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)

Glutamate, one of the excitatory neurotransmitters, contributes to the neuronal death associated with neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, and with ischemia. In Alzheimer's disease brains, there is a decreased number of dopamine D2 receptors, which might cause neuronal dysfunction or death. In the present study, bromocriptine exerted a protective effect against glutamate-induced cytotoxicity in rat cortical neurons. This neuroprotective effect was mediated via D2 receptors, because it was attenuated by domperidone, a D2 dopaminergic receptor antagonist. Another dopamine D2 agonist, quinpirole, also protected cells against glutamate toxicity. D2 agonists protected cells from calcium influx, nitric oxide, and peroxynitrite toxicity, which are thought to be the mediators of glutamate toxicity. The phosphatidylinositol 3 kinase (PI3K) inhibitor (LY294002) inhibited this neuroprotective effect of bromocriptine, in contrast to the mitogen-activated protein kinase kinase (MAPKK) inhibitor (PD98059), which did not counter the protective effect. Furthermore, Akt protein kinase, which is an effector of PI3K, was activated by bromocriptine, and the antiapoptotic protein Bcl-2 was up-regulated by bromocriptine treatment. These results suggest that D2 dopaminergic receptor activation plays an important role in neuroprotection against glutamate cytotoxicity and that the up-regulation of Bcl-2 expression via the PI3K cascade is, at least partially, involved in this effect.
 ...
PMID:Protective effect of dopamine D2 agonists in cortical neurons via the phosphatidylinositol 3 kinase cascade. 1239 86

The output of GABAergic medium-sized spiny neurons in the dorsal striatum is controlled in part by glutamatergic input from the neocortex and the thalamus, and dopaminergic input from ventral midbrain. We acutely isolated these neurons from juvenile (P14-24) rats to study the consequences of the interaction between glutamate and dopamine for neuronal excitability. Single-cell RT-PCR analysis was used to identify the expression patterns of dopamine receptors. D1 and D2 dopamine receptor mRNA was detected in 11/22 and 3/22 of isolated neurons, respectively. Receptor mRNA co-expression was detected in 1/22 cells tested. Whole-cell voltage clamp recording (V(h)=-70 mV) was combined with local or bath application of dopaminergic and glutamatergic agonists to explore dopamine receptor modulation of glutamatergic excitation. Glutamate-evoked inward currents (5 microM, Mg(2+)-free, 1 microM glycine) were attenuated by dopamine (5 microM) to 83.2+/-3.6% (n=31). NMDA-evoked (20 microM), APV-sensitive currents were attenuated by dopamine to 80.9+/-4.5% (n=24). NMDA-induced responses were also attenuated by the D1 receptor agonist SKF 38393 (1 microM; n=28), while the D2/3 receptor agonist quinpirole (10 microM) had no effect. The currents evoked by application of AMPA (5 microM) displayed a steady rundown. Application of dopamine abolished or significantly reduced the rundown in the cells tested (n=17). A similar effect was observed after the application of SKF 38393 (1 microM), while quinpirole (10 microM) had no significant effect. Our results provide direct evidence for modulation by dopamine of glutamatergic responses of striatal medium spiny neurons, and demonstrate that the effects of this neuromodulator are receptor subtype specific. Disruption of this modulatory effect is likely to contribute to movement disorders associated with Parkinson's disease.
 ...
PMID:Receptor subtype-specific modulation by dopamine of glutamatergic responses in striatal medium spiny neurons. 1249 13

