Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The subthalamic nucleus (SThN) provides a glutamate mediated excitatory drive to several other component nuclei of the basal ganglia, thereby significantly influencing locomotion and control of voluntary movement. We have characterised functionally the metabotropic glutamate (mGlu) receptors in the SThN using extracellular single unit recording from rat midbrain slices. SThN neurones fired action potentials spontaneously at a rate of 10 Hz which was increased by the group I/II mGlu receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (1S,3 R-ACPD; 1-30 microM) and the group I selective agonist (S, R)-dihydroxyphenylglycine (DHPG; 1-30 microM). However, both the group II selective agonist (1S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV; 1 microM) and the group III selective agonist (S)-2-amino-4-phosphonobutanoic acid (L-AP4; 10 microM) were without effect, indicating that the excitation was mediated by a group I mGlu receptor. The excitation caused by DHPG (3 microM) was reversed by co-application of the mGlu receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine (MCPG; 500 microM). Thus a group I mGlu receptor mediates excitation of SThN neurones, and suggests a use for group I mGlu receptor ligands for treatment of both hypo- and hyperkinetic disorders of basal ganglia origin, such as Parkinson's disease and Huntington's disease.
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PMID:Excitation of rat subthalamic nucleus neurones in vitro by activation of a group I metabotropic glutamate receptor. 935 99

Recent findings have shown that dendritically released dopamine (DA) plays an important modulatory role in the substantia nigra pars reticulata (SNr). It is therefore possible that the loss of DA observed in Parkinson's disease (PD) could hold important consequences for nigral function. Previously, we have shown that activation of presynaptically localized group II metabotropic glutamate receptors (mGluRs) inhibits excitatory transmission at the subthalamic nucleus (STN)-SNr synapse and that activation of presynaptically localized group III mGluRs decreases excitatory and inhibitory transmission in the SNr. To test the hypothesis that nigral DA can modulate mGluR function in the SNr, we performed whole-cell patch-clamp recordings from gamma-aminobutyric acidergic SNr neurons in slices obtained from rats that were acutely reserpinized. In slices obtained from reserpinized animals, the effect of group II mGluR activation by the selective agonist (+)-2-aminobicyclo[3.1.0]-hexane-2,6-dicarboxylate monohydrate (LY354740) (100 nM), but not group III mGluR activation [L-(+)-2-amino-4-phosphonobutyric acid, L-AP4, 500 microM], at STN-SNr synapses is significantly decreased. This effect could be mimicked in control slices by prior bath application of haloperidol (20 microM) and R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390) (20 microM) but not sulpiride (50 microM). Furthermore, application of dopamine (100 microM) and (+/-)-6-chloro-7,8-dyhydroxy-3allyl-1-phenyl-2,3,4,5-tetra-hydro-1H-benzazepine (SKF82958) (1 microM) but not quinpirole (10 microM) could rescue the group II mGluR effect in reserpinized slices. The effect of group III mGluR activation (L-AP4, 100 microM) on inhibitory synaptic transmission was also significantly reduced in slices from reserpine-treated animals. This effect was mimicked by haloperidol (20 microM), SCH23390 (20 microM), and sulpiride (50 microM) in control slices. Thus, in a Parkinsonian state, the loss of nigral DA may add to the overall pathophysiological changes in basal ganglia output.
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PMID:Dopamine modulates the function of group II and group III metabotropic glutamate receptors in the substantia nigra pars reticulata. 1213 Jul

Excessive activation of ionotropic glutamate receptors in the striatum contributes to the pathophysiology of motor symptoms in Parkinson's disease. Metabotropic glutamate (mGlu) receptors regulate striatal excitatory synaptic transmission, and adaptive changes in their function might occur following dopaminergic denervation and chronic levodopa-treatment (L-DOPA). Corticostriatal glutamatergic transmission was examined in striatal slices obtained from rats unilaterally denervated with the dopaminergic neurotoxin, 6-hydroxy dopamine (6-OHDA), and from denervated rats chronically treated with L-DOPA plus benserazide (25 + 6.25 mg/kg, intraperitoneally, twice daily for 21 days). Selective agonists of mGlu2 and -3 receptor subtypes [compounds LY379268 and (2S,2'R,3'R)-2-(2',3'-[(3)H]-dicarboxycyclopropyl)glycine ([(3)H]DCG-IV)] exhibited a much greater potency in depressing excitatory transmission and corticostriatal synapses in slices prepared from 6-OHDA-lesioned animals. Dopaminergic denervation affected neither the ability of L-(+)-2-amino-4-phosphonobutyric acid (L-AP4; a selective agonist of mGlu4, -6, -7 and -8 receptors) to inhibit corticostriatal transmission, nor the ability of (S)-3,5-dihydroxyphenylglycine (3,5-DHPG; a selective agonist of mGlu1 and -5 receptors) to potentiate responses mediated by N-methyl-D-aspartate (NMDA) receptor activation in striatal neurones. The increased responsiveness to mGlu2/3 receptor agonists was no longer detected in slices from 6-OHDA-lesioned animals chronically treated with L-DOPA. 6-OHDA-induced denervation also led to an increased expression of striatal mGlu2/3 receptor proteins and to a >2-fold increase in the maximal density (B(max)) of [(3)H]DCG-IV binding sites. These increases were again reversed by chronic treatment with L-DOPA. No changes in the expression of mGlu4 receptors or the alpha(i1) and alpha(i2) subunits of the G(i) proteins were induced by any of the treatments. We suggest that an enhanced sensitivity of pre-synaptic inhibitory mGlu2/3 receptors might represent an adaptive change triggered by dopaminergic denervation, which can be reversed by L-DOPA treatment.
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PMID:Striatal metabotropic glutamate receptor function following experimental parkinsonism and chronic levodopa treatment. 1242 91

