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)

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

In this investigation, 40 mg/kg of the excitatory neurotoxin kainic acid (KA) was subcutaneously administered to CD2-F1 mice. In this mouse strain morphological damage induced by KA in the hippocampus was markedly concentrated in the CA3 pyramidal neurons. Neuronal injury was accompanied by several pathological neurobehavioral activities including arching of tail, tremors and seizures, and by certain biochemical changes, i.e., increased lipid peroxidation products (LPO) in the brain. When melatonin was injected intraperitoneally at a single dose of 5 mg/kg 10 min before KA administration, it significantly reduced these pathological neurobehavioral changes and almost completely attenuated the increase in LPO and morphological damage induced by KA. The neuroprotective effect of melatonin against KA-induced brain damage in mice is believed to be in part related to its oxygen radical scavenging properties as well as its antiepileptic and GABA receptor regulatory actions. Considering melatonin's relative lack of toxicity and ability to enter the brain, these results along with previous evidence suggest that melatonin, which is a natural substance, may be useful in combating free radical-induced neuronal injury in acute situations such as stroke and brain trauma as well as neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease that have free radicals as causative factors.
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PMID:Melatonin protects hippocampal neurons in vivo against kainic acid-induced damage in mice. 981 43

Dual probe microdialysis was employed in intact rat brain to investigate the effect of intrastriatal perfusion with selective dopamine D1 and D2 receptor agonists and with c-fos antisense oligonucleotide on (a) local GABA release in the striatum; (b) the internal segment of the globus pallidus and the substantia nigra pars reticulata, which is the output site of the strionigral GABA pathway; and (c) the external segment of the globus pallidus, which is the output site of the striopallidal GABA pathway. The data provide functional in vivo evidence for a selective dopamine D1 receptor-mediated activation of the direct strionigral GABA pathway and a selective dopamine D2 receptor inhibition of the indirect striopallidal GABA pathway and provides a neuronal substrate for parallel processing in the basal ganglia regulation of motor function. Taken together, these findings offer new therapeutic strategies for the treatment of dopamine-linked disorders such as Parkinson's disease, Huntington's disease, and schizophrenia.
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PMID:Functional neuroanatomy of the basal ganglia as studied by dual-probe microdialysis. 986 60

Patients with fibromyalgia sometimes have sign of a movement disorder in addition to sensory disturbances sometimes similar as those found in akinetic syndromes. Akinesia is due to disturbances in the functions of the cortico-thalamo-nigro-striatal system and associated areas. The reason of this dysfunction in Parkinson's disease is a decreased nigral dopaminergic efferent innervation due to a neuronal degeneration in the pars compacta of the substantia nigra. Changes in other neurotransmitters, like GABA or serotonin, and in receptors and second messengers also occur, with additional modulation due to therapy. The aetiology of nigral malfunction is in only rarely known. Drugs and mutations of some genes are examples which give much insight in the pathogenesis of movement disorders in general. In other akinetic disorders, like multisystem atrophy, corticobasal ganglionic degeneration, and progressive supranuclear palsy, more complex patterns of degeneration have been found. This pathological anatomical disturbances have typical clinical effects which can be studied physiologically and with imaging in vivo. Since basal ganglia play also a role in pain, a comparative study of their involvement in movement disorders and nociception seems to be fruitful, especially in devising new therapeutic strategies.
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PMID:Pathophysiology of akinetic movement disorders: a paradigm for studies in fibromyalgia? 1002 78

Intrastriatal transplantation of fetal ventral mesencephalon (VM) is currently explored as a potential clinical therapy in Parkinson's disease (PD). Although providing substantial benefit for the patient, behavioral recovery so far obtained with intrastriatal VM grafts is not complete. Using the 6-hydroxydopamine lesion model of PD, we show here that near-complete restoration of the striatal dopamine (DA) innervation can be achieved by multiple intrastriatal microtransplants of fetal DA cells; nevertheless, complete recovery in complex sensorimotor behaviors was not obtained in these animals. In line with the current model of basal ganglia function, this suggests that the lesion-induced overactivity of the basal ganglia output structures, i.e., the substantia nigra (SN) and the entopeduncular nucleus, may not be completely reversed by intrastriatal VM grafts. In the present study, we have transplanted fetal VM tissue or fetal striatal tissue, as a source of DA and GABA neurons, respectively, into the SN of DA-depleted rats. Intranigral VM grafts induced behavioral recovery in some sensorimotor behaviors (forelimb akinesia and balance tests), but the effect did not exceed the recovery observed after intrastriatal VM grafts. Intranigral grafts of striatal tissue induced a pattern of functional recovery which was distinctly different from that observed after intranigral VM grafts, and recovery in coordinated forelimb use in the paw-reaching test was even more pronounced than after intrastriatal transplantation of VM cells. Combined transplantation of DA neurons into the striatum and GABA-rich striatal neurons into the SN induced additive effects of behavioral recovery observed in the forelimb akinesia test. We propose that intranigral striatal transplants, by a GABA-mediated inhibitory action, can reduce the overactivity of the host SN projection neurons and can induce significant recovery in complex motor behavior in the rat PD model and that such grafts may be used to increase the overall functional efficacy of intrastriatal VM grafts.
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PMID:Intranigral transplants of GABA-rich striatal tissue induce behavioral recovery in the rat Parkinson model and promote the effects obtained by intrastriatal dopaminergic transplants. 1007 93

