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)

6R-L-erythro-5, 6, 7, 8-Tetrahydrobiopterin (6R-BH4) is known as a cofactor for the hydroxylases of phenylalanine, tyrosine and tryptophan and also as a cofactor for nitric oxide synthase. Recently, a novel function of 6R-BH4 has been found: that is, 6R-BH4 acts on specific membrane receptors to directly stimulate the release of monamine neurotransmitters such as dopamine and serotonin, independently of its cofactor activity. In addition, it indirectly stimulates the release of non-monoamine neurotransmitters such as acetylcholine and glutamate, through activation of monoaminergic systems. In this paper, we briefly review recent experimental data, which provide new insights into the role of 6R-BH4 as a regulator of neuronal function. We also discuss the possibility of treatment by 6R-BH4 of neuropsychiatric diseases such as Parkinson's disease, Alzheimer's disease, depression and infantile autism.
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PMID:[A novel function of tetrahydrobiopterin]. 136 Nov 76

We measured fasting plasma amino acids in 20 patients with Parkinson's disease (PD) and 20 controls matched for age and sex. PD patients had significant elevations in plasma levels of aspartate, glutamate and glycine. The levels of other amino acids were not significantly different from those found in controls. No correlation was noted between PD severity and the degree of abnormality of plasma amino acids. We conclude that excitatory amino acids may be altered in patients with PD, and raise the possibility that neuroexcitotoxic mechanisms may be involved in the neurodegeneration of PD.
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PMID:Increased plasma concentrations of aspartate, glutamate and glycine in Parkinson's disease. 136 Dec 23

Memantine is a 1-amino-adamantane derivative which has been proposed to be useful in the treatment of Parkinson's disease. Its beneficial effect has been related to its novel properties as an NMDA receptor blocker which can neutralize the effect of glutamate at striatal and subthalamic levels. In the present study, conducted in an open-fashion, 14 parkinsonian patients with motor fluctuations taking L-dopa, were given a supplement of memantine 30 mg/day. After one month, 10 patients completed the treatment (4 discontinued it due to abdominal pain, psychomotor agitation, confusion and dizziness). In 5 patients, the main parkinsonian features improved significantly (1 point or more on the Webster scale). In 6 patients, "off" episodes improved (from daily mean of 273 minutes, to 172 minutes). In summary, memantine addition to parkinsonian features, could form a basis for novel therapeutic strategies directed to neutralize the effects of glutamate at striatal and subthalamic levels.
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PMID:Efficacy of memantine, an NMDA receptor antagonist, in the treatment of Parkinson's disease. 138 98

Excessive activation of NMDA receptors is thought to mediate the calcium-dependent neurotoxicity associated with hypoxic-ischemic brain injury, trauma, epilepsy, and several neurodegenerative diseases. For this reason, various NMDA antagonists have been investigated for their therapeutic potential in these diseases, but heretofore none have proven to be both effective and safe. In the present study, memantine, an adamantane derivative similar to the antiviral drug amantadine, is shown to block the channels activated by NMDA receptor stimulation. From whole-cell and single-channel recording experiments, the mechanism of action of memantine is deduced to be open-channel block, similar to MK-801; however, unlike MK-801, memantine is well tolerated clinically. Compared to MK-801, memantine's safety may be related to its faster kinetics of action with rapid blocking and unblocking rates at low micromolar concentrations. Furthermore, at these levels memantine is an uncompetitive antagonist and should theoretically allow near-normal physiological NMDA activity throughout the brain even in the face of pathologically high focal concentrations of glutamate. These pharmacological properties confer upon memantine a therapeutic advantage against NMDA receptor-mediated neurotoxicity with few side effects compared with other organic NMDA open-channel blockers. Moreover, memantine is increasingly effective against escalating levels of glutamate, such as those observed during a stroke. Low micromolar concentrations of memantine, levels known to be tolerated by patients receiving the drug for the treatment of Parkinson's disease, prevent NMDA receptor-mediated neurotoxicity in cultures of rat cortical and retinal ganglion cell neurons; memantine also appears to be both safe and effective in a rat stroke model. These results suggest that memantine has considerable therapeutic potential for the myriad of clinical entities associated with NMDA receptor-mediated neurotoxicity.
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PMID:Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity. 143 3

Owing to a lack of knowledge of the pathophysiology and pathochemistry of Parkinson's disease, conservative treatment was long restricted to the treatment of symptoms. In recent decades, as the role of dopamine became better known, progressive improvements in therapy were achieved, which initially meant the administration of the precursor, L-Dopa, of the primarily non-replaceable neurotransmitter, and later augmentation of the activity of dopamine in addition. Amantadine, a highly effective drug with a wide spectrum of action and a high level of tolerability, was successfully introduced in 1969. The recently discovered NMDA antagonism, also in conjunction with a description of the mechanism of action of amantadine, which makes it possible to inhibit the effect of excitatory amino acids--in particular glutamate--in the CNS, led to the principle of neuro-protection, which is now considered the key to the treatment of Parkinson's disease.
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PMID:[Parkinson therapy yesterday, today, tomorrow. Neuroprotection gains in importance]. 147 95

