, bradykinesia, and rigidity. Levodopa (L-DOPA) is considered the standard of care for providing symptomatic relief in PD [1]. However, long-term L-DOPA treatment leads to the appearance of motor complications in the majority of responding patients and severely affects their quality of life [2]. After 9 years of L-DOPA treatment, ~90% of PD patients experience dyskinesia [3]. The dyskinesia that develops is often a combination of choreic and dystonic abnormal involuntary movements, collectively termed L-DOPA-induced dyskinesia (PD-LID). Once PD-LID is established, increasing the L-DOPA dose typically worsens dyskinesia and this may prevent the use of L-DOPA at optimal doses required to control motor fluctuations. There are currently no licensed therapies for the treatment of PD-LID, although a number of clinical strategies are employed including adding dopamine agonists, monoamine oxidase inhibitors, adenosine (2A) receptor antagonists, catechol-O-methyl transferase inhibitors, and anticholinergic drugs as part of a L-DOPA-sparing
Glutamate-induced swelling of cultured astrocytes is mediated by metabotropic glutamate receptor
YUAN Fang,WANG Tianyou,
袁芳
,王天佑

中国科学C辑(英文版) , 1996,
Abstract: The effects of glutamate and its agonists and antagonists on the swelling of cultured astrocytes were studied. Swelling of astrocytes was measured by 3H]-O-methyl-D-glucose uptake. Glutamate at 0.5, 1 and 10mmol/L and irons-l-aminocyclopentane-1,3-dicarboxylic acid (trans-ACPD), a metabotropic glutamate receptor (mGluR) agonist, at 1 mmol/L caused a significant increase in astrocytic volume, whereas alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) was not effective. L-2-amino-3-phosphonopropionic acid (L-AP3), an antagonist of mGluR, blocked the astrocytic swelling induced by trans-ACPD or glutamate. In Ca2+-free condition, glutamate was no longer effective. Swelling of astrocytes induced by glutamate was not blocked by CdCl2 at 20 μmol/L, but significantly reduced by CdCl2 at 300 μmol/L and dantrolene at 30 μmol/L. These findings indicate that mGluR activation results in astrocytic swelling and both extracellular calcium and internal calcium stores play important roles in the genesis of astrocytic swelling induced by glutamate.
Page 1 /100
Display every page Item


Home
Copyright © 2008-2017 Open Access Library. All rights reserved.