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)

Prior work has shown that intrastriatal injection of the metabotropic glutamate receptor agonist 1S,3R-ACPD results in pronounced contralateral rotation, and the basis for this effect is thought to be increased activity of dopaminergic nigrostriatal neurons. We tested this hypothesis by determining the expression of Fos-like immunoreactivity after intrastriatal injection of 1S,3R-ACPD. Intense Fos-like immunoreactivity was noted in the globus pallidus, entopeduncular nucleus, subthalamic nucleus and substantia nigra pars reticulata. Ablation of the subthalamic nucleus 10 days prior to intrastriatal injection of 1S,3R-ACPD abolished rotational behaviour but not Fos-like immunoreactivity in the globus pallidus, entopeduncular nucleus and substantia nigra. Intrasubthalamic injection of 1S,3R-ACPD produced marked contralateral rotation and a pattern of Fos-like immunoreactivity similar to that seen after intrastriatal 1S,3R-ACPD injection. These results suggest that stimulation of striatal metabotropic glutamate receptors inhibits striatal projection neuron activity, while stimulation of subthalamic metabotropic glutamate receptors increases subthalamic nucleus activity. Increased subthalamic nucleus activity is necessary and sufficient for the expression of rotational behavior. These results also suggest that metabotropic glutamate receptor antagonists may be useful in the treatment of Parkinson's disease.
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PMID:Intrastriatal and intrasubthalamic stimulation of metabotropic glutamate receptors: a behavioral and Fos immunohistochemical study. 763 75

The etiology of neurodegenerative diseases remains enigmatic; however, evidence for defects in energy metabolism, excitotoxicity, and for oxidative damage is increasingly compelling. It is likely that there is a complex interplay between these mechanisms. A defect in energy metabolism may lead to neuronal depolarization, activation of N-methyl-D-aspartate excitatory amino acid receptors, and increases in intracellular calcium, which are buffered by mitochondria. Mitochondria are the major intracellular source of free radicals, and increased mitochondrial calcium concentrations enhance free radical generation. Mitochondrial DNA is particularly susceptible to oxidative stress, and there is evidence of age-dependent damage and deterioration of respiratory enzyme activities with normal aging. This may contribute to the delayed onset and age dependence of neurodegenerative diseases. There is evidence for increased oxidative damage to macromolecules in amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and Alzheimer's disease. Potential therapeutic approaches include glutamate release inhibitors, excitatory amino acid antagonists, strategies to improve mitochondrial function, free radical scavengers, and trophic factors. All of these approaches appear promising in experimental studies and are now being applied to human studies.
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PMID:Aging, energy, and oxidative stress in neurodegenerative diseases. 766 20

The pathogenesis of nerve cell death in neurodegenerative diseases is unknown. An attractive hypothesis is that an impairment of energy metabolism may underlie slow excitotoxic neuronal death. Several studies have demonstrated mitochondrial or oxidative defects in neurodegenerative diseases. Impaired energy metabolism results in decreases in high-energy phosphate stores and a deteriorating membrane potential. Under these conditions, the voltage-sensitive Mg2+ block of NMDA receptors is relieved, allowing the receptors to be persistently activated by endogenous concentrations of glutamate. In this way, metabolic defects may lead to neuronal death by a slow 'excitotoxic' mechanism. Recent studies indicate that such a mechanism occurs in vivo, and it may play a role in animal models of Huntington's disease and Parkinson's disease. If a similar mechanism occurs in neurodegenerative diseases in humans it may be possible to use either excitatory amino acid antagonists or agents to improve neuronal bioenergetics as therapeutic treatments for these disorders.
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PMID:Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? 751 25

Increased glutamatergic transmission in the basal ganglia is implicated in the pathophysiology of Parkinson's disease. However, the mechanisms by which activation of glutamate receptors produce parkinsonism are unknown. Therefore, we examined whether the glutamate agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainate, and trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylate produce parkinsonism in rats after microapplication into different subregions of the basal ganglia. Electromyographic activity was used as a measure of parkinsonian rigidity. We found that in the rostral striatum, excitation mediated by NMDA but not by non-NMDA receptors led to parkinsonism. In the substantia nigra pars reticulata, internal pallidal segment/entopeduncular nucleus, and subthalamic nucleus, activation of AMPA/kainate and metabotropic receptors but not of NMDA receptors led to parkinsonian rigidity. Rigidity occurred also in animals bearing ibotenate-induced lesions of the posterior part of the striatum and of the external pallidal segment, but not in animals with lesions of the anterior striatum, subthalamic nucleus, internal pallidal segment/entopeduncular nucleus, or substantia nigra pars reticulata. These observations suggest that the activation of glutamate receptor subtypes in the basal ganglia may be differentially involved in the expression of parkinsonian symptoms.
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PMID:Toward an understanding of the role of glutamate in experimental parkinsonism: agonist-sensitive sites in the basal ganglia. 769 10