Abnormal involuntary movements, or dyskinesias, plague current symptomatic approaches to the treatment of Parkinson's disease. The neural mechanisms underlying the generation of dyskinesia following repeated l-3,4-dihydroxyphenylalanine (L-DOPA) or dopamine agonist administration in Parkinson's disease remain unknown. However, de novo administration of bromocriptine or lisuride to either l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned primates or patients can alleviate parkinsonian symptoms without the development of dyskinesia. In this study, we have investigated behavioral responses and alterations in the expression of opioid neuropeptide precursors preproenkephalin-A (PPE-A, encoding methionine- and leucine-enkephalin) and preproenkephalin-B (PPE-B), the precursor encoding dynorphins (dynorphin A1-17 and B1-13, leucine-enkephalin, and alpha-neoendorphin) in striatal output pathways of the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease. Expression was assessed following repeated L-DOPA, bromocriptine, or lisuride administration. Given the functional organization of basal ganglia circuitry into anatomically discrete parallel circuits, we investigated alterations in peptide expression with reference to the detailed topography of the striatum. Following repeated L-DOPA administration (6.5 mg/kg, b.d., 21 days) in the 6-OHDA-lesioned rat a rotational response was observed. This became markedly enhanced with repeated treatment. We have previously characterized the pharmacology of this enhanced response and have suggested that it is a useful model for the elucidation of the cellular and molecular mechanisms underlying L-DOPA- and dopamine agonist-induced dyskinesia. In contrast to l-DOPA, de novo administration of bromocriptine (1 or 5 mg/kg, b.d., 21 days) or lisuride (0.01 or 0.1 mg/kg, b.d., 21 days) did not lead to an enhanced behavioral response. In vehicle-treated, 6-OHDA-lesioned animals, PPE-A expression was elevated rostrally and dorsally, while PPE-B expression was reduced in the striatum at all rostrocaudal levels. Repeated l-DOPA administration was accompanied by elevations in striatal PPE-B mRNA levels and a further elevation, above lesion-induced levels, in PPE-A expression. This further elevation was restricted to the dorsolateral striatum. However, following repeated bromocriptine or lisuride administration no increase in PPE-B expression was observed and the lesion-induced increase in PPE-A expression was normalized to prelesion levels. Increased PPE-A and PPE-B levels may, through decreasing GABA and glutamate release, respectively, in output nuclei of the basal ganglia, play a role in the development of L-DOPA- and dopamine-agonist induced dyskinesia in Parkinson's disease. These studies suggest that anti-parkinsonian treatments which are not associated with an elevation in PPE-B and/or normalize elevated PPE-A precursor expression, such as NMDA-receptor antagonists or long-acting dopamine D2 receptor agonists, e.g., cabergoline or ropinirole, may reduce dyskinesia in Parkinson's disease.
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PMID:Effect of repeated L-DOPA, bromocriptine, or lisuride administration on preproenkephalin-A and preproenkephalin-B mRNA levels in the striatum of the 6-hydroxydopamine-lesioned rat. 1007 96

The goal of this study was to determine if high-dose methamphetamine treatment altered presynaptic immunoreactivity for the amino acid neurotransmitters GABA and glutamate within the basal ganglia. Methamphetamine (15 mg/kg every 6 h, four doses) treatment in rats resulted in severe hyperthermia and a long-lasting (four weeks) depletion of striatal dopamine content (>80%). Severe dopamine loss correlated with a decrease in the density of presynaptic immunolabeling for GABA one week post-drug, and an increase after four weeks. Although no changes were seen in presynaptic striatal glutamate immunoreactivity, there was a significant increase in the percentage of glutamate-immuno-positive terminals associated with perforated postsynaptic densities. Rats given the same dose of methamphetamine but prevented from becoming hyperthermic showed less severe dopamine depletions and a lack of ultrastructural or immunocytochemical changes. In addition, induction of hyperthermia in the absence of drug decreased immunolabeling within mitochondria, but had no effect on dopamine content, morphology or nerve terminal immunoreactivity. Altered presynaptic GABA immunolabeling and terminal size were found in both the striatum and globus pallidus, suggesting that dynamic changes occur in the striatopallidal pathway following methamphetamine-induced dopamine loss. In addition, ultrastructural changes in glutamate-positive synapses which have been correlated with increased synaptic activity were found. These results are similar to changes in GABA and glutamate synapses that follow nigrostriatal dopamine loss in 6-hydroxydopamine-lesioned animals and in Parkinson's disease, and provide the first direct evidence that methamphetamine-induced dopamine loss alters the GABAergic striatopallidal pathway. Exposure to either methamphetamine or prolonged hyperpyrexia decreased mitochondrial Immunoreactivity, indicating that hyperthermia may contribute to methamphetamine toxicity by affecting energy stores.
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PMID:High-dose methamphetamine treatment alters presynaptic GABA and glutamate immunoreactivity. 1021 84