The objective of the work was to study, by in vivo microdialysis, the effect of the adenosine A(2A) receptor antagonist 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH 58261) on glutamate outflow in the striata of unilateral 6-hydroxydopamine-infused rats. Two vertical microdialysis probes were implanted bilaterally in both the denervated striatum and in the intact striatum. Glutamate concentrations in the dialysate were determined by high-performance liquid chromatography (HPLC). Infusion of the adenosine A(2A) receptor antagonist SCH 58261 (50 nM), through the microdialysis fiber, significantly increased glutamate outflow from the denervated striatum while it decreased glutamate outflow from the intact striatum. The opposite effects of SCH 58261 on glutamate outflow in the intact and 6-hydroxydopamine-lesioned striatum might be attributed to blockade of striatal adenosine A(2A) receptors located on either striatal indirect output pathways or glutamatergic terminals. These results may be relevant to our understanding of the mechanism of action of adenosine A(2A) receptor antagonists in Parkinson's disease.
 ...
PMID:Adenosine A2A receptor antagonism increases striatal glutamate outflow in dopamine-denervated rats. 1260 Jun 92

Parkinson's disease is a debilitating neurodegenerative movement disorder that is the result of a degeneration of dopaminergic neurons in the substantia nigra pars compacta. The resulting loss of striatal dopaminergic tone is believed to underlie a series of changes in the circuitry of the basal ganglia that ultimately lead to severe motor disturbances due to excessive basal ganglia outflow. Glutamate plays a central role in the disruption of normal basal ganglia function, and it has been hypothesised that agents acting to restore normal glutamatergic function may provide therapeutic interventions that bypass the severe motor side effects associated with current dopamine replacement strategies. Analysis of the effects of glutamate receptor ligands in the basal ganglia circuit suggests that both ionotropic and metabotropic glutamate receptors could have antiparkinsonian actions. In particular, NMDA receptor antagonists that selectively target the NR2B subunit and antagonists of the metabotropic glutamate receptor mGluR5 appear to hold promise and deserve future attention.
 ...
PMID:Glutamate receptors and Parkinson's disease: opportunities for intervention. 1269 97

Glutamate is the major excitatory transmitter in the brain. Recent developments in the molecular biology and pharmacology of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) subtype of glutamate receptors have led to the discovery of selective, potent, and systemically active AMPA receptor potentiators. These molecules enhance synaptic transmission and play important roles in plasticity and cognitive processes. In the present study, we first characterized a novel AMPA receptor potentiator, (R)-4'-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4-carboxylic acid methylamide (LY503430), on recombinant human GLUA1-4 and native preparations in vitro and then evaluated the potential neuroprotective effects of the molecule in rodent models of Parkinson's disease. Results indicated that submicromolar concentrations of LY503430 selectively enhanced glutamate-induced calcium influx into human embryonic kidney 293 cells transfected with human GLUA1, GLUA2, GLUA3, or GLUA4 AMPA receptors. The molecule also potentiated AMPA-mediated responses in native cortical, hippocampal, and substantia nigra neurons. We also report here that LY503430 provided dose-dependent functional and histological protection in animal models of Parkinson's disease. The neurotoxicity after unilateral infusion of 6-hydroxydopamine into either the substantia nigra or the striatum of rats and that after systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice were reduced. Interestingly, LY503430 also had neurotrophic actions on functional and histological outcomes when treatment was delayed until well after (6 or 14 days) the lesion was established. LY503430 also produced some increase in brain-derived neurotrophic factor in the substantia nigra and a dose-dependent increases in growth associated protein-43 (GAP-43) expression in the striatum. Therefore, we propose that AMPA receptor potentiators offer the potential of a new disease modifying therapy for Parkinson's disease.
 ...
PMID:LY503430, a novel alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor potentiator with functional, neuroprotective and neurotrophic effects in rodent models of Parkinson's disease. 1273 Mar 50

