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)

The N-methyl-D-aspartic acid (NMDA) receptor is an intriguing target for the development of drugs with anti-Parkinsonian activity as well as with protective actions against degenerative processes induced by brain ischemia. Amantadine is used in the treatment of Parkinson's disease without a well established mechanism of action. We show here that amantadine inhibits, in a non-competitive way, the NMDA receptor-mediated stimulation of acetylcholine release from rat neostriatum in vitro in "therapeutic" (i.e., low micromolar) concentrations. This indicates that amantadine might exert its anti-Parkinsonian effect via blockade of NMDA receptors. Sustained stimulation of NMDA receptors induces so-called excitotoxicity. Recently, it was demonstrated that amantadine is able to inhibit NMDA induced cell death in a neuronal culture. On the basis of these findings it seems worth investigating if amantadine is also able to protect against neurodegenerative processes caused by brain ischemia in vivo.
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PMID:Amantadine as N-methyl-D-aspartic acid receptor antagonist: new possibilities for therapeutic applications? 132 May 14

N-methyl-D-aspartic acid (NMDA; 40 mg/kg, i.p.) did not elicit catalepsy, but it potentiated the cataleptic effect of haloperidol and GABAB receptor agonist, baclofen. MK-801 (0.2 mg/kg, i.p.), NMDA-receptor antagonist, reversed haloperidol- but not baclofen-induced catalepsy. MK-801 also potentiated the anticataleptic effect of scopolamine and bromocriptine against haloperidol-induced catalepsy. Dihydropyridine (DHP) calcium-channel antagonists such as nimodipine and nitrendipine (10 mg/kg, i.p.), reversed the anticataleptic effect of MK-801, and potentiated the cataleptic effect of haloperidol, as well as baclofen. These observations indicate the involvement of NMDA receptors in catalepsy, and suggest a potential clinical implication of NMDA-receptor antagonists in Parkinson's disease.
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PMID:Role of N-methyl-D-aspartate (NMDA) receptors in experimental catalepsy in rats. 215 85

The incorporation of labelled carbon from glucose U-14C into CSF amino acids was investigated in three patients with Parkinson's disease and in three control persons with comparable age and physical stature. Comparing the specific radioactivities of serum and CSF one can postulate that the labelled amino acids found in the CSF are synthesized mainly by brain tissue. The resorption of glucose into the CNS and therefore the synthesis of amino acids from glucose was more rapid in controls; labelled alanine and glutamine appeared later in the CSF of the patients. As expected, in the controls the specific radioactivity of glutamic acid was found to be higher than that of glutamine, in patients the labelling of glutamine was higher as was that of serine, glycine, aspartic acid and asparagine. From our knowledge concerning the compartmentation of the metabolism of glutamate, we assume that in Parkinsonism the metabolic activity of neurons is reduced but that of astroglia is enhanced.
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PMID:[Biosynthesis of amino acids from glucose in the central nervous system in the Parkinson syndrome]. 665 3

Budipine is a novel antiparkinsonian drug which is particularly beneficial in the treatment of parkinsonian tremor. The mechanism of action of budipine is not fully understood. To study whether budipine has dopaminergic activity in vivo, we used the 6-hydroxydopamine rotational model of Parkinson's disease. Budipine (0.78-12.5 mg/kg i.p.) did not induce ipsilateral or contralateral rotations, suggesting that it does not possess direct or indirect dopaminergic activity. This conclusion is further supported by the observation that budipine (10 mg/kg) i.v. did not facilitate striatal dopamine release measured in vivo by brain microdialysis. To investigatate possible antimuscarinic and N-methyl-D-aspartic acid (NMDA) antagonistic properties of budipine, we compared budipine with the antimuscarinic antiparkinsonian drug biperiden and the NMDA receptor antagonist 3-[(+/-)-2-carboxypiperazine-4-yl]-propyl-1-phosphonic acid (CPP). In receptor-binding assays, budipine inhibited thienylcyclohexylpiperidyl-3,4-[3H](n) ([I3H]TCP) (2.5 nM)-binding with an IC50 of 36 microM and [3H]3-quinuclidinol benzilate-binding with an IC50 of 1.1 microM. The respective values for biperiden were 170 and 0.053 microM. In line with these findings, budipine and CPP increased the threshold for NMDA-induced seizures in mice with an ED50 of 10.2 and 4.4 mg/kg, respectively, whereas biperiden was not effective. In 6-hydroxydopamine-lesioned rats, budipine (3.13-12.5 mg/kg) and CPP (0.1-0.39 mg/kg) increased the number of contralateral rotations induced by apomorphine, whereas biperiden was not effective. The present data suggest that budipine acts by blocking muscarinic and NMDA transmission while facilitation of dopaminergic transmission does not appear to contribute to its in vivo action. In comparison to biperiden, which has also antimuscarinic and NMDA receptor antagonistic properties, the anti-NMDA action of budipine is more prominent.
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PMID:Effects of the antiparkinsonian drug budipine on central neurotransmitter systems. 877 48

