Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
Add more filters










Database
Language
Publication year range
1.
Parkinsons Dis ; 20102010 May 23.
Article in English | MEDLINE | ID: mdl-20948891

ABSTRACT

Clinical trials have demonstrated positive proof of efficacy of dual metabotropic glutamate receptor 2/3 (mGluR2/3) agonists in both anxiety and schizophrenia. Importantly, evidence suggests that these drugs may also be neuroprotective against glutamate excitotoxicity, implicated in the pathogenesis of Parkinson's disease (PD). However, whether this neuroprotection also translates into functional recovery is unclear. In the current study, we examined the neuroprotective efficacy of the dual mGluR2/3 agonist, 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), and whether this is accompanied by behavioral recovery in a rodent 6-hydroxydopamine (6-OHDA) model of PD. We now report that delayed post lesion treatment with 2R,4R-APDC (10 nmol), results in robust neuroprotection of the nigrostriatal system, which translated into functional recovery as measured by improved forelimb use asymmetry and reduced (+)-amphetamine-induced rotation compared to vehicle treated animals. Interestingly, these beneficial effects were associated with a decrease in microglial markers in the SNc, which may suggest an antiinflammatory action of this drug.

2.
Neuroreport ; 19(4): 475-8, 2008 Mar 05.
Article in English | MEDLINE | ID: mdl-18287950

ABSTRACT

Pharmacological activation of group III metabotropic glutamate receptors (mGluR) or inhibition of group I mGluR by subtype-selective ligands is neuroprotective in experimental models of Parkinson's disease. The aim of this study was to investigate whether targeting both receptor subtypes simultaneously produces enhanced neuroprotection. Rodents bearing a 6-hydroxydopamine lesion were intranigrally administered either the group III mGluR agonist L-(+)-2-amino-4-phosphonobutyric acid or the group I mGluR antagonist 2-methyl-6-(phenylethynyl)pyridine, alone or in combination. Coadministration of L-(+)-2-amino-4-phosphonobutyric acid and 2-methyl-6-(phenylethynyl)pyridine resulted in robust nigrostriatal neuroprotection that was significantly increased compared with either compound alone. These data suggest that targeting multiple mGluR subtypes with low doses of selective ligands may provide an enhanced therapeutic response in experimental models of Parkinson's disease.


Subject(s)
Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Neuroprotective Agents/pharmacology , Parkinson Disease/drug therapy , Receptors, Metabotropic Glutamate/agonists , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Aminobutyrates/pharmacology , Animals , Brain/drug effects , Brain/metabolism , Brain/physiopathology , Cytoprotection/drug effects , Cytoprotection/physiology , Disease Models, Animal , Drug Therapy, Combination , Excitatory Amino Acid Agonists/therapeutic use , Excitatory Amino Acid Antagonists/therapeutic use , Ligands , Male , Neuroprotective Agents/therapeutic use , Oxidopamine , Parkinson Disease/metabolism , Parkinson Disease/physiopathology , Parkinsonian Disorders/drug therapy , Parkinsonian Disorders/metabolism , Parkinsonian Disorders/physiopathology , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Metabotropic Glutamate/drug effects , Receptors, Metabotropic Glutamate/metabolism , Treatment Outcome
3.
J Neurochem ; 103(3): 1075-91, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17714448

ABSTRACT

Evidence suggests that increased glutamatergic input to the substantia nigra pars compacta as a result of hyperactivity of subthalalmic nucleus output pathways may contribute to the progressive degeneration of nigral dopaminergic neurones in Parkinson's disease (PD), a debilitating neurodegenerative disorder which affects approximately 1% of people aged over 65. Substantial electrophysiological evidence suggests that the excitation of nigral dopaminergic neurones is regulated by the activation of Group I metabotropic glutamate receptors (mGluR), comprising mGluR1 and mGluR5 subtypes. As activation of these receptors by endogenous glutamate may promote multiple cascades leading to excitotoxic neuronal death, it may be hypothesised that functional antagonism of Group I mGluR should be neuroprotective and could form the basis of a novel neuroprotective treatment for PD. To investigate this hypothesis, the neuroprotective potential of the selective competitive mGlu1 antagonist (+)-2-methyl-4-carboxyphenylglycine ((S)-(+)-alpha-amino-4-carboxy-2-methlybenzeneacetic acid; LY367385) and the selective allosteric mGlu5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) was tested in a rodent 6-hydroxydopamine (6-OHDA) model of PD in vivo. Both acute and subchronic intranigral administration of either LY367385 or MPEP resulted in significant neuroprotection of nigral tyrosine hydroxylase immunoreactive cell bodies, which correlated closely with prevention of striatal monoamine depletion following 6-OHDA lesioning. This neuroprotective action of LY367385 and MPEP displayed a clear concentration-dependent effect, suggesting a receptor-mediated mechanism of action. LY367385 produced robust neuroprotection at all concentrations tested (40, 200 and 1000 nmol in 4 microL), whilst MPEP displayed a bell-shaped neuroprotective profile with significant neuroprotection at low concentrations (2 and 10 nmol in 4 microL) but not at higher concentrations (50 nmol). Importantly, subchronic intranigral administration of MPEP and LY367385 appeared to slow the degeneration of remaining nigral dopaminergic neurones and prevented further striatal dopamine depletion in animals with established 6-OHDA induced nigrostriatal lesions, suggesting that these compounds may significantly influence disease progression in this model.


