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

Prior work has shown that intrastriatal injection of the metabotropic glutamate receptor agonist 1S,3R-ACPD results in pronounced contralateral rotation, and the basis for this effect is thought to be increased activity of dopaminergic nigrostriatal neurons. We tested this hypothesis by determining the expression of Fos-like immunoreactivity after intrastriatal injection of 1S,3R-ACPD. Intense Fos-like immunoreactivity was noted in the globus pallidus, entopeduncular nucleus, subthalamic nucleus and substantia nigra pars reticulata. Ablation of the subthalamic nucleus 10 days prior to intrastriatal injection of 1S,3R-ACPD abolished rotational behaviour but not Fos-like immunoreactivity in the globus pallidus, entopeduncular nucleus and substantia nigra. Intrasubthalamic injection of 1S,3R-ACPD produced marked contralateral rotation and a pattern of Fos-like immunoreactivity similar to that seen after intrastriatal 1S,3R-ACPD injection. These results suggest that stimulation of striatal metabotropic glutamate receptors inhibits striatal projection neuron activity, while stimulation of subthalamic metabotropic glutamate receptors increases subthalamic nucleus activity. Increased subthalamic nucleus activity is necessary and sufficient for the expression of rotational behavior. These results also suggest that metabotropic glutamate receptor antagonists may be useful in the treatment of Parkinson's disease.
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PMID:Intrastriatal and intrasubthalamic stimulation of metabotropic glutamate receptors: a behavioral and Fos immunohistochemical study. 763 75

The distribution of ionotropic glutamate receptor subunits GluR1, GluR2/3 and NMDAR1, and meta-botropic receptor mGluR1 alpha was studied in the monkey substantia nigra. High levels of immunoreactivity to GluR1, GluR2/3 and NMDAR1, and moderate levels of immunoreactivity to mGluR1 alpha were observed in the substantia nigra pars compacta. GluR1 and GluR2/3 were mostly in cell bodies and larger stem dendrites, whilst NMDAR1 and mGluR1 alpha were present on medium sized and small dendrites, respectively. The substantia nigra receives glutamatergic afferents from the subthalamic nucleus and the frontal cortex. Overactivity of the subthalamic nucleus, coupled with high levels of glutamate receptors on the neurons in the pars compacta, could predispose these neurons to excitotoxic injury, and could contribute to the development of Parkinson's disease.
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PMID:Localisation of glutamate receptors in the substantia nigra pars compacta of the monkey. 935 Apr 99

The localization of glutamate receptors in the substantia nigra is of critical importance since glutamate receptor-mediated excitotoxicity is implied in the cause for the neuronal degeneration in Parkinson's disease. The major glutamatergic synaptic inputs to the substantia nigra originate in the subthalamic nucleus, in which hyperactivity is reported in Parkinson's disease. In order to compare directly the localization of different ionotropic and metabotropic glutamate receptors in the substantia nigra of the same animals, rats were perfuse-fixed under deep anesthesia. Sections of the substantia nigra were obtained and receptor immunocytochemistry was performed using commercially available antibodies (against subunits of ionotropic glutamate receptors: GluR1, GluR2/3, GluR4, NMDAR1, NMDAR2A/B; and subtypes of metabotropic glutamate receptors: mGluR1alpha, mGluR2/3). When compared to the localization of tyrosine hydroxylase immunoreactivity, immunoreactivity for GluR1, GluR2/3 and NMDARI was mainly localized in the perikarya and proximal dendrites of the compacta neurons and only in a few reticulata neurons. In contrast, GluR4 immunoreactivity was only detected in the reticulata neurons. Consistent results were obtained by double labeling experiments that revealed tyrosine hydroxylase and GluR1, GluR2/3, GluR4 or NMDAR1 immunoreactivity in the same sections. Immunoreactivity for NMDAR2A/B, mGluR1alpha. and mGluR2/3 was detected in the neuropil of the substantia nigra pars reticulata. No NMDAR2A/B- and mGluR2/3-immunoreactive perikarya were detected. However, a few neurons in the reticulata were found to be mGluR1alpha-immunoreactive. The present results indicate there is a differential localization of different subunits and subtypes of glutamate receptors in the substantia nigra and there may be functional implications in different neuronal elements in the substantia nigra in normal and in Parkinson's disease.
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PMID:Localization of ionotropic and metabotropic glutamate receptors in distinct neuronal elements of the rat substantia nigra. 984 Feb 22