It has previously been shown that glutamatergic overactivity of the subthalamic nucleus (STN) is involved in hypokinetic movement disorders such as Parkinson's disease. Conversely, it has been hypothesized that hyperkinetic behavioral syndromes may be associated with reduced glutamatergic transmission of the STN to its target areas, the substantial nigra pars reticulata (SNR) and the globus pallidus pars interna (GPI). In the present experiment, apomorphine injected systemically into unilaterally dopamine-denervated rats induced the hyperkinetic syndrome of contralateral rotation. The involvement of glutamatergic input to the SNR in this hyperkinesia was investigated by pharmacological manipulation with an agonist or an antagonist at the AMPA subtype of glutamate receptors. Either the agonist AMPA or the antagonist CNQX was infused directly into the SNR at a dose of 1.0 nmol. Intra-SNR AMPA attenuated the contralateral rotation induced by apomorphine without eliciting any effects on rotation by itself. Infusions of the antagonist CNQX did not affect either apomorphine-induced or spontaneous rotation. These results support the notion that underactivity of the SNR and its glutamatergic afferent projection from the STN may underlie hyperkinetic movement disorders and that local stimulation of the AMPA subtype of glutamate receptors can ameliorate such syndromes.
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PMID:Intra-nigra infusion of AMPA attenuates dopamine-dependent rotation in the rat. 769 18

A substantial number of adults and half of the children with acquired immunodeficiency syndrome (AIDS) suffer from neurological manifestations. Among the various pathologies reported in brains of patients with AIDS is neuronal injury and loss, although neurons themselves do not appear to be infected by HIV-1. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions between macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells, especially after interacting with astrocytes, secrete neurotoxic substances. Not all of these substances are yet known, but they may include eicosanoids, platelet-activating factor, quinolinate, cysteine, cytokines, and free radicals. Macrophages activated by HIV-1 envelope protein gp120 also appear to release similar toxins. Some of these factors can lead to increased glutamate release or decreased glutamate reuptake. A final common pathway for neuronal suceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-asparate (NMDA) receptor-operated channels, and therefore offers hope for future pharmacological intervention. This review focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.
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PMID:Neuronal injury associated with HIV-1 and potential treatment with calcium-channel and NMDA antagonists. 770 21

Excitotoxins constitute a group of agents that are capable of activating excitatory amino acid receptors and producing axonsparing neuronal lesions. Focal injections of the exogenous excitotoxins kainic acid and ibotenic acid result in depletion of neurotransmitter markers in neuronal cell bodies located in areas of injection or in terminal zones of their projections. The discovery of endogenous agents that behave as excitotoxins has generated interest in the idea that excitotoxicity may contribute to the neuronal degeneration associated with a number of neurological diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease) which involve selective neurotransmitter deficits. Quinolinic acid (QUIN), a pyridine dicarboxylic acid and metabolite of tryptophan, which has been detected in the central nervous system (CNS), behaves as an excitotoxin. In the mammalian brain QUIN has been localized to glial and immune cells, and its content increases with age. The neuro-excitatory and neurotoxic actions of QUIN are mediated via the Mg(2+)-sensitive N-methyl-D-aspartate (NMDA) receptor. The toxicity of QUIN, like that of kainate, but not ibotenate, is dependent on the presence of an intact glutamate-aspartate afferent input to the target area. Focal injections of QUIN into the nucleus basalis magnocellularis (nbM), a major source of cholinergic innervation to diencephalic areas, produce sustained loss of cholinergic neuron markers in the neocortex and amygdala. The neurotoxic action of QUIN on nbM results in an impairment of performance on memory-related tasks. Cortical and amygdaloid projecting cholinergic neurons show differential sensitivity to QUIN and other excitotoxic agents. This factor may partly explain the reported discrepancy between mnemonic deficits and the loss of cholinergic markers in the cerebral cortex induced by intra-nbM injections of certain excitotoxins. Cortical muscarinic receptor function is not significantly influenced by QUIN injections into the nbM producing loss of cortical cholinergic neurons. In the striatum, focal QUIN injections have been found to largely replicate the neurotransmitter deficits prevailing in Huntington's disease, an inherited movement disorder. Intrastriatal QUIN produces a profound loss of the NADPH diaphorase staining neurons in the area of injection but relatively spares these in the adjacent transition zone. QUIN is also highly damaging to the striatopallidal enkephalinergic neurons. However, at doses that are neurotoxic to striatal neurons, QUIN and several other excitotoxins produce significant elevations in enkephalin levels both in the striatum and globus pallidus. This elevation reflects the presence of a plasticity in the striatal enkephalinergic neuron population. The metabolic pathway yielding QUIN produces a number of intermediates that act as excitotoxin antagonists.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The 1993 Upjohn Award Lecture. Quinolinic acid induced brain neurotransmitter deficits: modulation by endogenous excitotoxin antagonists. 773 38

