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)

The reticular thalamic nucleus consists of densely packed neurons containing the neurotransmitter GABA. It surrounds the lateral border of the thalamus, has extensive reciprocal connections with thalamocortical neurons, and is thought to be involved in attentional processes. The reticular thalamic nucleus also receives direct and indirect inputs from the basal ganglia, suggesting that it may be involved in relaying motor information to the thalamus and cortex. We examined the possibility that decreased dopaminergic transmission in the basal ganglia indirectly affects the reticular thalamic nucleus. Rats received unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta and were killed two or three weeks after the lesion. Sections of the reticular thalamic nucleus were processed for in situ hybridization histochemistry at the single cell level with RNA probes for both isoforms of glutamate decarboxylase (M(r) 65,000: glutamate decarboxylase 65 and M(r) 67,000: glutamate decarboxylase 67), the rate limiting enzyme of GABA synthesis. Unilateral nigrostriatal dopaminergic lesions induced a topographically specific, bilateral increase in glutamate decarboxylase 67 messenger RNA in neurons of the lateral and ventral reticular thalamic nucleus. A much smaller increase in glutamate decarboxylase 65 messenger RNA was observed which was significant only ipsilateral to the lesion. Short- (seven day) and long-term (eight month) treatments with the antipsychotic drug haloperidol, in regimens that preferentially block D2 dopamine receptors, induced catalepsy and orofacial dyskinesia, respectively, but did not alter glutamate decarboxylase 67 messenger RNA levels in the reticular thalamic nucleus. Thus, loss of dopaminergic terminals, but not blockade of D2 dopamine receptors, induced the effects observed in the reticular thalamic nucleus. The results reveal a novel bilateral effect of unilateral dopamine depletion. In view of the role of the reticular thalamic nucleus in tremor and attentional processes, which are altered in Parkinson's disease, this effect may contribute to the clinical manifestations of nigrostriatal dopamine depletion.
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PMID:Unilateral nigrostriatal lesions induce a bilateral increase in glutamate decarboxylase messenger RNA in the reticular thalamic nucleus. 905 94

In Parkinson's disease the dopaminergic nigrostriatal pathway degenerates, resulting in an imbalance in activity of two pathways of information flow through the basal ganglia. In animal models of the disease, the striatonigral pathway becomes underactive and the striatopallidal pathway becomes overactive. In the present study immunocytochemistry for enkephalin and GABA and anterograde labelling were used to investigate whether morphological plasticity occurs in striatopallidal terminals following unilateral removal of the nigrostriatal dopaminergic pathway. Pallidal terminals were immunostained to reveal enkephalin and examined in the electron microscope (n=399). Immunoreactive synaptic bouton profiles were on average 64% larger on the experimental side 26 days after the lesion. Analysis of their shape revealed that those on the dopamine-depleted side of the brain were more irregular in profile and that their synaptic specialisations were more complex in shape but not significantly different in length. Striatopallidal terminals were also identified by GABA immunocytochemistry combined with anterograde labelling (n=20). Double-labelled boutons were significantly larger in cross-sectional area on the experimental side (57%). Analysis of terminals that were simply labelled by the immunogold method to reveal GABA (n=278) showed no significant differences in size between terminals from the dopamine-depleted and control side. This suggests that a substantial number of GABAergic terminals in the globus pallidus do not belong to the striatopallidal population of terminals. These morphological changes correlate with previous studies suggesting striatopallidal boutons are more active after destruction of dopaminergic input to the neostriatum.
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PMID:Plasticity of striatopallidal terminals following unilateral lesion of the dopaminergic nigrostriatal pathway: a morphological study. 930 13

There is now good reason to believe that blockade of the adenosine A2A receptor could be of value in the treatment of Parkinson's disease. Peter J. Richardson, Hiroshi Kase and Peter G. Jenner review the actions of this receptor in the striatum, emphasizing its ability to modulate the neuronal activity of striatal GABA-releasing output neurones, and showing that recently developed A2A receptor antagonists are capable of reducing the disabling effects of nigral cell degeneration in primates. They conclude that such antagonists may be useful as novel therapeutic agents for the treatment of Parkinson's disease.
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PMID:Adenosine A2A receptor antagonists as new agents for the treatment of Parkinson's disease. 955 Sep 40