The effect of treatment with the D1 dopamine receptor agonist SKF 38393 on the expression of metabotropic glutamate receptor 1, 3, 4 and 5 receptor subtypes and of the glutamate N-methyl-D-aspartate ionotropic receptor subunits NRI, NR2A and NR2B was analysed using in situ hybridization. We studied the neocortex and neostriatum of normal rats and of rats unilaterally treated with 6-hydroxydopamine, a neurotoxin that, after intracerebral injection into the ventral tegmental area, causes selective degeneration of the ascending dopamine pathway. In the 6-hydroxydopamine-lesioned rats, metabotropic glutamate receptor subtype 3 messenger RNA levels were ipsilaterally increased in the neocortex and neostriatum, while the levels of metabotropic glutamate receptor subtype 4 messenger RNA were bilaterally increased in both regions. When administered to the 6-hydroxydopamine-lesioned rats, the D1 receptor agonist SKF 38393 (3 x 20 mg/kg, s.c.) produced a bilateral decrease in the expression of the metabotropic glutamate receptor subtype 1 and 5 receptor messenger RNA levels in the neocortex and neostriatum. In the neostriatum, SKF 38393 attenuated the ipsilateral increase in the expression of striatal metabotropic glutamate receptor subtype 3 messenger RNA produced by the 6-hydroxydopamine lesion. Furthermore, SKF 38393 produced a bilateral decrease in the levels of NRI receptor subunit messenger RNA and, in contrast, an increase in the striatal NR2B messenger RNA levels. All of these effects were abolished by the D1 receptor antagonist SCH 23360. These results indicate a differential D1 receptor-mediated modulation of the expression of some glutamate receptor subtypes in the neostriatum and neocortex, in agreement with the idea of a functional coupling between dopamine and excitatory amino acid systems in both regions. Thus, pharmacological targeting of excitatory amino acid systems could provide alternative or complementary treatment strategies for diseases involving dopaminergic systems in the striatum (e.g., Parkinson's disease) and cortex (e.g., schizophrenia).
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PMID:Dopamine D1 receptor modulation of glutamate receptor messenger RNA levels in the neocortex and neostriatum of unilaterally 6-hydroxydopamine-lesioned rats. 1019 13

Metabotropic glutamate receptors are a major class of excitatory amino acid receptors. Eight metabotropic glutamate receptor subtypes have been cloned, and are classified into three groups (I, II and III) based on amino acid sequence identity, effector systems and pharmacological profile. Previous results have shown that unilateral stimulation of metabotropic glutamate receptors in the subthalamic nucleus with the non-subtype-selective metabotropic glutamate receptor agonist 1S,3R-1-amino-1,3-cyclopentane dicarboxylate results in contralateral rotation in rats and Fos expression in the subthalamic nucleus. This suggests that metabotropic glutamate receptor stimulation results in altered subthalamic nucleus activity with consequent altered basal ganglia activity on the injected side. We sought to determine the metabotropic glutamate receptor subtype(s) involved and the functional neuroanatomy underlying the rotational behavior. Unilateral intrasubthalamic nucleus injection of group II or group III metabotropic glutamate receptor agonists induced contralateral rotation. In addition to producing rotation, group II and group III metabotropic glutamate receptor agonists induce toxicity in the subthalamic nucleus and overlying thalamus. Following group II or group III subthalamic nucleus metabotropic glutamate receptor stimulation, there is Fos-like immunoreactivity in the globus pallidus, subthalamic nucleus, substantia nigra pars reticulata and entopeduncular nucleus, suggesting altered activity in subthalamic nucleus target regions. However, examination of [14C]2-deoxyglucose uptake suggests that the alterations in basal ganglia activity are different following group II versus group III metabotropic glutamate receptor stimulation, suggesting that rotation is occurring via different mechanisms. It appears that stimulation of subthalamic nucleus group II metabotropic glutamate receptors induces rotation by increasing subthalamic nucleus activity. These results suggest that group II metabotropic glutamate receptor antagonists may be useful for alleviating subthalamic nucleus overactivity in Parkinson's disease.
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PMID:Intrasubthalamic nucleus metabotropic glutamate receptor activation: a behavioral, Fos immunohistochemical and [14C]2-deoxyglucose autoradiographic study. 1065 20