Subject(s)
Excitatory Amino Acid Antagonists/pharmacology , Neuroprotective Agents/pharmacology , Parkinsonian Disorders/drug therapy , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Substantia Nigra/drug effects , Animals , Benzoates/pharmacology , Benzoates/therapeutic use , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Corpus Striatum/physiopathology , Dopamine/metabolism , Dose-Response Relationship, Drug , Excitatory Amino Acid Antagonists/therapeutic use , Glutamic Acid/metabolism , Glycine/analogs & derivatives , Glycine/pharmacology , Glycine/therapeutic use , Male , Molecular Structure , Nerve Degeneration/chemically induced , Nerve Degeneration/drug therapy , Nerve Degeneration/prevention & control , Neural Pathways/drug effects , Neural Pathways/metabolism , Neural Pathways/physiopathology , Neuroprotective Agents/therapeutic use , Neurotoxins/antagonists & inhibitors , Neurotoxins/toxicity , Oxidopamine/antagonists & inhibitors , Oxidopamine/toxicity , Parkinsonian Disorders/metabolism , Parkinsonian Disorders/physiopathology , Pyridines/pharmacology , Pyridines/therapeutic use , Rats , Rats, Sprague-Dawley , Receptors, Metabotropic Glutamate/metabolism , Substantia Nigra/metabolism , Substantia Nigra/physiopathology , Treatment Outcome , Tyrosine 3-Monooxygenase/drug effects , Tyrosine 3-Monooxygenase/metabolism
4.
J Pharmacol Exp Ther ; 320(1): 397-409, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17012606

ABSTRACT

Evidence from several studies suggests that the progressive degeneration of dopaminergic (DA) neurones of the substantia nigra pars compacta (SNc) in Parkinson's disease (PD) may in part be due to excessive release of glutamate from subthalamic projections onto nigral DA neurones. Previous in vitro studies have demonstrated that selective activation of Group III metabotropic glutamate receptors (mGluR) negatively modulates excitatory transmission in the SNc and is neuroprotective against glutamate-mediated toxicity. Consistent with this, we have reported preliminary data indicating that the selective group III mGluR agonist l-(+)-2-amino-4-phosphonobutyric acid (l-AP4) can also protect the nigrostriatal system against 6-hydroxydopamine (6-OHDA) toxicity in vivo. We have now extended these preliminary studies in this model and report here that both acute and subchronic intranigral injections of l-AP4 provide significant protection of the nigrostriatal system against 6-OHDA toxicity. This neuroprotection displays a bell-shaped profile with a clear concentration-dependent relationship. In contrast, when administered to animals 7 days post-6-OHDA lesioning, l-AP4 significantly protects the functionality but not the integrity of the nigrostriatal system. We further demonstrate that neuroprotection by l-AP4 in vivo is reversed by coadministration of the selective Group III mGluR antagonist (RS)-alpha-methylserine-O-phosphate, confirming a receptor-mediated mechanism of action. These data provide further compelling evidence that selective activation of Group III mGluR is neuroprotective in an in vivo experimental model of PD, a finding that may have important implications for the future treatment of this disease.


Subject(s)
Aminobutyrates/pharmacology , Corpus Striatum/drug effects , Neuroprotective Agents/pharmacology , Oxidopamine/toxicity , Receptors, Metabotropic Glutamate/drug effects , Substantia Nigra/drug effects , 3,4-Dihydroxyphenylacetic Acid/analysis , Animals , Homovanillic Acid/analysis , Male , Phosphoserine/pharmacology , Rats , Rats, Sprague-Dawley , gamma-Aminobutyric Acid/metabolism
5.
Neuroreport ; 14(17): 2271-4, 2003 Dec 02.
Article in English | MEDLINE | ID: mdl-14625461

ABSTRACT

Using the novel rat retinal-vitreal model we have investigated the effect of metabotropic glutamate receptor activation on amyloid precursor protein (APP) metabolism. The release of low mol. wt fragments of APP, at 15-23 kDa in particular, was markedly up-regulated by the metabotropic glutamate receptor agonist (1S,3R)-1-amino-1,3-cyclopentane dicarboxylic acid ((1S,3R)-ACPD) in a concentration- and time-dependent manner, and this response was blocked by the receptor antagonist (S)-alpha-methyl-4-caboxyphenylglycine ((S)-MCPG). These results, together with the observation of a lack of deleterious effects of (1S,3R)-ACPD on the retinal neurons, support a physiological role of metabotropic glutamate receptors in mediating the release of soluble APP fragments, an action which may have important functional and therapeutic implications for Alzheimer's disease.