The recent availability of selective ligands for NMDA and AMPA receptors has enabled neuroscientists to test the hypothesis that Parkinson's disease is a glutamate hyperactivity disorder and hence treatable with glutamate antagonists. This review takes a critical look at the motor characteristics of this new class of drugs in rodent and primate models of parkinsonism and assesses the clinical potential and pitfalls of this radical new approach. Monotherapy of Parkinson's disease with glutamate antagonists appears impractical at the present time, due to their low efficacy and unacceptable side effects, but polypharmacy with L-DOPA and a glutamate antagonist as adjuvant is a more realistic prospect. This review will focus on the ways in which glutamate receptor blockade facilitates motor recovery with L-DOPA and will examine whether the basis for this beneficial effect can be traced to a specific interaction with dopamine at D1 or D2 receptors, and therefore to discrete motor pathways within the basal ganglia.
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PMID:Glutamate/dopamine D1/D2 balance in the basal ganglia and its relevance to Parkinson's disease. 779 21

Brain imaging is performed using radiopharmaceuticals by single photon emission computed tomography (SPECT) and positron emission tomography (PET). SPECT and PET radiopharmaceuticals are classified according to blood-brain-barrier permeability, cerebral perfusion and metabolism receptor-binding, and antigen-antibody binding. The blood-brain-barrier (BBB) SPECT agents, such as 99mTcO4-, [99mTc]DTPA, 201TI and [67Ga]citrate are excluded by normal brain cells, but enter into tumor cells because of altered BBB. These agents were used in the earlier period for the detection of brain tumors. SPECT perfusion agents such as [123I]IMP, [99mTc]HMPAO, [99mTc]ECD are lipophilic agents and therefore, diffuse into the normal brain. These tracers have been successfully used to detect various cerebrovascular diseases such as stroke, Parkinson disease, Huntington's disease, epilepsy, dementia, and psychiatric disorders. Xenon-133 and radiolabeled microspheres have been used for the measurement of cerebral blood flow (CBF). Important receptor-binding SPECT radiopharmaceuticals include [123I]QNE, [123I]IBZM, and [123I]iomazenil. These tracers bind to specific receptors in the brain, thus displaying their distribution in various receptor-related cerebral diseases. Radioiodinated monoclonal antibodies were used for the detection of brain tumors. PET radiopharmaceuticals for brain imaging are commonly labeled with positron-emitters such as 11C, 13N, 15O, and 18F, although other radionuclides such as 82Rb, 62Cu and 68Ga also were used. The brain uptake of [13N]glutamate, [68Ga]EDTA and [82Rb]RbCl depends on the BBB permeability, but these are rarely used for brain imaging. Several cerebral perfusion agents have been introduced, of which [15O]water, [13N]ammonia, and [15O]butanol have been used more frequently. Regional CBF has been quantitated by using these tracers in normal and different cerebral disease states. Other perfusion agents include [15O]O2, [11C]CO, [11C]CO2, [18F]fluoromethane, [15O]O2, [11C]butanol, and [62Cu]PTSM. Among the PET cerebral metabolic agents, [18F]fluorodeoxyglucose (FDG) is most commonly used to detect metabolic abnormalities in the brain. Various brain tumors have been graded by [18F]FDG PET. This technique was used to detect epileptic foci by showing increased uptake in the foci during the ictal period and decreased uptake in the interictal period. Differentiation between recurrent tumors and radiation necrosis and the detection of Alzheimer's disease have been made successfully by [18F]FDG PET. Other PET metabolic agents such as [11C]deoxyglucose, and [11C]methylmethionine have drawn attention in the detection of brain tumors. [18F]fluorodopa is a cerebral neurotransmitter agent, which has been found very useful in the detection of Parkinson disease that shows reduced uptake of the tracer in the striatum of the brain.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Radiopharmaceuticals for brain imaging. 781 3

The effect of pros-methylimidazoleacetic acid (p-MIAA) was measured on the release of glutamate and aspartate from cerebral cortex, hippocampus, and striatum of freely moving rats, and on the uptake of 14C by striatal slices incubated in the presence of L-[14C]-glutamate. Twenty-four hours after implantation of a dialysis fiber, striatum, hippocampus, or cerebral cortex spontaneously released both glutamate and aspartate in the micromolar range. p-MIAA (1 microM to 1 mM), added to the dialysis perfusate, elicited a concentration-dependent increase of glutamate release from striatum with a maximal increase of about threefold. This effect did not occur in hippocampus or cortex. In none of these regions did p-MIAA increase aspartate release significantly. The p-MIAA effect was not mimicked by its isomer tele-methyl-imidazoleacetic acid. p-MIAA did not influence the uptake of glutamate by striatal slices. The glutamate-releasing action of p-MIAA may affect striatal function and explain the positive correlation between levels of p-MIAA in CSF and the severity of Parkinson's disease.
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PMID:Release of glutamate from striatum of freely moving rats by pros-methylimidazoleacetic acid. 783 72


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