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)

Altered glial function in the substantia nigra in Parkinson's disease may lead to the release of toxic substances that cause dopaminergic cell death or increase neuronal vulnerability to neurotoxins. To investigate this concept, we examined the effects of subjecting astrocytes to lipopolysaccharide (LPS)-induced activation alone or combined with L-buthionine-[S,R]-sulfoximine-induced glutathione depletion or inhibition of complex I activity by 1-methyl-4-phenylpyridinium (MPP+) on the viability of primary ventral mesencephalic neurones or susceptibility to MPP+ and 6-hydroxydopamine (6-OHDA) in co-cultures. LPS-activated astrocytes caused neuronal death in a time-dependent manner, but glutathione-depleted or complex I-inhibited astrocytes had no effect on neuronal viability. The neurotoxicity of LPS-activated astrocytes was inhibited by the inducible nitric oxide synthase inhibitor aminoguanidine, by the nitric oxide scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, and by reduced glutathione (GSH). MPP+-induced neuronal death was greater in ventral mesencephalic cultures previously cultured with LPS-activated, glutathione-depleted, or complex I-inhibited astrocytes compared with co-cultures containing normal astrocytes. The increased neuronal susceptibility to MPP+ caused by LPS-activated or complex I-inhibited astrocytes and glutathione-depleted astrocytes was inhibited by the NMDA/glutamate antagonist MK-801 and by GSH, respectively. Neuronal death caused by 6-OHDA was increased in ventral mesencephalic cultures previously cultured with LPS-activated and glutathione-depleted, but not complex I-inhibited astrocytes, compared with co-cultures containing normal astrocytes. Treatment of co-cultures with GSH prevented the increased neuronal susceptibility to 6-OHDA. These findings suggest that glial dysfunction may cause neuronal death or render neurones susceptible to toxic insults via a mechanism involving the release of free radicals and glutamate. Such a mechanism may play a role in the development or progression of nigrostriatal degeneration in Parkinson's disease.
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PMID:Altered glial function causes neuronal death and increases neuronal susceptibility to 1-methyl-4-phenylpyridinium- and 6-hydroxydopamine-induced toxicity in astrocytic/ventral mesencephalic co-cultures. 1058 7

Defects in energy metabolism have been detected in patients with Parkinson's disease and have been proposed as a contributing factor in the disease. Previous in vitro studies showed that NMDA receptors contribute to the loss of dopamine neurons caused by the metabolic inhibitor malonate. In vivo, it is not known whether this interaction occurs through a postsynaptic action on the cell body in the substantia nigra or through a presynaptic action at the dopamine terminal in the striatum. So we could discern the anatomical level of NMDA receptor involvement, rats were infused with malonate, either into the left striatum or into the left substantia nigra. NMDA receptors were locally blocked by an intranigral or intrastriatal coinfusion of malonate plus MK-801 followed by a second infusion of MK-801 3 h later. Animals were examined at 1 week for striatal and nigral dopamine and GABA levels. Intranigral infusion of malonate (0.5 micromol) produced an approximate 50% loss of both nigral dopamine and GABA. MK-801 (0.1 micromol) provided significant protection against both nigral dopamine and GABA loss and against anterograde damage to dopamine terminals in the striatum. Intrastriatal administration of malonate (2 micromol) produced a 68 and 35% loss of striatal dopamine and GABA, respectively. In contrast to intranigral administration, intrastriatal blockade of NMDA receptors did not protect against striatal dopamine loss, although GABA loss was significantly attenuated. Core body temperature monitored several hours throughout the experiment was unchanged. Consistent with a lack of effect of NMDA antagonists on malonate-induced toxicity to dopamine neurons in striatum, intrastriatal infusion of NMDA had a pronounced effect on long-term GABA toxicity with little effect of dopamine loss. These findings are consistent with a postsynaptic action of NMDA receptors on mediating toxicity to dopamine neurons during impaired energy metabolism.
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PMID:NMDA receptors modulate dopamine loss due to energy impairment in the substantia nigra but not striatum. 1068 83