Rats were treated intraperitoneally with a mixture of 250 mg/kg L-DOPA and 40 mg/kg carbidopa or with vehicle and sacrificed 30 min later. Plasma, heart and cortex, midbrain, brainstem and cerebellum were removed from each animal and assayed by HPLC for L-DOPA and a large number of amino acids and related amino compounds. L-DOPA levels increased from undetectable (<0.2 nmol/ml or g) to 1,146, 1,007, 399, 376, 368 and 850 nmol/ml or g in the above tissues. In addition, several amino compounds were significantly affected by L-DOPA/carbidopa (p < or = 0.01). Plasma concentrations of phosphoserine, oxidized glutathione, citrulline, phenylalanine, tyrosine and 1-methylhistidine increased and arginine, glutamic acid and lysine decreased. In the heart, concentrations of phosphoserine, taurine, reduced glutathione, threonine, serine, glutamine, glycine, alanine, valine, GABA, ethanolamine, ammonia and arginine decreased. In the cortex, camosine and homocarnosine increased. In the midbrain, valine increased and leucine, ornithine and oxidized glutathione decreased. In the cerebellum, citrulline increased. In the brainstem, threonine, serine, asparagine, glutamine, oxidized glutathione, alanine, and leucine decreased. In the brainstem, arginine was slightly decreased with a concomitant increase in citrulline (p < 0.05), indicative of nitrous oxide formation. These results show that administration of L-DOPA/ carbidopa not only raises dopamine levels but can also affect other biochemicals and that the observed changes in amino acids and related compounds can perhaps contribute to the beneficial and/or adverse effects of L-DOPA/carbidopa therapy of Parkinson's disease.
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PMID:Effects of L-DOPA/carbidopa administration on the levels of L-DOPA, other amino acids and related compounds in the plasma, brain and heart of the rat. 934 99

Zinc is an important trace element in biology. An important pool of zinc in the brain is the one present in synaptic vesicles in a subgroup of glutamatergic neurons. In this form it can be released by electrical stimulation and may serve to modulate responses at receptors for a number of different neurotransmitters. These include both excitatory and inhibitory receptors, particularly the NMDA and GABA(A) receptors. This pool of zinc is the only form of zinc readily stained histochemically (the chelatable zinc pool), but constitutes only about 8% of the total zinc content in the brain. The remainder of the zinc is more or less tightly bound to proteins where it acts either as a component of the catalytic site of enzymes or in a structural capacity. The metabolism of zinc in the brain is regulated by a number of transport proteins, some of which have been recently characterized by gene cloning techniques. The intracellular concentration may be mediated both by efflux from the cell by the zinc transporter ZrT1 and by complexing with apothionein to form metallothlonein. Metallothionein may serve as the source of zinc for incorporation into proteins, including a number of DNA transcription factors. However, zinc is readily released from metallothionein by disulfides, increasing concentrations of which are formed under oxidative stress. Metallothionein is a very good scavenger of free radicals, and zinc itself can also reduce oxidative stress by binding to thiol groups, decreasing their oxidation. Zinc is also a very potent inhibitor of nitric oxide synthase. Increased levels of chelatable zinc have been shown to be present in cell cultures of immune cells undergoing apoptosis. This is very reminiscent of the zinc staining of neuronal perikarya dying after an episode of ischemia or seizure activity. Thus a possible role of zinc in causing neuronal death in the brain needs to be fully investigated. intraventricular injections of calcium EDTA have already been shown to reduce neuronal death after a period of ischemia. Pharmacological doses of zinc cause neuronal death, and some estimates indicate that extracellular concentrations of zinc could reach neurotoxic levels under pathological conditions. Zinc is released in high concentrations from the hippocampus during seizures. Unfortunately, there are contrasting observations as to whether this zinc serves to potentiate or decrease seizure activity. Zinc may have an additional role in causing death in at least some neurons damaged by seizure activity and be involved in the sprouting phenomenon which may give rise to recurrent seizure propagation in the hippocampus. In Alzheimer's disease, zinc has been shown to aggregate beta-amyloid, a form which is potentially neurotoxic. The zinc-dependent transcription factors NF-kappa B and Sp1 bind to the promoter region of the amyloid precursor protein (APP) gene. Zinc also inhibits enzymes which degrade APP to nonamyloidogenic peptides and which degrade the soluble form of beta-amyloid. The changes in zinc metabolism which occur during oxidative stress may be important in neurological diseases where oxidative stress is implicated, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Zinc is a structural component of superoxide dismutase 1, mutations in which give rise to one form of familiar ALS. After HIV infection, zinc deficiency is found which may be secondary to immune-induced cytokine synthesis. Zinc is involved in the replication of the HIV virus at a number of sites. These observations should stimulate further research into the role of zinc in neuropathology.
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PMID:Zinc metabolism in the brain: relevance to human neurodegenerative disorders. 936 Dec 93