Altered expression of CYP2D6 (debrisoquine hydroxylase), resulting from genetic polymorphism at the CYP2D6 gene locus, is responsible for pronounced interindividual variation in the metabolism of many clinically important drugs. Although CYP2D6 substrates are structurally diverse, most are small molecules that interact with the protein via an electrostatic interaction between a basic nitrogen which is common to the majority of CYP2D6 substrates and an aspartic acid residue in the active site of the protein. As CYP2D6 substrates have a wide range of pharmacological functions, any variation in CYP2D6 expression can have profound clinical consequences. CYP2D6 activity can be determined both by phenotyping methods with a variety of probe drugs and by genotyping methods where PCR-based techniques are used to investigate the inheritance of individual CYP2D6 alleles. Allele frequencies have been shown to vary widely between populations of different racial origin. For example, the PM genotype is particularly rare in Orientals. The inheritance of certain CYP2D6 allelic variants has been associated with altered susceptibility to Parkinson's disease and several types of cancer.
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PMID:Cytochrome P450 CYP2D6. 1049 60

In Parkinson's disease the neurones of the subthalamic nucleus show increased synchrony and oscillatory burst discharge, thought to reflect a breakdown of parallel processing in basal ganglia circuitry. To understand better the mechanisms underlying this transition, we sought to mimic this change in firing pattern within sagittal slices of rat midbrain. The firing patterns of up to four simultaneously extracellularly recorded subthalamic nucleus (STN) neurones were analysed using burst and oscillation detection programs, and correlated activity between pairs of neurones assessed. In control conditions all but 11 of 488 (2%) neurones fired in a predominantly tonic pattern (with mean oscillation frequency >3 Hz), with no significantly cross-correlated activity in any of 393 pairs of neurones. The glutamate antagonists DL-2-amino-phosphonopentanoic acid (APV), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6-methyl-2-(phenylethynyl)pyridine (MPEP) did not change the firing rate or pattern of these cells, providing no evidence for a role of glutamatergic collaterals within the STN under these conditions. The GABA(A) receptor antagonist bicuculline and GABA(B) receptor antagonist (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl]phenylmethyl phosphinic acid (CGP 55845) were also without effect on firing rate or pattern in these cells, suggesting that there was no active input from other GABAergic basal ganglia nuclei in this slice. The dopamine receptor antagonist haloperidol caused no significant change to firing rate or pattern of firing in these cells, suggesting that there was no active dopaminergic input in this slice. Excitations of STN neurones by muscarine, (+)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (ACPD), N-methyl-D-aspartic acid (NMDA) or dopamine were all unaccompanied by a change in firing pattern or any significant correlated activity between STN neurone pairs. Burst firing could be induced in STN neurones with either the potassium channel blocker tetraethylammonium (TEA; 10 mM; in 100/138 [72%] of cells) or with a combination of NMDA and the calcium-activated potassium channel blocker apamin (in 101/216 [47%] of cells). Burst firing in TEA was unchanged by CNOX and APV, MPEP, CGP55845, haloperidol, dopamine, and ACPD, although muscarine produced a significant increase in oscillation frequency. Burst firing in NMDA and apamin was unchanged by CNQX and APV, dopamine, muscarine and ACPD, although bicuculline caused a significant increase in oscillation frequency. Such burst firing was not accompanied by synchrony in any condition, either alone, or during application of excitatory agents or glutamate or GABA antagonists. As the bursting seen here was unaccompanied by the synchronous activity that has often been observed (pathologically) in vivo, it probably reflects solely intrinsic STN neuronal properties, rather than network activity. No functional role was found for glutamatergic collaterals within the STN, either when cells are firing tonically or burst firing. The circuitry needed to produce synchrony in the STN is most likely not intrinsic to the STN itself, but requires connections with other basal ganglia nuclei, and/or the cortex, which are not present in this preparation.
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PMID:Overwhelmingly asynchronous firing of rat subthalamic nucleus neurones in brain slices provides little evidence for intrinsic interconnectivity. 1466 53