The globus pallidus (GP) is a key GABAergic nucleus in the basal ganglia (BG). The predominant input to the GP is an inhibitory striatal projection that forms the first synapse in the indirect pathway. The GP GABAergic neurons project to the subthalamic nucleus, providing an inhibitory control of these glutamatergic cells. Given its place within the BG circuit, it is not surprising that alterations in GP firing pattern are postulated to play a role in both normal and pathological motor behavior. Because the inhibitory striatal input to the GP may play an important role in shaping these firing patterns, we set out to determine the role that the group III metabotropic glutamate receptors (GluRs) play in modulating transmission at the striatopallidal synapse. In rat midbrain slices, electrical stimulation of the striatum evoked GABA(A)-mediated IPSCs recorded in all three types of GP neurons. The group III mGluR-selective agonist L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) inhibited these IPSCs through a presynaptic mechanism of action. L-AP4 exhibited high potency and a pharmacological profile consistent with mediation by mGluR4. Furthermore, the effect of L-AP4 on striatopallidal transmission was absent in mGluR4 knock-out mice, providing convincing evidence that mGluR4 mediates this effect. The finding that mGluR4 may selectively modulate striatopallidal transmission raises the interesting possibility that activation of mGluR4 could decrease the excessive inhibition of the GP that has been postulated to occur in Parkinson's disease. Consistent with this, we find that intracerebroventricular injections of L-AP4 produce therapeutic benefit in both acute and chronic rodent models of Parkinson's disease.
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PMID:Group III metabotropic glutamate receptor-mediated modulation of the striatopallidal synapse. 1290 82

Increasing evidence implicates glutamate-mediated excitotoxicity as a contributory factor in dopaminergic cell death in the substantia nigra pars compacta (SNc) in Parkinson's disease (PD). Previous studies have suggested that metabotropic glutamate receptor (mGluR) ligands are neuroprotective against excitotoxicity in vitro. In the present study, the neurotoxin 6-hydroxydopamine (6-OHDA) produced a significant loss (61.2 +/- 8.9%; P < 0.01) of tyrosine hydroxylase-immunopositive (TH+) cells in both the SNc and striatal dopamine (58.02 +/- 1.27%; P < 0.05) in control male Sprague-Dawley rats. Both losses were significantly attenuated by sub-chronic (7 day) treatment with the Group I mGluR antagonists, 2-methyl-6(phenylethynyl)-pyridine (MPEP) or (S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385); the Group II mGluR agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC); or the Group III mGluR agonist, L(+)-2-amino-4-phosphonobutyric acid (L-AP4). These data demonstrate a neuroprotective action of mGluR ligands in vivo against 6-OHDA toxicity that has important implications for the treatment of PD.
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PMID:Neuroprotective effects of metabotropic glutamate receptor ligands in a 6-hydroxydopamine rodent model of Parkinson's disease. 1619 21

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.
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PMID:Selective activation of group III metabotropic glutamate receptors by L-(+)-2-amino-4-phosphonobutryic acid protects the nigrostriatal system against 6-hydroxydopamine toxicity in vivo. 1701 6

Drugs activating group III metabotropic glutamate receptors (mGluRs) represent therapeutic alternatives to L-DOPA (L-3,4-dihydroxyphenylalanine) for the treatment of Parkinson's disease (PD). Their presynaptic location at GABAergic and glutamatergic synapses within basal ganglia nuclei provide a critical target to reduce abnormal activities associated with PD. The effects of selective group III mGluR agonists (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I) and L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) infused into the globus pallidus (GP) or the substantia nigra pars reticulata (SNr) were thus studied in rat models of PD. Bilateral infusions of ACPT-I (1, 2.5, and 5 nmol/microl) into the GP fully reverse the severe akinetic deficits produced by 6-hydroxydopamine nigrostriatal dopamine lesions in a reaction-time task without affecting the performance of controls. Similar results were observed after L-AP4 (1 nmol) or picrotoxin, a GABA(A) receptor antagonist, infused into the GP. In addition, intrapallidal ACPT-I counteracts haloperidol-induced catalepsy. This effect is reversed by concomitant administration of a selective group III receptor antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine. In contrast, ACPT-I (0.05, 0.1, and 0.25 nmol) infusions into the SNr enhance the lesion-induced akinetic deficits in control and lesioned rats and do not reverse haloperidol-induced catalepsy. L-AP4 (0.05 nmol) and picrotoxin in the SNr produce the same effects. Together, these results show that activation of group III mGluRs in the GP provides benefits in parkinsonian rats, presumably by modulating GABAergic neurotransmission. The opposite effects produced by group III mGluR activation in the SNr, also observed with a selective mGluR8 agonist, support the use of subtype-selective group III mGluR agonists as a potential antiparkinsonian strategy.
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PMID:Targeting group III metabotropic glutamate receptors produces complex behavioral effects in rodent models of Parkinson's disease. 1758 57