Dopamine-glutamate interactions contribute to normal striatal function and have been implicated in neurotoxicity at nigrostriatal dopamine (DA) terminals. The present study examined the striata of idiopathic Parkinson's disease (PD) patients and age-matched controls for regional differences in the DA transporter and binding to N-methyl-D-aspartate (NMDA) receptors. [3H]Mazindol labeling of the DA transporter was reduced by 70-80% in the caudate and putamen of PD patients, with reductions being more extensive dorsally than ventrally. In contrast, L-[3H]glutamate binding to NDMA-sensitive receptors was 20-40% higher in PD cases than in controls. These findings raise the possibility that modifications occur within corticostriatal glutamate synapses of PD patients, possibly as a consequence of reduced nigrostriatal DA activity.
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PMID:Elevated NMDA receptors in parkinsonian striatum. 148 68

Recent findings of impaired mitochondrial function, altered iron metabolism and increased lipid peroxidation in the substantia nigra in Parkinson's disease emphasize the significance of oxidative stress and free radical formation in the pathogenesis of the disease. Future research will focus on improvements in neuroprotective therapy to prevent or slow the rate of progression of Parkinson's disease. Possible neuroprotective strategies include free radical scavengers, monoamine oxidase-B inhibitors, iron chelators and glutamate antagonists.
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PMID:Neurotoxicity and neuroprotection in Parkinson's disease. 149 Dec 47

In Parkinson's disease the dopaminergic inhibition--mediated by DA2 receptors in the striatum--is reduced. Therefore glutamatergic excitation predominates in the antero-dorsal striatum. In turn the glutamatergic neurons of the subthalamic nucleus become disinhibited. Antagonists of the NMDA-subtype of glutamate receptors injected locally into the glutamatergically innervated nuclei or competitive and non-competitive NMDA-antagonists administered systemically, counteract parkinsonian symptoms in animals.
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PMID:Behavioural pharmacology of glutamate in the basal ganglia. 149 Dec 49

Features common to amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD) are reviewed. Shared epidemiological aspects include an increasing frequency which is proportional for each disease. We draw attention to geographic non-uniform distribution which, for ALS and PD, correlates positively with latitude. Clinical and pathological overlap occurs in the same patients, and in members of the same family. A high early morning plasma cysteine/sulphate ratio possibly related to the development of proteinacious inclusions, as well as ubiquinated neuronal inclusions, characterize ALS, PD and AD. HLA-DR (the human group II major histocompatibility class) staining is marked in ALS, PD and AD and may represent autoimmunity-incited by-products of neuronal degeneration. Based upon demonstrated glutaminergic connections between the neocortex and anterior horn cells, the entorhinal cortex and the basal ganglia we hypothesize that ALS, AD and PD are phylogenetic disturbances of the neocortical cell. The postsynaptic neuron may degenerate secondarily to anterograde effects of deranged glutamate metabolism. Future therapeutic strategies should be directed to agents that decrease transmission induced by excitatory amino-acids.
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PMID:Amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease: phylogenetic disorders of the human neocortex sharing many characteristics. 157 56

Although dopamine (DA)-containing neurons participate in a number of important cerebral functions, the physiology of their synaptic connections is poorly understood. By using whole-cell patch-clamp recording in thin slices of rat mesencephalon, we have investigated the biophysical properties of synaptic events and the nature of neurotransmitter(s) and receptors involved in the synaptic input to DA neurons in substantia nigra. The histological and electrophysiological characteristics of these cells were consistent with those described by recent in vivo and in vitro studies, thus allowing their unequivocal identification. Under appropriate experimental conditions, intranigral stimulation produced excitatory synaptic inputs in DA neurons. By voltage-clamp analysis, most of these excitatory postsynaptic currents (EPSCs) had a rise time of about 1.0 msec and a decay phase that could be fit by the sum of two exponential curves so that a fast and a slow component could be distinguished. The slow component was enhanced by glycine, by removing Mg2+ from the bath medium, or by membrane depolarization. Moreover, the slow component was consistently decreased by selective antagonists of NMDA receptors, whereas an antagonist for the non-NMDA receptors abolished the fast component slightly affecting the slow component and reduced peak EPSC amplitude. The results indicate that both NMDA-sensitive and non-NMDA-sensitive glutamate receptors contribute to EPSCs of DA neurons. Therefore, it is suggested that these receptors may play a critical role in the physiology (control of excitability, pacemaker firing, and dendritic DA release) as well as pathology (neuronal death in Parkinson's disease, psychosis, and mechanism of action of drugs of abuse, such as ethanol) related to DA neurons.
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PMID:Glutamate receptor subtypes mediate excitatory synaptic currents of dopamine neurons in midbrain slices. 167 3


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