It has been shown that the primary striatal dopaminergic hypofunction which is at the origin of Parkinson's disease, results in a secondary hyperactivity of glutamatergic neurotransmission. In the search for a therapy of Parkinson's disease, ionotropic, mainly NMDA, receptor antagonists were found to have moderately beneficial, yet also some undesirable side-effects. Therefore the present study was aimed at determining whether some metabotropic glutamate receptor (mGluR) ligands may have antiparkinsonian effects in the haloperidol-induced muscle rigidity. To this end three mGluR ligands were used: the potent and selective mGluR I antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), the mixed group II agonist/ group I antagonist (S)-4-carboxy-3-hydroxyphenyl-glycine ((S)-4-C3HPG), and the potent group II agonist (+)-2-aminobicyclo[3.1.0.]hexane-2,6,-dicarboxylic acid (LY354740). Only LY354740 penetrated the brain from the periphery; for this reason other drugs were injected bilaterally into the rostral striatum or nucleus accumbens. The muscle tone was recorded by a mechanomyographic/electromyographic (MMG/EMG) method which measured the resistance of a rat's hind foot and the EMG reflex response of its muscles to passive movements. (S)-4C3HPG (5 and 15 microg/0.5 microl) and LY354740 (5 and 10mg/kg i.p.) diminished the muscle rigidity induced by haloperidol (1 mg/kg i.p.). AIDA (0.5-15 microg/0.5 microl) injected into the striatum was only slightly effective in the highest dose used. However, when injected into the nucleus accumbens AIDA (15microg/0.5microl) significantly and strongly counteracted the haloperidol-induced muscle rigidity. Our results suggest that stimulation of group II striatal mGluRs seems to play a major role in diminution of parkinsonian-like muscle rigidity. However, it seems that the antagonism of group I mGluRs located in the nucleus accumbens may also be of importance to the antiparkinsonian effect.
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PMID:The role of metabotropic glutamate receptor (mGluR) ligands in parkinsonian muscle rigidity. 1102 78

In the present study, we evaluated the effect of the prototypical metabotropic glutamate receptor 5 (mGlu(5)) antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) on motor behaviour in rats using the accelerating rotarod, spontaneous locomotor activity and the 6-hydroxy-dopamine (6-OHDA) lesion model to assess its treatment potential for Parkinson's disease. The data indicate that MPEP at doses between 7.5 and 300 mg/kg, p.o. did not disrupt endurance performance on the accelerating rotarod (4-40 rpm in 300 s) which indicates that MPEP has a relatively high safety margin. However, while ineffective at doses of 3.75, 7.5 and 15 mg/kg (p.o.) MPEP inhibited spontaneous locomotor activity at doses of 30 and 100 mg/kg (p.o.). In the 6-OHDA rat rotation model, at doses of 7.5, 15 and 30 mg/kg (p.o.), MPEP induced a dose-dependent ipsilateral rotational response that reached statistical significance at the highest dose tested. This effect was relatively small but consistent. In combination with direct or indirect dopamine agonists, i.e. apomorphine (0.25 mg/kg, s.c.) and D-amphetamine (2.5 mg/kg, i.p.), MPEP (7.5, 15 or 30 mg/kg, p.o.) was found to significantly inhibit these dopamine receptor mediated rotational responses. MPEP injected at a dose of 30 mg/kg also inhibited the rotational response induced by L-DOPA (25 mg/kg, i.p.). (+)MK-801 was used in these rotation experiments as the reference compound. In view of these findings, it could be concluded that MPEP and potentially other mGlu(5) receptor antagonists are probably not appropriate drug candidates for the symptomatic treatment of Parkinson's disease.
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PMID:Effects of the prototypical mGlu(5) receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine on rotarod, locomotor activity and rotational responses in unilateral 6-OHDA-lesioned rats. 1104 Mar 47