Stereoisomers of 1-amino-2-phosphonomethylcyclopropanecarboxylic acid (APCPr), conformationally restricted analogues of L-AP4 (2-amino-4-phosphonobutyric acid), have been prepared and evaluated at recombinant group III metabotropic glutamate receptors. They activate these receptors over a broad range of potencies. The most potent isomer (1S,2R)-APCPr displays a similar pharmacological profile as that of L-AP4 (EC50 0.72, 1.95, >500, 0.34 microM at mGlu4, 6, 7, 8 receptors, respectively, and no effect at group I/II mGluRs). It was characterized on native receptors located in the basal ganglia (BG) where it induced a robust and reversible inhibition of synaptic transmission. It was tested in vivo in haloperidol-induced catalepsy, a model of Parkinsonian akinesia, by direct infusion in the globus pallidus of the BG. At a dose of 0.5 nmol/microL, catalepsy was significantly antagonized. This study reveals that (1S,2R)-APCPr is a potent group III mGluR agonist and confirms that these receptors may be considered as a therapeutic target in the Parkinson's disease.
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PMID:Synthesis and biological evaluation of 1-amino-2-phosphonomethylcyclopropanecarboxylic acids, new group III metabotropic glutamate receptor agonists. 1760 46

Metabotropic glutamate receptors (mGluRs) have been recently implicated as robust therapeutic targets for Parkinson's disease (PD). Here, we explored how activation of mGluRs in globus pallidus (GP) affected the amphetamine-induced rotational behavior in the unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of PD. The amphetamine-induced rotations were completely suppressed by the ipsilateral intrapallidal injection of the non-selective mGluR agonist, 1-aminocyclopentane-1S,3R-dicarboxylic acid (ACPD) and the selective group I mGluR agonist, (R,S)-3,5-dihydroxyphenylglycine (DHPG), but not the selective group III mGluR agonist, l-2-amino-4-phosphonobutyric acid (l-AP4). The suppressive effects were detected at 2, 4, 6, 8, and 12 h after ACPD injection, but returned to the control level at 24 h. A remarkable c-fos expression was found in the lesioned side of GP, subthalamic nucleus (STN), and substantia nigra pars reticulata (SNr) of rats that received the ACPD or DHPG injection, compared to rats treated with L-AP-4 or phosphate buffer-injection. The results indicate that the blockade of amphetamine-induced rotations might be at least partially mediated by group I mGluR activation. This study advances the use of selective group I mGluRs directed toward the GP for PD treatment.
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PMID:Intrapallidal metabotropic glutamate receptor activation in a rat model of Parkinson's disease: behavioral and histological analyses. 1831 47

An altered glutamatergic input at corticostriatal synapses has been shown in experimental models of Parkinson's disease (PD). In the present work, we analyzed the membrane and synaptic responses of striatal neurons to metabotropic glutamate (mGlu) receptor activation in two different mouse models of inherited PD, linked to mutations in PINK1 or Parkin genes. Both in PINK1 and Parkin knockout ((-/-)) mice, activation of group I mGlu receptors by 3,5-DHPG caused a membrane depolarization coupled to an increase in firing frequency in striatal cholinergic interneurons that was comparable to the response observed in the respective wild-type (WT) interneurons. The sensitivity to group II and III mGlu receptors was tested on cortically-evoked excitatory postsynaptic potentials (EPSPs) recorded from medium spiny neurons (MSNs). Both LY379268 and L-AP4, agonists for group II and III, respectively, had no effect on intrinsic membrane properties, but dose-dependently reduced the amplitude of corticostriatal EPSPs. However, both in PINK1(-/-) and Parkin(-/-) mice, LY379268, but not L-AP4, exhibited a greater potency as compared to WT in depressing EPSP amplitude. Accordingly, the dose-response curve for the response to LY379268 in both knockout mice was shifted leftward. Moreover, consistent with a presynaptic site of action, both LY379268 and L-AP4 increased the paired-pulse ratio either in PINK1(-/-) and Parkin(-/-) or in WT mice. Acute pretreatment with L-dopa did not rescue the enhanced sensitivity to LY379268. Together, these results suggest that the selective increase in sensitivity of striatal group II mGlu receptors represents an adaptive change in mice in which an altered dopamine metabolism has been documented.
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PMID:Enhanced sensitivity to group II mGlu receptor activation at corticostriatal synapses in mice lacking the familial parkinsonism-linked genes PINK1 or Parkin. 1907 Nov 14


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