Recent in vitro studies have described the toxicity of levodopa (L-DOPA) to dopamine (DA) neurons. We investigated whether metabolic inhibition with rotenone, an inhibitor of complex I of the mitochondrial respiratory chain, may enhance the toxicity of L-DOPA toward DA neurons in mesencephalic cultures. The uptakes of DA and GABA were determined to evaluate the functional and morphological integrity of DA and non-DA neurons, respectively. Pretreatment with rotenone significantly augmented the toxic effect of L-DOPA on DA neurons. Interestingly, prior metabolic inhibition with rotenone rendered DA cells susceptible to a dose (5 microM) of L-DOPA that otherwise exhibited no toxic effect. DA uptake was more intensely attenuated than GABA uptake after the combined exposure to rotenone and L-DOPA. This was confirmed by cell survival estimation showing that tyrosine hydroxylase-positive DA cells are more vulnerable to the sequential exposure to the drugs than total cells. The selective toxic effect of L-DOPA on rotenone-pretreated DA neurons was significantly blocked by antioxidants, but not antagonists of NMDA or non-NMDA glutamate receptors. This indicates that oxidative stress play a central role in mediating the selective damage of DA cells in the present experimental paradigm. Our results raise the possibility that long-term L-DOPA treatment could accelerate the progression of degeneration of DA neurons in patients with Parkinson's disease where potential energy failure due to mitochondrial defects has been demonstrated to take place.
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PMID:Metabolic inhibition enhances selective toxicity of L-DOPA toward mesencephalic dopamine neurons in vitro. 944 29

GABAergic neurons in the rat substantia nigra die after inhibitory inputs to the nigra have been killed, and glutamatergic inputs disinhibited, by striatal-pallidal injections of ibotenic acid. This delayed transneuronal injury model imitates the neuron loss observed in Huntington's disease, and may also imitate neuron loss distant from the primary injury in stroke and Parkinson's disease. Because the neurotrophins brain-derived neurotrophic factor and neurotrophin-3 can prevent excitotoxic killing of cultured GABA neurons, we tested whether either factor could protect nigral neurons from transneuronal degeneration. A continuous, three week supranigral infusion of brain-derived neurotrophic factor completely prevented the loss of nigral neurons caused by the ibotenic acid-induced destruction of the caudate-putamen and globus pallidus, and brain-derived neurotrophic factor increased nigral neuron size by 25%. These effects were specific to the TrkB tyrosine kinase receptor that mediates brain-derived neurotrophic factor actions, since supranigral infusions of saline or the TrkC preferring neurotrophin-3, did not prevent nigral neuron loss or induce a hypertrophic response. Neither trophic factor influenced the ibotenic acid destruction of striatal or pallidal neurons. These results demonstrate that exogenously supplied brain-derived neurotrophic factor can prevent delayed, transneuronal loss, and implicate decreased excitatory amino acid transmission or diminished nigral neuron susceptibility to glutamate inputs in the protective effect of brain-derived neurotrophic factor.
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PMID:Brain-derived neurotrophic factor prevents the loss of nigral neurons induced by excitotoxic striatal-pallidal lesions. 948 58