Subject(s)
Amyloid beta-Protein Precursor/metabolism , Receptors, Metabotropic Glutamate/biosynthesis , Receptors, Metabotropic Glutamate/physiology , Retina/metabolism , Up-Regulation/physiology , Amyloid beta-Protein Precursor/agonists , Amyloid beta-Protein Precursor/biosynthesis , Animals , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Female , Rats , Rats, Sprague-Dawley , Receptors, Metabotropic Glutamate/agonists , Retina/drug effects , Up-Regulation/drug effects
6.
J Neurochem ; 86(6): 1346-58, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12950444

ABSTRACT

In this study we have tested the effects of a wide range of metabotropic glutamate receptor ligands on (i) depolarisation-evoked efflux of pre-accumulated d-[3H]aspartic acid (d-[3H]asp) from rapidly superfused rat cerebrocortical minislices, and (ii) Na+-dependent uptake of d-[3H]asp into cerebrocortical tissue. Transient elevations in extracellular K+ produced concentration-dependent increases in d-[3H]asp efflux. A submaximally effective concentration (50 mm) was used in all subsequent experiments. The broad-spectrum mGlu receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD; EC50 17.8 microm], the group I mGlu-selective agonist (S)-3,5-dihydroxyphenylglycine [(S)-3,5-DHPG; EC50 0.5 microm] and the mGlu5 receptor subtype-selective agonist (RS)-2-chloro-5-hydroxyphenylglycine [(RS)-CHPG; EC50 7.3 microm] all concentration-dependently potentiated high K+-evoked d-[3H]asp efflux in the absence of effects on basal outflow of radiolabel. At concentrations selective for mGlu1 receptors, the antagonists (RS)-1-aminoindan-1,5-dicarboxylic acid [(RS)-AIDA; 10-300 microm]; (+)-2-methyl-4-carboxyphenylglycine [LY367385; 1-100 microm] and 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylate ethyl ester [CPCCOEt, 1-30 microm] all failed to inhibit responses to (S)-3,5-DHPG. However, the broad-spectrum mGlu receptor antagonist (S)-alpha-methyl-4-carboxyphenylglycine [(S)-MCPG; IC50 88.5 microm] together with the recently described mGlu5-selective antagonists, 2-methyl-6-(phenylethynyl)-pyridine (MPEP; IC50 0.6 microm), 6-methyl-2-(phenyl-azo)-3-pyridinol (SIB-1757; IC50 4.4 microm) and (E)-2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893; IC50 3.1 microm), at mGlu5-selective concentrations, all powerfully and concentration-dependently inhibited (S)-3,5-DHPG-evoked responses. Two selective excitatory amino acid (EAA) uptake inhibitors, l-trans-2,4-pyrrolidine dicarboxylate (l-trans-2,4-PDC; IC50 229 microm) and dl-threo-beta-benzyloxyaspartate (dl-TBOA; IC50 665 microm) both inhibited the Na+-dependent uptake of d-[3H]asp into cerebrocortical minislices. Importantly, none of the mGlu ligands utilized in the present study significantly inhibited d-[3H]asp uptake at concentrations shown to potentiate K+-evoked efflux. These data demonstrate for the first time that mGlu5 ligands modulate extracellular EAA concentrations by a direct effect on mGlu5-type autoreceptors on EAA nerve terminals as they evoke clear changes in EAA release in the absence of any effects on EAA uptake. Selective mGlu5 receptor antagonists that show high potency and good central bioavailability may provide novel classes of neuroprotective agents for the treatment of brain disorders associated with abnormal EAAergic neurotransmission.


Subject(s)
Cerebral Cortex/metabolism , Excitatory Amino Acids/metabolism , Glycine/analogs & derivatives , Receptors, Metabotropic Glutamate/metabolism , Sodium/metabolism , Animals , Binding, Competitive/drug effects , Biological Transport/drug effects , Cerebral Cortex/drug effects , D-Aspartic Acid/metabolism , D-Aspartic Acid/pharmacokinetics , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Amino Acids/pharmacokinetics , Glycine/pharmacology , In Vitro Techniques , Ligands , Male , Potassium/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Metabotropic Glutamate 5 , Receptors, Metabotropic Glutamate/agonists , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Receptors, Metabotropic Glutamate/drug effects , Resorcinols/pharmacology , Sodium/pharmacology , Tritium
SELECTION OF CITATIONS
SEARCH DETAIL
...