Glutamate overactivity within the basal ganglia has been shown to be central to the expression of motor symptoms in advanced stages of Parkinson's disease, and metabotropic glutamate receptors (mGluRs) represent promising targets for new therapeutic strategies in this pathology. Little is known, however, about the cellular and behavioral changes occurring in the early stages of the disease when dopamine depletion is moderate. Here, we report that rats with partial bilateral dopamine lesions exhibit akinetic deficits associated with dramatically increased neuronal metabolic activity in selective structures of the basal ganglia such as the subthalamic nucleus and the substantia nigra pars reticulata, but not in the entopeduncular nucleus. Furthermore, chronic treatment with the mGluR5 antagonist 2-methyl-6-(phenylethylnyl)-pyridine alleviated the akinesia and was associated with a normalization of the activity of these two overactive structures. These data stress the therapeutic potential of mGluR5 antagonists in the treatment of parkinsonian patients in the early stages of the disease.
 ...
PMID:Metabotropic glutamate 5 receptor blockade alleviates akinesia by normalizing activity of selective basal-ganglia structures in parkinsonian rats. 1296 92

Neurodegenerative diseases of the human brain comprise a variety of disorders that affect an increasing percentage of the population. Some of these are age dependent (e.g. Alzheimer's and Parkinson's diseases) and some are infection dependent, e.g. human immunodeficiency virus (HIV/AIDS). The vulnerable brain regions in HIV/AIDS individuals include the dentate nucleus in the cerebellum, the red nucleus, substantia nigra (SN) in the mid-brain, the subthalamic nucleus, thalamic fasciculus in the diencephalons, the globus pallidus and striatum (or neostriatum, which consists of caudate and putamen) in the forebrain. Lesion in these regions may lead to progressive dementia, which is similar to what is observed in Alzheimer's disease and Parkinson's disease. The entry of calcium into the cytoplasm of cells at concentrations that can activate oxidative enzymes such as phospholipase A(2) and xanthine oxidase, deplete cells of cysteine and glutathione, cause mitochondrial release of free radicals and cell death. Glutamate and its receptors are key molecular elements at the interface between neurons and glia. Dietary factors can modulate physiological functions (including brain function) thereby increasing the economic productivity of a population as a function of health. A greater understanding of the molecular mechanisms of neuroprotection, oxidative stress and immune function will facilitate definition of the prophylactic potentials of diet, nutritional/food supplements, medicinal plants and herbal extracts.
 ...
PMID:Neuroprotection by bioactive components in medicinal and food plant extracts. 1464 22

Glutamate receptors were studied in the brains of controls and Parkinson's disease (PD) patients, of which 10 of 14 developed motor complications (dyskinesias and/or wearing-off) following levodopa therapy. (125)I-RTI binding to the dopamine transporter and dopamine concentrations show comparable nigrostriatal denervation between the subgroups of PD patients. (3)H-Ro 25-6981 binding to the NR1/NR2B NMDA receptor was increased in the putamen of PD patients experiencing motor complications compared to those who did not (+53%) and compared to controls (+18%) whereas binding remained unchanged in the caudate nucleus. (3)H-AMPA binding was increased in the lateral putamen (+23%) of PD patients with motor complications compared to those without whereas it was decreased in the caudate nucleus of the PD patients (-16%) compared to controls. Caudate and putamen (3)H-CGP39653 binding to NR1/NR2A NMDA receptor and NR1 subunit mRNA levels measured by in situ hybridization were unchanged in subgroups of PD patients compared to controls. These findings suggest that glutamate receptor supersensitivity in the putamen plays a role in the development of motor complications (both wearing-Off and dyskinesias) following long-term levodopa therapy in PD.
 ...
PMID:Levodopa-induced motor complications are associated with alterations of glutamate receptors in Parkinson's disease. 1467 57

Glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors mediate most of the excitatory neurotransmission in the mammalian central nervous system and also participate in forms of synaptic plasticity thought to underlie memory and learning, and the formation of neural networks during development. Molecular cloning techniques have shown that the AMPA receptor family is composed of four different subunits named GluR1-4 or GluRA-D (newly termed as Glu(A1)-Glu(A4)) and native AMPA receptors are most likely tetramers generated by the assembly of one or more of these subunits, yielding homomeric or heteromeric receptors. Additional complexity among AMPA receptors is conferred by alternative splicing of RNA for each subunit giving rise to flip and flop variants. Clinical and experimental data have suggested that positive modulation of AMPA receptors may be therapeutically effective in the treatment of cognitive deficits. Several classes of AMPA receptor potentiators have been reported, including pyrroliddones (piracetam, aniracetam), benzothiazides (cyclothiazide), benzylpiperidines (CX-516, CX-546) and more recently biarylpropylsulfonamides (LY392098, LY404187 and LY503430). These molecules enhance cognitive function in rodents, which appears to correlate with increased hippocampal activity. In addition, clinical studies have suggested that AMPA receptor modulators enhance cognitive function in elderly subjects, as well as patients suffering from neurological and psychiatric disorders. Several independent studies have suggested that AMPA receptors can increase BDNF expression by both calcium-dependent and independent pathways. For example, recent studies have shown that AMPA receptors interact with the protein tyrosine kinase, Lyn. Activation of Lyn can recruit the mitogen-activated protein kinase (MAPK) signalling pathway and increase the expression of BDNF. Therefore, in addition to directly enhancing glutamatergic synaptic transmission, AMPA receptor activation can increase the expression of BDNF in vitro and in vivo. This may account for activity of AMPA receptor potentiators in rodent models predictive of antidepressant activity (forced swim and tail suspension tests). The increase in neurotrophin expression also may contribute to the functional, neuroprotective and neurotrophic actions of LY404187 and LY503430 after infusion of 6-OHDA into the substantia nigra. In conclusion, several potent, selective and systemically active AMPA receptor potentiators have been reported. Data indicate that these molecules modulate glutamatergic transmission, enhance synaptic transmission, long-term potentiation (LTP) and increase neurotrophin expression. Therefore, these AMPA receptor potentiators offer an exciting new class of drugs with potential for treating (1) cognitive impairment associated with Alzheimer's disease and schizophrenia, (2) depression, (3) slowing the progression and potentially enhancing recovery from Parkinson's disease.
 ...
PMID:AMPA receptor potentiators for the treatment of CNS disorders. 1518 Apr 79

Glutamate plays an important role in the regulation of dopamine neuron activity. In particular, the glutamatergic input from the subthalamic nucleus is thought to provide control over dopamine neuron firing patterns. The degeneration of dopamine neurons in the substantia nigra pars compacta (SNc) observed in Parkinson's disease (PD) is believed to be due to a complex interplay of factors, including oxidative stress and mitochondrial dysfunction. Although glutamate is not the primary cause of cell death in PD, there is evidence suggesting excessive glutamate release onto dopamine neurons may play a role in continued degeneration. Although many studies have focused on the role of glutamate in the SNc, little work has been directed at exploring the modulatory control of glutamate release in this region. Previous studies have found a high-potency inhibitory effect of nonselective group III mGluR agonist on glutamatergic transmission in the SNc. Using whole-cell patch-clamp methods and novel pharmacological tools, we have determined that mGluR4 mediates the group III mGluR modulation of excitatory transmission in the rat SNc. The group III mGluR-selective agonist l-(+)-2-amino-4-phosphonobutyric acid inhibits excitatory transmission in the SNc at low micromolar concentrations with a maximal inhibition occurring at 3 muM. This effect was potentiated by the mGluR4-selective allosteric modulator N-phenyl-7-(hydroxymino)cyclopropa[b]chromen-1a-carboxamide and was not mimicked by the mGluR8-selective agonist (S)-3,4-dicarboxyphenylglycine. Interestingly, in an attempt to employ knockout mice to confirm the role of mGluR4, we discovered an apparent species difference suggesting that in mice, both mGluR4 and mGluR8 modulate excitatory transmission in the SNc.
 ...
PMID:Group III metabotropic glutamate-receptor-mediated modulation of excitatory transmission in rodent substantia nigra pars compacta dopamine neurons. 1576 Nov 15


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>