Alterations in the glutathione system and impairment in energy metabolism have both been implicated in the loss of dopamine neurons in Parkinson's disease. This study examined the importance of cellular glutathione and the involvement of oxidative stress in the loss of mesencephalic dopamine and GABA neurons due to inhibition of energy metabolism with malonate, the reversible, competitive inhibitor of succinate dehydrogenase. Consistent with previous findings, exposure to malonate for 24 h followed by 48 h of recovery caused a dose-dependent loss of the dopamine population with little effect on the GABA population. Toxicity was assessed by simultaneous measurement of the high-affinity uptake of [3H]dopamine and [14C]GABA. Total glutathione content in rat mesencephalic cultures was decreased by 65% with a 24-h pretreatment with 10 microM buthionine sulfoxamine. This reduction in glutathione level greatly potentiated damage to both the dopamine and GABA populations and removed the differential susceptibility between the two populations in response to malonate. These findings point to a role for oxidative stress occurring during energy impairment by malonate. Consistent with this, several spin-trapping agents, alpha-phenyl-tert-butyl nitrone and two cyclic nitrones, MDL 101,002 and MDL 102,832, completely prevented malonate-induced damage to the dopamine neurons in the absence of buthionine sulfoxamine. The spin-trapping agents also completely prevented toxicity to both the dopamine and GABA populations when cultures were exposed to malonate after pretreatment with buthionine sulfoxamine to reduce glutathione levels. Counts of tyrosine hydroxylase-positive neurons verified enhancement of cell loss by buthionine sulfoxamine plus malonate and protection against cell loss by the spin-trapping agents. NMDA receptors have also been shown to play a role in malonate-induced dopamine cell loss and are associated with the generation of free radicals. Consistent with this, toxicity to the dopamine neurons due to a 1-h exposure to 50 microM glutamate was attenuated by the nitrone spin traps. These findings provide evidence for an oxidative challenge occurring during inhibition of energy metabolism by malonate and show that glutathione is an important neuroprotectant for midbrain neurons during situations when energy metabolism is impaired.
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PMID:Role of oxidative stress and the glutathione system in loss of dopamine neurons due to impairment of energy metabolism. 952 58

We investigated the effects of continuous intranigral perfusion of dopamine D1 and D2 receptor agonists and antagonists on the biotransformation of locally applied L-DOPA to dopamine in the substantia nigra of freely moving rats by means of in vivo microdialysis. The "dual-probe" mode was used to monitor simultaneously changes in extracellular dopamine levels in the substantia nigra and the ipsilateral striatum. Intranigral perfusion of 10 microM L-DOPA for 20 min induced a significant 180-fold increase in extracellular nigral dopamine level. No effect of the intranigral L-DOPA administration was observed on dopamine levels in the ipsilateral striatum, suggesting a tight control of extracellular dopamine in the striatum after enhanced nigral dopamine levels. Continuous nigral infusion with the D1 receptor agonist CY 208243 (10 microM) and with the D2 receptor agonist quinpirole at 10 microM (a nonselective concentration) attenuated the L-DOPA-induced increase in dopamine in the substantia nigra by 85 and 75%, respectively. However, perfusion of the substantia nigra with a lower concentration of quinpirole (1 microM) and the D1 antagonist SCH 23390 (10 microM) did not affect the nigral L-DOPA biotransformation. The D2 antagonist (-)-sulpiride (10 microM) also attenuated the L-DOPA-induced dopamine release in the substantia nigra to approximately 10% of that of the control experiments. We confirm that there is an important biotransformation of L-DOPA to dopamine in the substantia nigra. The high concentrations of dopamine formed after L-DOPA administration may be the cause of dyskinesias or further oxidative stress in Parkinson's disease. Simultaneous administration of D1 receptor agonists with L-DOPA attenuates the biotransformation of L-DOPA to dopamine in the substantia nigra. The observed effects could occur via changes in nigral GABA release that in turn influence the firing rate of the nigral dopaminergic neurons.
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PMID:Biotransformation of L-DOPA to dopamine in the substantia nigra of freely moving rats: effect of dopamine receptor agonists and antagonists. 952 92

Putative modulatory effects of L-3,4-dihydroxyphenylalanine (L-DOPA) on D2 dopamine receptor function in the striatum of anaesthetised rats were investigated using both in vivo microdialysis and positron emission tomography (PET) with carbon-11 labelled raclopride as a selective D2 receptor ligand. A single dose of L-DOPA (20 or 100mg/kg i.p.) resulted in an increase in [11C]raclopride binding potential which was also observed in the presence of the central aromatic decarboxylase inhibitor NSD 1015, confirming that the effect was independent of dopamine. This L-DOPA evoked D2 receptor sensitisation was abolished by a prior, long-term administration of L-DOPA in drinking water (5 weeks, 170mg/kg/day). In the course of acute L-DOPA treatment (20mg/kg), extracellular GABA levels were reduced by approximately 20% in the globus pallidus. It is likely that L-DOPA sensitising effect on striatal D2 receptors, as confirmed by PET, may implicate striato-pallidal neurones, hence a reduced GABA-ergic output in the projection area. Since the L-DOPA evoked striatal D2 receptor supersensitivity habituates during long-term treatment, the effects reported here may contribute to the fluctuations observed during chronic L-DOPA therapy in Parkinson's disease.
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PMID:Modulatory effects of L-DOPA on D2 dopamine receptors in rat striatum, measured using in vivo microdialysis and PET. 972 Sep 67


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