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)

Dopamine D2 receptors (D2Rs) are of crucial importance in the striatal processing of motor information received from the cortex. Disruption of the D2R gene function in mice results in a severe locomotor impairment. This phenotype has analogies with Parkinson's disease symptoms. D2R-null mice were used to investigate the role of this receptor in the generation of striatal synaptic plasticity. Tetanic stimulation of corticostriatal fibers produced long-term depression (LTD) of EPSPs in slices from wild-type (WT) mice. Strikingly, recordings from D2R-null mice showed the converse: long-term potentiation (LTP). This LTP, unlike LTD, was blocked by an NMDA receptor antagonist. In magnesium-free medium, LTP was also revealed in WT mice and found to be enhanced by L-sulpiride, a D2R antagonist, whereas it was reversed into LTD by LY 17555, a D2R agonist. In D2R-null mice this modulation was lost. Thus, our study indicates that D2Rs play a key role in mechanisms underlying the direction of long-term changes in synaptic efficacy in the striatum. It also shows that an imbalance between D2R and NMDA receptor activity induces altered synaptic plasticity at corticostriatal synapses. This abnormal synaptic plasticity might cause the movement disorders observed in Parkinson's disease.
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PMID:Abnormal synaptic plasticity in the striatum of mice lacking dopamine D2 receptors. 916 14

Glutamate receptors play a major role in the transmitter balance within the basal ganglia (BG). N-methyl-D-aspartate (NMDA) receptor stimulation within the striatum acts behaviourally depressant while intrastriatal as well as systemic administration of NMDA receptor-antagonists have rather stimulatory effects despite the different profiles of non-competitive-, competitive NMDA receptor- and glycine site-antagonists. In animal models of Parkinson's disease all these NMDA receptor antagonists counteract parkinsonian symptoms or act synergistically with L-3,4-dihydroxyphenylalanine (L-DOPA). The strong locomotion-inducing effect of the non-competitive NMDA receptor antagonists is partly, but not fully, mediated by a dopamine (DA) release in the nucleus accumbens. Manipulations at alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors produce poor behavioural effects. These, however, are different or even opposed to NMDA receptor mediated effects. Local infusions of AMPA receptor-antagonists into the BG output nuclei have an anti-parkinsonian effect but systemic injections are ineffective. These drugs even counteract the anti-parkinsonian effect of DA agonists and of non-competitive NMDA receptor antagonists as well as the DA releasing effects of the latter drugs. Only few data on the role of metabotropic receptors exist but the different receptor subtypes with different regional distribution represent a promising target for pharmacological interventions.
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PMID:Behavioural pharmacology of glutamate receptors in the basal ganglia. 919 96

In Parkinson's disease, the tonic inhibition by basal ganglia output structures may be exacerbated by the action of the subthalamic nucleus. As expected, the reduction of excitatory impact from this structure has been shown to reduce akinesia in monkeys with experimental parkinsonism. The findings of receptor binding studies supporting an increased neuronal activity of efferents of the subthalamic nucleus in patients with Parkinson's disease, suggest that subthalamic nucleotomy or pallidotomy may be effective lesions in the neurosurgical treatment of Parkinson's disease. Systemic administration of glutamate antagonists has been shown to have anti-akinetic effects in animal models of Parkinson's disease. Other observations in monkeys indicate that excitatory amino acids such as glutamate are involved in the pathophysiological cascade of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced neuronal cell death. The neuroprotective effects of competitive and non-competitive NMDA (N-methyl-D-aspartate) receptor antagonists against MPTP toxicity support the hypothesis that NMDA receptor-mediated events are involved in the neurotoxicity of MPTP. Glutamate antagonists may therefore be able to retard the progression and to improve the symptomatology of Parkinson's disease. Several compounds with anti-parkinsonian effects such as amantadine, memantine, budipine and orphenadrine have been shown to be non-competitive NMDA receptor antagonists and are candidates for clinical trials on the neuroprotective efficacy of NMDA receptor antagonism. Furthermore, glutamate antagonists are useful in the treatment of the akinetic parkinsonian crisis, a severe form of clinical deterioration in patients with Parkinson's disease.
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PMID:Dopamine/glutamate interactions in Parkinson's disease. 919 97