The electrophysiological and neurochemical characteristics of the nondopaminergic nigrostriatal (NO-DA) cells and their functional response to the degeneration of dopaminergic nigrostriatal (DA) cells were studied. Three different criteria were used to identify NO-DA cells: (1) antidromic response to striatal stimulation with an electrophysiological behavior (firing rate, interspike interval variability, and conduction velocity) different from that of DA cells; (2) retrograde labeling after striatal injection of HRP but showing immunonegativity for DA cell markers (tyrosine hydroxylase, calretinin, calbindin-D28k, and cholecystokinin); and (3) resistance to neurotoxic effect of 6-hydroxydomine (6-OHDA). Our results showed that under normal conditions, 5-8% of nigrostriatal neurons are immunoreactive for GABA, glutamic acid decarboxylase, and parvalbumin, markers of GABAergic neurons, a percentage that reached 81-84% after 6-OHDA injection. Electrophysiologically, NO-DA cells showed a behavior similar to that found in other nigral GABAergic (nigrothalamic) cells. In addition, the 6-OHDA degeneration of DA cells induced a modification of their electrophysiological pattern similar to that found in GABAergic nigrothalamic neurons. Taken together, the present data indicate the existence of a small GABAergic nigrostriatal pathway and suggest their involvement in the pathophysiology of Parkinson's disease.
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PMID:Electrophysiological and morphological evidence for a GABAergic nigrostriatal pathway. 1034 Dec 66

Parkinson's disease (PD) is characterized by progressive neuronal loss associated with Lewy bodies in many subcortical nuclei leading to multiple biochemical and pathophysiological changes of clinical relevance. Loss of nigral neurons causing striatal dopamine deficiency is related to both the duration and clinical stages (severity) of the disease. The clinical subtypes of PD have different morphological lesion patterns: a) The akinetic-rigid type shows more severe cell loss in the ventrolateral part of substantia nigra zona compacta (SNZC) that projects to the dorsal putamen than the medial part projecting to caudate nucleus and anterior putamen, with negative correlation between SNZC cell counts, severity of akinesia-rigidity, and dopamine loss in the posterior putamen. Reduced dopaminergic input causes overactivity of the GABA ergic inhibitory striatal neurons projecting via the "indirect loop" to SN zona reticulata (SNZR) and medial pallidum (GPI) leading to inhibition of the glutamatergic thalamo-cortical motor loop and reduced cortical activation. b) The tremor-dominant type shows more severe neuron loss in medial than in lateral SNZC and damage to the retrorubral field A8 containing only few tyrosine hydroxylase and dopamine transporter immunoreactive (IR) neurons but mainly calretinin-IR cells. A8 that is rather preserved in rigid-akinetic PD (protective role of calcium-binding protein?) projects to the matrix of dorsolateral striatum and ventromedial thalamus. Together with area A10 it influences the strial efflux via SNZR to thalamus and from there to prefrontal cortex. Rest tremor in PD is associated with increased metabolism in the thalamus, subthalamus, pons, and premotor-cortical network suggesting an increased functional activity of thalamo-motor projections. In essential tremor, no significant pathomorphological changes but overactivity of cerebello-thalamic loop have been observed. c) In the akinetic-rigid forms of multisystem atrophy, degeneration is more severe in the lateral SNZC with severe loss of calbindin-IR cells reflecting initial degeneration of the striatal matrix in the caudal putamen with transsynaptic degeneration of striatonigral efferences that remain intact in PD. This fact and loss of striatal D2 receptors--as in advanced stages of PD--are reasons for negative response to L-dopa substitution. These data suggest different pathophysiological mechanisms of the clinical subtypes of PD that have important therapeutic implications. d) Involvement of extranigral structures in PD includes the mesocortical dopaminergic system, the noradrenergic locus coeruleus, dorsal vagal nucleus and medullary nuclei, serotonergic dorsal raphe, nucleus basalis of Meynert and other cholinergic brainstem nuclei, e.g. Westphal-Edinger nucleus (controlling pupillomotor function), posterolateral hypothalamus and the limbic system, e.g. amygdaloid nucleus, part of hippocampal formation, limbic thalamic nuclei with prefrontal projections, etc. Damage to multiple neuronal systems by the progressing degenerative process causing complex biochemical changes may explain the variable clinical picture of PD including vegetative, behavioural and cognitive dysfunctions, depression, pharmacotoxic psychoses, etc. Future comparative clinico-morphological and pathobiochemical studies will further elucidate the pathophysiological basis of specific clinical symptoms of PD and related disorders providing a broader basis for effective treatment strategies. Parkinson's disease (PD) is characterized by progressive degeneration of the nigrostriatal dopaminergic system and other subcortical neuronal systems leading to striatal dopamine deficiency and other biochemical deficits related to the variable clinical signs and symptoms of the disorder. (ABSTRACT TRUNCATED)
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PMID:Post mortem studies in Parkinson's disease--is it possible to detect brain areas for specific symptoms? 1037 Sep 1


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