In order to investigate the functional interaction between the native dopamine receptors and their coupled guanine nucleotide-binding regulatory (G) proteins, dopamine-stimulated [(35)S]guanosine 5'-O-(gamma-thiotriphosphate) ([(35)S]GTPgammaS) binding was pharmacologically characterized in rat striatal membranes. Following optimizing the experimental conditions as to the concentrations of GDP, MgCl(2) and NaCl in the assay medium, the agonist and antagonist properties for a series of dopamine receptor ligands were determined mainly under the standard assay condition. The pharmacological profile of this response clearly indicated the involvement of dopamine D(2)-like receptors, but not of dopamine D(1)-like receptors. Among the types of dopamine D(2)-like receptors, dopamine D(2) receptors most likely appeared to be involved in dopamine-stimulated [(35)S]GTPgammaS binding in rat striatal membranes, because the affinities of agonists and antagonists determined in the present study were significantly correlated with those reported in the previous literature only for dopamine D(2) receptors, but not for dopamine D(3) or D(4) types. Though the concentration-dependent inhibition curves of dopamine-stimulated [(35)S]GTPgammaS binding by spiperone and S(-)-raclopride were apparently biphasic, the origin of the low-affinity minor components was not fully determined. The antiparkinsonian drugs with the properties of dopamine receptor agonism were shown to behave as stimulants with varied affinities and relative efficacies in the current assay system. On the other hand, neither phencyclidine (PCP) nor ketamine stimulated the specific [(35)S]GTPgammaS binding, in contrast with the previous report demonstrating that these two N-methyl-D-aspartic acid (NMDA) receptor antagonists behaved as agonists at human dopamine D(2) receptors expressed in Chinese hamster ovary (CHO) cells. These results provide important information about the functional activation of G proteins coupled with dopamine D(2) receptors as well as agonist actions of various compounds at native dopamine D(2) receptors, which are potentially involved in pathophysiology and pharmacotherapy of neuropsychiatric diseases such as Parkinson's disease, schizophrenia and depression.
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PMID:Dopamine D2 receptor-mediated G protein activation assessed by agonist-stimulated [35S]guanosine 5'-O-(gamma-thiotriphosphate) binding in rat striatal membranes. 1682 59

