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)

Glutamic acid and its analogs are excitotoxins that might contribute to the pathogenesis of Parkinson's disease (PD). We measured four subtypes of glutamate binding sites autoradiographically in 20-microns sections from control and PD midbrains. N-Methyl-D-aspartate (NMDA) binding sites (eight control, eight PD) were very low in control (20 +/- 7 [SEM] fmol/mg protein) and were reduced in the PD pars compacta (2.6 +/- 1.1 fmol/mg protein; p less than 0.02). NMDA binding was also reduced in the red nucleus but not in periaqueductal gray (PAG). We measured alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), metabotropic, and non-NMDA, nonkainate, non-quisqualate (NNKQ) sites in 10 PD and 12 control midbrains. AMPA binding sites were reduced from 175 +/- 20 to 99 +/- 16 (p less than 0.05) fmol/mg protein in PD pars compacta, NNKQ sites from 86 +/- 10 to 50 +/- 12 (p less than 0.05) fmol/mg protein in total nigra, and metabotropic sites (15 +/- 5 fmol/mg protein) were unchanged. AMPA, metabotropic, and NNKQ binding were unchanged in red nucleus and PAG. The very low number of NMDA binding sites suggests that factors other than excitotoxicity mediated via NMDA receptors on nigral cell bodies play roles in the pathogenesis of PD. There may be a generalized loss of NMDA receptors in PD brains. AMPA and NNKQ binding sites appear to be located on dopamine neurons, although the role of NNKQ sites in normal nervous system function and human disease is unknown.
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PMID:Glutamate receptors in the substantia nigra of Parkinson's disease brains. 134 48

The lateral tuberal nucleus is a circumscribed cell mass in the lateral posterior part of the hypothalamus, containing about 60000 neurons. It can be recognized in man and higher primates, probably not in other mammals. Its neurotransmitter content and connections with other parts of the brain are as yet unknown. But receptors for corticotropin-releasing factor and somatostatin, as well as muscarinic cholinergic receptors, benzodiazepine receptors and N-methyl-D-aspartate receptors have been localized within the confines of the nucleus. The lateral tuberal nucleus is affected in a number of human neurodegenerative diseases. Changes in Parkinson's disease are the least obvious: Lewy bodies appear in small amounts, the majority of them apparently lying outside a neuronal perikaryon. Neuronal loss does not occur. In Alzheimer's disease the number of neurons seems to be normal as well. Rarely silver staining tangles occur, and the deposition of A4/beta-protein in amorphous plaques is moderate. Yet, NTL neurons stain heavily in Alz-50 immunocytochemistry, while Alz-50 staining in NTL neurites is very dense. These changes are interpreted as indicating early Alzheimer-related pathology. In Huntington's disease the NTL loses neurons. This loss is related to the severity of the disease: patients who first display motor disturbances at an early age will lose more neurons than those who start later. The relation between these clinical characteristics and the severity of neuronal loss is such, that it seems likely that NTL neurons possess a special vulnerability for the effect of the Huntington gene. This could be related to their NMDA-receptor content. It is hypothesized that the NTL is involved in a neuronal network that regulates feeding and metabolism. NTL pathology may explain the peculiar catabolic state of many patients with Alzheimer's or Huntington's diseases.
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PMID:The hypothalamic lateral tuberal nucleus: normal anatomy and changes in neurological diseases. 136 79

After incubation of rat cortical cell cultures with the human immunodeficiency virus type 1 (HIV-1) coat protein gp120 for 12 h, cells showed fragmentation of DNA at internucleosomal linkers, the characteristic feature of apoptosis. In a quantitative approach, it was determined that the percentage of DNA fragmentation increased from 7%, in the absence of gp120, to 62% following incubation with 24 ng/ml of gp120. Simultaneously, the percentage of viable cells decreased from 94% to 33%. Memantine (1-amino-3,5-dimethyladamantane), a drug currently used in the therapy of spasticity and Parkinson's disease as well as the NMDA antagonist MK-801 both prevented the effects of gp120 at micromolar concentrations. In human cultured astrocytes, gp120 was ineffective with respect to DNA fragmentation and cell toxicity. From these data, we conclude that the gp120-induced apoptosis may contribute to the neurological complications frequently associated with the immunodeficiency syndrome. The cytoprotective effect of memantine in cortical cell cultures may qualify the drug for the treatment of AIDS-related dementia.
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PMID:gp120 of HIV-1 induces apoptosis in rat cortical cell cultures: prevention by memantine. 142 20

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

N-Methyl-D-aspartate (NMDA) receptor activation has been implicated in the pathogenesis and clinical expression of Parkinson's disease. Because some antiparkinsonian drugs have NMDA antagonist properties, we examined their effects on NMDA toxicity, measured by lactate dehydrogenase (LDH) release, in neuron-enriched cerebrocortical cultures. Amantadine reduced NMDA toxicity with half-maximal reduction at approximately 30 microM, while trihexphenidyl, L-3,4-dihydroxyphenylalanine (L-DOPA), bromocriptine and selegiline were ineffective, and benztropine was itself toxic. Amantadine and related drugs could not only reduce parkinsonian symptoms, but also modify underlying neurodegenerative processes.
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PMID:Antiparkinsonian drugs and in vitro excitotoxicity. 147 27

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

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

Dopamine (DA) is a neurotransmitter which modulates the transfer of information along fast-conducting pathways at the level of two main nodal points: the ventral striatum, composed by limbic areas (nucleus accumbens, tuberculum olfactorium) and the dorsal striatum, composed by extrapyramidal nuclei (caudate-putamen). These two subdivisions of the enlarged basal ganglia, are provided with different functions; accordingly, limbic DA plays an active role in goal-oriented (motivated) behaviour; instead, extrapyramidal DA is essential for execution of learned motor programs and its impairment results in the symptoms of Parkinson's disease. Various centrally acting drugs are able to interfere with DA transmission or with other neurotransmitter systems which interact with DA. Drugs of abuse owe their incentive properties to a preferential stimulation of DA transmission at the level of the limbic dopaminergic areas. On the other hand, drugs able to block glutamatergic transmission on NMDA receptors are able to selectively potentiate the action of DA at the level of a specific type of DA-receptors, the D-1 type. Knowledge of the role of DA in the brain can provide the basis not only for understanding the mechanism of drug action but also for developing new strategies for the treatment of drug abuse and extrapyramidal disorders.
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PMID:Functions of dopamine in the extrapyramidal and limbic systems. Clues for the mechanism of drug actions. 158 94

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

The purpose of the present investigation was to study the effects of simultaneous manipulations of central cholinergic, adrenergic and glutamatergic systems on locomotion in an animal model of Parkinson's disease. Mice were deprived of their monoamine stores by pretreatment with the monoamine depleter reserpine and the catecholamine synthesis inhibitor alpha-methyl-p-tyrosine, given 18 h and 60 min, respectively, before the acute experiment. Traditionally, only dopaminergic agonists have been shown to reverse the akinesia thus produced. However, in the present study it is demonstrated that if a muscarine receptor antagonist (atropine or biperiden) is combined with an alpha-adrenergic agonist/alpha-adrenergic agonist precursor (clonidine or L-alpha-methyl-dopa), a marked locomotor stimulation can be achieved, although either agent given alone is ineffective. Adding an NMDA antagonist (MK-801, ketamine or SDZ EAA 494) to the combination biperiden + clonidine resulted in further potentiation of the locomotor stimulatory effects.
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PMID:Synergistic interactions between muscarinic antagonists, adrenergic agonists and NMDA antagonists with respect to locomotor stimulatory effects in monoamine-depleted mice. 168 16


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