Previous work in our laboratories investigating compounds with structural similarity to ifenprodil (5) and 6 (CP101,606) resulted in compound 7 as a potent and selective antagonist of the NR1/2B subtype of the NMDA receptors. Replacement of the phenol group of 7 with a benzimidazalone group tethered by a three-carbon chain to 4-benzylpiperidine resulted in a slightly less active, but selective, compound. Lengthening the carbon tether resulted in a decrease in NR1/2B potency. Replacement of the phenol ring with a hydantoin resulted in weak antagonists. Compound 11a was one of the most potent NR1/2B antagonists from this study. Compound 11a also potentiated the effects of L-DOPA in a rat model of Parkinson's disease (the 6-hydroxydopamine-lesioned rat), dosed at 30 mg/kg orally.
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PMID:Subtype-selective N-methyl-D-aspartate receptor antagonists: benzimidazalone and hydantoin as phenol replacements. 1079 6

Dopamine-replacement strategies form the basis of most symptomatic treatments for Parkinson's disease. However, since long-term dopamine-replacement therapies are characterized by many side effects, most notably dyskinesia, the concept of a nondopaminergic therapy for Parkinson's disease has attracted great interest. To date, it has proved difficult to devise a nondopaminergic therapy with efficacy comparable to that of dopamine replacement. In animal models of Parkinson's disease, loss of striatal dopamine leads to enhanced excitation of striatal NR2B-containing NMDA receptors. This is responsible, in part at least, for generating parkinsonian symptoms. Here we demonstrate that, in the MPTP-lesioned marmoset, monotherapy with the NR2B-selective NMDA receptor antagonist, ifenprodil, administered de novo, has antiparkinsonian effects equivalent to those of l-DOPA (administered as its methyl ester form). In MPTP-lesioned marmosets, median mobility scores, following vehicle-treatment were 12.5/h (range 6-21), compared to 61/h (range 26-121) in normal, non-MPTP-lesioned animals. Following ifenprodil (10 mg/kg) treatment in MPTP-lesioned marmosets, the median mobility score was 66/h (range 34-93), and following l-DOPA (10 mg/kg i.p.) treatment 89/h (range 82-92). The data support the proposal that NR2B-selective NMDA receptor antagonists have potential as a nondopaminergic monotherapy for the treatment of parkinsonian symptoms when given de novo.
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PMID:Antiparkinsonian actions of ifenprodil in the MPTP-lesioned marmoset model of Parkinson's disease. 1096 92

Quantitative receptor autoradiography was used to examine the sequential patterns of changes in dopaminergic and glutamatergic receptors in the brain of rats lesioned with 6-hydroxydopamine. The animals were unilaterally lesioned in the medial forebrain bundle and the brains were analyzed at 1, 2, 4 and 8 weeks of postlesion. Degeneration of the nigrostriatal pathway caused a significant increase in dopamine D(2) receptors in the ipsilateral striatum from 1 to 8 weeks of postlesion. In the ipsilateral substantia nigra (SN), a significant decrease in dopamine D(2) receptors was also observed from 1 to 8 weeks of postlesion. On the other hand, dopamine D(1) receptors were increased in the ipsilateral ventromedial striatum from 2 to 4 weeks of postlesion. In the ipsilateral SN, a transient increase in dopamine D(1) receptors was observed only 1 week after lesioning. However, other regions in both ipsilateral and contralateral sides showed no significant change in dopamine D(1) and D(2) receptors during postlesion except for a transient change in a few regions. N-Methyl-D-aspartate (NMDA) receptors showed no significant changes in all brain regions studied during the postlesion. In contrast, a transient increase in excitatory amino acid transport sites was observed only in the frontal cortex and ventromedial striatum of the ipsilateral side at 2 weeks of postlesion. However, glycine receptors showed a significant change in any brain areas of both ipsilateral and contralateral sides after lesioning. The change in the brain areas of contralateral side was more pronounced than that of ipsilateral side for glycine receptors. In addition, dopamine uptake sites showed a severe damage in the ipsilateral striatum from 1 to 8 weeks after lesioning. In the contralateral side, in contrast, no significant change in dopamine uptake sites was found in the striatum during the postlesion. These results indicate that unilateral injection of 6-hydroxydopamine in the medial forebrain bundle can cause a significant increase in dopamine D(1) and D(2) receptors in the striatum. The increase in dopamine D(2) receptors was more pronounced than that in dopamine D(1) receptors in the striatum after 6-hydroxydopamine treatment. In contrast, dopamine uptake sites showed a severe damage in the striatum during the postlesion. Furthermore, our results support the existence of dopamine D(2) receptors on the neurons of SN, but not dopamine D(1) receptors. For glutamatergic receptor system, the present study suggests that the changes in glycine receptors may be more susceptible to degeneration of nigrostriatal pathway than NMDA receptors and excitatory amino acid transport sites. Thus, our findings are of interest in relation of degeneration of the nigrostriatal pathway that occurs in Parkinson's disease
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PMID:Temporal changes of dopaminergic and glutamatergic receptors in 6-hydroxydopamine-treated rat brain. 1097 8