Both Lesch-Nyhan syndrome and Parkinson's disease are associated with decreased brain dopamine, yet each disorder is characterized by a different set of motor symptoms. Lesch-Nyhan syndrome is manifested in early childhood, while parkinsonism usually does not appear until adulthood, suggesting that age at the time of dopamine loss is one determinant of the effects of neurotransmitter deficiency. Support for this view is found in studies of animals given dopamine-depleting lesions at different ages and then tested in adulthood. Animals lesioned as neonates show a supersensitivity to dopamine agonists, especially D1-dopamine receptor agonists, and to MK-801, an NMDA receptor antagonist. In addition, neonatally treated animals show a 'priming' effect following repeated exposure to D1-dopamine agonists. Animals depleted of dopamine as adults are more supersensitive to agonists acting on the D2-dopamine receptor, and do not evidence priming to dopamine agonists or an enhanced response to MK-801. These differential pharmacological profiles suggest that the changes in neurotransmitter systems following dopamine depletion are, at least in part, determined by age at the time of the lesion.
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PMID:Differential effects of bilateral dopamine depletion in neonatal and adult rats. 919

The complex dopamine-glutamate interactions within the basal ganglia are disrupted by chronic nigrostriatal denervation and standard replacement therapy with levodopa. Acute N-methyl-D-aspartate (NMDA) receptor blockade is able to overcome the changes in dopamine D1- and D2-dependent responses and the progressive shortening in the duration of response induced by long-term exposure to levodopa in 6-hydroxydopamine-lesioned rats. Preliminary results further suggest that NMDA receptor blockade can counteract levodopa-induced dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned non-human primates and parkinsonian patients without substantially altering the motor benefit derived from levodopa. These results appear to be in accordance with our 2-deoxyglucose studies in 6-hydroxydopamine-lesioned rats showing that NMDA receptor blockade can attenuate many of the changes in synaptic activity induced by levodopa, particularly in the striatopallidal complex. Taken together, our observations suggest that abnormal glutamate transmission or dysregulation of NMDA receptor-mediated mechanisms contribute to levodopa-induced motor response complications. Additional preclinical and clinical experiments need to be completed with well tolerated glutamate antagonists to determine the full potential of glutamate receptor blockade as a long-term strategy against levodopa-related motor response complications in Parkinson's disease.
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PMID:Modulation of levodopa-induced motor response complications by NMDA antagonists in Parkinson's disease. 919 2

Aminoadamantanes such as 1-aminoadamantane (amantadine) and 1-amino-3,5-dimethyladamantane (memantine) are N-methyl-D-aspartate (NMDA) receptor antagonists which show antiparkinsonian-like activity in animal models and in Parkinson's patients. The issue of whether NMDA antagonism plays a role in the symptomatological antiparkinsonian activity of amantadine and memantine is addressed by comparing: behaviourally effective doses, serum/brain levels, and their potency as NMDA receptor antagonists. In the case of memantine, blockade of NMDA receptors is probably the only mechanism responsible for antiparkinsonian activity, whereas for amantadine the situation is clearly far more complex. There are a number of differences between memantine and amantadine both in vitro and in vivo, and although NMDA receptor antagonism certainly participates in the antiparkinsonian activity of amantadine, other effects, some of which are elusive, also play a role. Moreover, it has been suggested that the pathomechanism of Parkinson's disease involves excitotoxic processes and that treatment with NMDA receptor antagonists might also slow the progression of neurodegeneration. If this claim is true, such an effect could be achieved with amantadine and memantine which show neuroprotective activity in animals at therapeutically relevant doses.
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PMID:Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents--preclinical studies. 919 3

Several lines of evidence demonstrate that glutamate antagonists can reverse experimental parkinsonism in animals. However, few clinical studies have been undertaken, principally because there is a shortage of glutamate antagonists which are considered safe for human use. This paper details the results of preliminary studies carried out on dextromethorphan, an anti-tussive agent and a weak open-channel blocker of the NMDA receptor; and the cerebral anti-ischaemic drug ifenprodil, a novel non-competitive inhibitor of the polyamine modulatory site on the NMDA receptor. Trials with these two compounds in small groups of parkinsonian volunteers have not demonstrated conclusive symptomatic improvement. These results do not exclude a possible role for NMDA receptor antagonists in the pharmacotherapy of Parkinson's disease, but rather point to the need for developing more potent and safe NMDA antagonists, with better pharmacodynamic and pharmacokinetic profiles.
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PMID:Glutamate antagonists and Parkinson's disease: a review of clinical data. 919 5