The subthalamic nucleus (STN) is a key nucleus in the basal ganglia motor circuit that provides the major glutamatergic excitatory input to the basal ganglia output nuclei. The STN plays an important role in normal motor function, as well as in pathological conditions such as Parkinson's disease (PD) and related disorders. Development of a complete understanding of the roles of the STN in motor control and the pathophysiological changes in STN that underlie PD will require a detailed understanding of the mechanisms involved in regulation of excitability of STN neurons. Here, we report that activation of group I metabotropic glutamate receptors (mGluRs) induces a direct excitation of STN neurons that is characterized by depolarization, increased firing frequency, and increased burst-firing activity. In addition, activation of group I mGluRs induces a selective potentiation of NMDA-evoked currents. Immunohistochemical studies at the light and electron microscopic levels indicate that both subtypes of group I mGluRs (mGluR1a and mGluR5) are localized postsynaptically in the dendrites of STN neurons. Interestingly, pharmacological studies suggest that each of the mGluR-mediated effects is attributable to activation of mGluR5, not mGluR1, despite the presence of both subtypes in STN neurons. These results suggest that mGluR5 may play an important role in the net excitatory drive to the STN from glutamatergic afferents. Furthermore, these studies raise the exciting possibility that selective ligands for mGluR5 may provide a novel approach for the treatment of a variety of movement disorders that involve changes in STN activity.
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PMID:Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus. 1105 Jan 6

By using an animal model of parkinsonism, we examined the expression of GABA(A) receptor (R) and metabotropic glutamate receptor (mGluR) 5 in the basal ganglia after transplantation with dopamine-rich tissue. The adult rats were unilaterally lesioned by the injection of 6-hydroxydopamine to their left medial forebrain bundles. At 5-10 weeks following the dopaminergic denervation, the levels of GABA(A)R in the left caudate-putamen and globus pallidus were about 20 and 16% lower than that of the right intact (control) sides, as shown by [3H]flunitrazepam binding autoradiography on the brain sections. However, the receptor density increased to around 132 and 130% of control levels in the entopeduncular nucleus and substantia nigra pars reticulata of the lesioned sides. Furthermore, in situ hybridization analysis exhibited parallel trends of changes in the levels of the GABA(A)R alpha1 and alpha2 subunit and mGluR5 mRNAs in the neurons of the brain regions with that of the proteins detected by the binding assay. A number of the rats 5 weeks postlesion were transplanted with the ventral mesencephalon of the embryonic rat into their left striata. Five weeks later, the changes in the [3H]flunitrazepam binding seemed to be recovered by approximately 50-63% on the grafted sides of the areas. Moreover, the transplantation appeared to produce a nearly complete reversal of the lesion-induced alterations in the levels of the mRNAs. Thus, the data indicate the mechanism of gene regulation for the modified expression of the receptors and could implicate the participation of the receptors in the pathogenesis of Parkinson's disease.
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PMID:Changes in the gene expression of GABA(A) receptor alpha1 and alpha2 subunits and metabotropic glutamate receptor 5 in the basal ganglia of the rats with unilateral 6-hydroxydopamine lesion and embryonic mesencephalic grafts. 1125 11

The basal ganglia (BG) are a set of interconnected subcortical structures that play a critical role in motor control. The BG are thought to control movements by a delicate balance of transmission through two BG circuits that connect the input and output nuclei: the direct and the indirect pathways. The BG are also involved in a number of movement disorders. Most notably, the primary pathophysiological change that gives rise to the motor symptoms of Parkinson's Disease (PD) is the loss of dopaminergic neurons of the substantia nigra pars compacta (SNc) that are involved in modulating function of the striatum and other BG structures. This ultimately results in an increase in activity of the indirect pathway relative to the direct pathway and the hallmark PD symptoms of rigidity, bradykinesia, and akinesia. A great deal of effort has been dedicated to finding treatments for this disease. The current pharmacotherapies are aimed at replacing the missing dopamine, while the current surgical treatments are aimed at reducing transmission through the indirect pathway. Dopamine replacement therapy has proven to be helpful, but is associated with severe side effects that limit treatment and a loss of efficacy with progression of the disease. Recently developed surgical therapies have been highly effective, but are highly invasive, expensive, and assessable to a small minority of patients. For these reasons, new effort has been dedicated to finding pharmacological treatment options that will be effective in reducing transmission through the indirect pathway. Members of the metabotropic glutamate receptor (mGluR) family have emerged as interesting and promising targets for such a treatment. This review will explore the most recent advances in the understanding of mGluR localization and function in the BG motor circuit and the implications of those findings for the potential therapeutic role of mGluR-targeted compounds for PD.
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PMID:Distribution and roles of metabotropic glutamate receptors in the basal ganglia motor circuit: implications for treatment of Parkinson's disease and related disorders. 1133 32


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