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

The striatum is the major input region of the basal ganglia, playing a pivotal role in the selection, initiation, and coordination of movement both physiologically and in pathophysiological situations such as Parkinson's disease. In the present study, we characterize interactions between NMDA receptors, adenosine receptors, and cAMP signaling within the striatum. Both NMDA (100 micrometer) and the adenosine A(2a) receptor agonist CPCA (3 micrometer) increased cAMP levels (218.9 +/- 19.9% and 395.7 +/- 67.2%, respectively; cf. basal). The NMDA-induced increase in cAMP was completely blocked when slices were preincubated with either the NMDA receptor antagonist 7-chlorokynurenate or the adenosine A(2) receptor antagonist DMPX (100 micrometer), suggesting that striatal NMDA receptors increase cAMP indirectly via stimulation of adenosine A(2a) receptors. Thus, NMDA receptors and adenosine A(2a) receptors might share a common signaling pathway within the striatum. In striatal slices prepared from the 6-hydroxydopamine-lesioned rat model of Parkinson's disease, NMDA receptor-mediated increases in cAMP were greater on the lesioned side compared with the unlesioned side (349.6 +/- 40.2% compared with 200.9 +/- 21.9% of basal levels, respectively). This finding substantiates previous evidence implicating overactivity of striatal NMDA receptors in parkinsonism and suggests that a common NMDA receptor-adenosine A(2a) receptor-cAMP signaling cascade might be an important mechanism responsible for mediating parkinsonian symptoms.
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PMID:A common signaling pathway for striatal NMDA and adenosine A2a receptors: implications for the treatment of Parkinson's disease. 1102 42

Changes in ionotropic glutamate NMDA, AMPA and KA receptor binding in rat caudate-putamen were examined by quantitative in vitro receptor autoradiography 5 weeks after lesioning nigrostriatal dopaminergic projections. In this animal model of Parkinson's disease, density of binding in caudate-putamen increased at KA, but not NMDA or AMPA receptors. The findings indicate that nigrostriatal dopamine denervation can selectively enhance KA receptor levels in rat basal ganglia, suggest that KA receptors contribute to the pathophysiology of Parkinson's disease, and may suggest innovative treatments.
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PMID:Effects of nigrostriatal dopamine denervation on ionotropic glutamate receptors in rat caudate-putamen. 1103 95

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

Characteristic changes involving interactions between dopamine and glutamate in striatal medium spiny neurons now appear to contribute to symptom production in Parkinson's disease (PD). The balance between kinase and phosphatase signaling modifies the phosphorylation state of glutamate receptors and thus their synaptic strength. Sensitization of spiny-neuron NMDA and AMPA receptors alters cortical glutamatergic input to the striatum and modifies striatal GABAergic output, and thus motor function. Conceivably, the pharmacological targeting of spiny-neuron mechanisms modified in PD will provide a safer and more effective therapy.
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PMID:Striatal dopamine- and glutamate-mediated dysregulation in experimental parkinsonism. 1105 25


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