Mitochondrial electron transport chain (ETC) function is selectively reduced in multiple tissues, including brain, from patients with Parkinson's disease (PD) and Alzheimer's disease (AD). The ETC defects are specific to each illness, involve complex I in PD and complex IV in AD, are transferable with mitochondrial DNA (mtDNA) and lead to increased production of reactive oxygen species (ROS) in mtDNA-deficient clonal neuronal cells hybridized with mtDNA ('cybrids') from PD or AD patients. C57BL/6 mice treated with MPTP developed elevated tissue hydroxyl radical ('OH) levels in striatum and ventral midbrain but not cerebellum. In brain microdialysis in awake rats, striatal 'OH output increased 3-5-fold after infusion of methylpyridinium ion (MPP+), a complex I inhibitor, or sodium azide, a complex IV inhibitor. Elevated 'OH after MPP+ was blocked stereospecifically by infusion of the nitric oxide synthase (NOS) inhibitor nitro-L-arginine or by the NMDA channel blocker MK801. Neither NOS inhibition nor NMDA blockade altered azide-induced 'OH production. ETC inhibition in vivo increases production of toxic 'OH, but the underlying mechanisms vary as a function of which ETC complex is inhibited. These results support the concept of developing oxygen free radical scavengers for both AD and PD and further suggest that inhibition of NOS and blockade of NMDA receptor function may alter progression of idiopathic PD.
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PMID:Mitochondrial toxins in models of neurodegenerative diseases. I: In vivo brain hydroxyl radical production during systemic MPTP treatment or following microdialysis infusion of methylpyridinium or azide ions. 931 90

Progression of Parkinson's disease has been associated with several biochemical changes in the substantia nigra including increased oxidative challenge, catechol oxidation, and inhibition of mitochondrial complex I activity. Cysteinylcatechols, formed by nucleophilic addition of cysteine to oxidized catechols, have been identified as markers of catechol oxidation in brain tissue. We have examined the neurotoxicity of a series of cysteinylcatechols. Of the compounds examined, only 5-S-cysteinyl-3,4-dihydroxyphenylacetate (cysdopac) was specifically cytotoxic to differentiated P19 neuroglial cultures. Cysdopac also was neurotoxic to pyramidal neurons in organotypic cultures of hippocampus, and this effect was ablated by selective N-methyl-D-aspartate (NMDA) receptor antagonists. In vitro, cysdopac was a potent inhibitor of mitochondrial complex I activity. However, electrophysiologic experiments failed to demonstrate NMDA receptor agonist activity for cysdopac, nor did cysdopac inhibit glutamate uptake. These results showed that cysdopac was the most potent neurotoxin of this series of cysteinylcatechols and suggest that cysdopac may function as an indirect excitotoxin, potentially via inhibition of mitochondrial respiration.
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PMID:Neurotoxicity of endogenous cysteinylcatechols. 939 47

The interaction of 7-hydroxy-delta6-tetrahydrocannabinol 1,1-dimethylheptyl (Dexanabinol: HU-211), a novel NMDA receptor antagonist, with the dopaminergic system was examined using in vitro and in vivo systems. HU-211 (50 or 100 microM) inhibited the binding of [3H]R(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepi n-7-ol hydrochloride ([3H]SCH-23390), a dopamine D1 receptor antagonist, by 29.7 +/- 1.8% and 52.7 +/- 6.3%, respectively. HU-211 10 microM, like the dopamine D1 receptor agonist R(+)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF-38393), enhanced the conversion of [3H]adenine to cyclic AMP (cAMP) (51.8 +/- 29.7% and 35.6 +/- 21.5% over control, respectively). The HU-211-induced increase was not inhibited by SCH-23390. HU-211 together with the dopamine D1 receptor agonist caused a synergistic elevation (314.7 +/- 14.3%). HU-211 reduced the catalepsy induced by dopamine receptor antagonists. At 10 mg/kg, HU-211 significantly (P < 0.001) reduced the catalepsy time induced by D1, D2 and non-selective dopamine receptor antagonists. Overall, the results of the present study demonstrate that HU-211 interacts with the dopaminergic system and enhances activity at the dopamine D1 receptor level. This activity may have implications in diseases involving the dopaminergic system, such as Parkinson's disease.
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PMID:Interaction of dexanabinol (HU-211), a novel NMDA receptor antagonist, with the dopaminergic system. 942 14


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