Excitatory amino acid carrier 1 (EAAC1) is a glutamate transporter expressed on mature neurons in the CNS, and is the primary route for uptake of the neuronal cysteine needed to produce glutathione (GSH). Parkinson's disease (PD) is a neurodegenerative disorder pathogenically related to oxidative stress and shows GSH depletion in the substantia nigra (SN). Herein, we report that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, an experimental model of PD, showed reduced motor activity, reduced GSH contents, EAAC1 translocation to the membrane and increased levels of nitrated EAAC1. These changes were reversed by pre-administration of n-acetylcysteine (NAC), a membrane-permeable cysteine precursor. Pretreatment with 7-nitroindazole, a specific neuronal nitric oxide synthase inhibitor, also prevented both GSH depletion and nitrotyrosine formation induced by MPTP. Pretreatment with hydrogen peroxide, L-aspartic acid beta-hydroxamate or 1-methyl-4-phenylpyridinium reduced the subsequent cysteine increase in midbrain slice cultures. Studies with chloromethylfluorescein diacetate, a GSH marker, demonstrated dopaminergic neurons in the SN to have increased GSH levels after NAC treatment. These findings suggest that oxidative stress induced by MPTP may reduce neuronal cysteine uptake, via EAAC1 dysfunction, leading to impaired GSH synthesis, and that NAC would exert a protective effect against MPTP neurotoxicity by maintaining GSH levels in dopaminergic neurons.
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PMID:Oxidative stress on EAAC1 is involved in MPTP-induced glutathione depletion and motor dysfunction. 1809 71

Alpha-synuclein (alpha-syn), a protein implicated in Parkinson's disease, is structurally diverse. In addition to its random-coil state, alpha-syn can adopt an alpha-helical structure upon lipid membrane binding or a beta-sheet structure upon aggregation. We used yeast biology and in vitro biochemistry to detect how sequence changes alter the structural propensity of alpha-syn. The N-terminus of the protein, which adopts an alpha-helical conformation upon lipid binding, is essential for membrane binding in yeast, and variants that are more prone to forming an alpha-helical structure in vitro are generally more toxic to yeast. beta-Sheet structure and inclusion formation, on the other hand, appear to be protective, possibly by sequestering the protein from the membrane. Surprisingly, sequential deletion of residues 2 through 11 caused a dramatic drop in alpha-helical propensity, vesicle binding in vitro, and membrane binding and toxicity in yeast, part of which could be mimicked by mutating aspartic acid at position 2 to alanine. Variants with distinct structural preferences, identified here by a reductionist approach, provide valuable tools for elucidating the nature of toxic forms of alpha-syn in neurons.
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PMID:The first N-terminal amino acids of alpha-synuclein are essential for alpha-helical structure formation in vitro and membrane binding in yeast. 1928 89

The clinical symptoms of Parkinson's disease (PD) appear late and only when the degenerative process at the level of the nigrostriatal dopamine (DA) pathway is quite advanced. An increase in brain-derived neurotrophic factor (BDNF) expression may be one of the molecular signals associated to compensatory and plastic responses occurring in basal ganglia during presymptomatic PD. In the present study, we used in vivo microdialysis, semiquantitative reverse transcriptase-polymerase chain reaction, and immunohistochemistry to study N-methyl-D-aspartic acid (NMDA) receptor regulation of BDNF expression in substantia nigra (SN) of adult rats after partial lesioning of the nigrostriatal DA pathway with unilateral striatal injections of 6-hydroxydopamine (6-OHDA). A time-dependent partial decrease of striatal DA tissue content as well as parallel and gradual increases in extracellular glutamate and aspartate levels in SN were found 1 to 7 days after unilateral 6-OHDA intrastriatal injection. Instead, the number of tyrosine hydroxylase-immunoreactive (IR) cells in the ipsilateral SN pars compacta remained statistically unchanged after neurotoxin injection. Intrastriatal administration of 6-OHDA also produced an early and transient augmentation of pan-BDNF, exon II-BDNF, and exon III-BDNF transcripts in the ipsilateral SN. The pan-BDNF and exon II-BDNF transcript increases were completely abolished by the prior systemic administration of MK-801, a selective antagonist of NMDA receptors. MK-801 also blocked the increase in BDNF-IR cells in SN observed 7 days after unilateral 6-OHDA intrastriatal injections. Our findings suggest that a coupling between glutamate release, NMDA receptor activation, and BDNF expression may exist in the adult SN and represent an important signal in this midbrain nucleus triggered in response to partial DA loss occurring in striatal nerve endings during presymptomatic PD.
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PMID:NMDA receptors mediate an early up-regulation of brain-derived neurotrophic factor expression in substantia nigra in a rat model of presymptomatic Parkinson's disease. 1932 33


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