UMLS:C0030567 - FACTA Search

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Query: UMLS:C0030567 (Parkinson's disease)
63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased GABAergic neurotransmission of the basal ganglia output nuclei projecting to the motor thalamus is thought to contribute to the pathophysiology of Parkinson's disease. We investigated the functional role of thalamic GABA(B) receptors in a rodent model of Parkinson's disease. First, we examined the effects of blockade of GABA(B) receptors in the ventromedial thalamic nucleus of rats with a unilateral 6-OHDA lesion of the substantia nigra on locomotor activity. In addition we studied the expression of GABA(B) receptor mRNA in the basal ganglia and thalamus using in situ hybridisation. Unilateral microinjections of the GABA(B) receptor antagonist 2-hydroxysaclofen into the ventromedial thalamic nucleus ipsilateral to the nigrostriatal lesion induced contralateral rotations in a dose-dependent manner. However, microinjection of antagonists with higher affinity for the GABA(B) receptor SCH 50911, CGP 56433 and CGP 55845 did not result in rotational behaviour, but did induce convulsions at higher doses. GABA(B) receptor mRNA expression was found throughout the basal ganglia and thalamus, including the ventromedial thalamic nucleus. No statistically significant differences in GABA(B) mRNA expression were observed in the ventromedial thalamic nucleus following a unilateral 6-OHDA lesion of the substantia nigra. These results make it improbable that thalamocortical GABA(B) receptors play an important role in the pathophysiology of parkinsonism. Therefore, GABA(B) receptors do not appear to be a promising target for novel antiparkinsonian drugs.
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PMID:Functional characterization and expression of thalamic GABA(B) receptors in a rodent model of Parkinson's disease. 1058 84

Much evidence indicates that abnormal GABA neurotransmission may be implicated in the pathophysiology of Parkinson's disease (PD) and dopaminomimetic-induced dyskinesias (DID). In this study, autoradiography using (125)I-CGP 64213 was performed to investigate GABA(B) receptor density in the brain of control monkeys as well as monkeys with MPTP-induced nigrostriatal depletion. Three MPTP monkeys received pulsatile administrations of the D1 dopamine (DA) receptor agonist (SKF 82958) whereas a long-acting D2 DA receptor agonist (cabergoline) was given to another three animals. SKF 82958 treatment relieved parkinsonian symptoms but two of three animals developed DID. Cabergoline induced a comparable motor benefit effect without persistent DID. (125)I-CGP 64213 binding to GABA(B) receptors was heterogeneous throughout the brain with the highest levels in the medial habenula of the thalamus. MPTP induced a decrease (-40%) of (125)I-CGP 64213 binding to GABA(B) receptors in the substantia nigra pars compacta (SNpc) and an increase (+29%) in the internal segment of the globus pallidus (GPi). This increase in the GPi was not affected by SKF 82958 but partly reversed by cabergoline. No change was seen in the striatum, the thalamus, the external segment of the globus pallidus, and the substantia nigra pars reticulata following MPTP and dopaminomimetic treatments. The changes of GABA(B) receptors observed in the SNpc and in the GPi suggest that alteration of GABA(B) receptors may play a role in the pathophysiology of PD and DID.
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PMID:125I-CGP 64213 binding to GABA(B) receptors in the brain of monkeys: effect of MPTP and dopaminomimetic treatments. 1078 58

1. This study examined whether GABA(B) receptor agonists injected directly into the substantia nigra pars reticulata (SNr) and globus pallidus (GP), or given intracerebroventricularly, could reverse reserpine-induced akinesia in the rat. 2. Male Sprague-Dawley rats, stereotaxically cannulated above the SNr, GP or third ventricle, were rendered akinetic by injection of reserpine (5 mg kg(-1) s.c.). After 18 h, the locomotor effects of the GABA(B) receptor agonists, baclofen or SKF 97541 were examined. 3. Unilateral injection of baclofen (1-5 micro g in 0.5 micro l) into the GP failed to evoke any locomotor response (n=6). In contrast, unilateral intranigral injection of baclofen (0.08-1.6 micro g in 0.5 micro l) produced a dose-dependent increase in net contraversive rotations reaching a maximum of 162+/-24 turns 90 min(-1) (n=6-8). Pretreatment with the selective GABA(B) receptor antagonist, CGP 46381 (2.4 micro g in 0.5 micro l), inhibited the effects of baclofen (0.8 micro g) by 68+/-9% (n=6). 4. Following intracerebroventricular injection, baclofen (0.8-4 micro g in 2 micro l) produced a dose-dependent increase in net arbitrary locomotor units (ALUs), reaching a maximum of 447+/-154 ALUs in 35 min (n=6-7). SKF 97541 (4-32 micro g in 2 micro l) similarly reversed akinesia, reaching 129+/-69 ALUs in 15 min (n=6). 5. These data show that activation of GABA(B) receptors within the SNr, but not the GP, reverses reserpine-induced akinesia. The success of intracerebroventricular injection of baclofen suggests a potential for systemically active GABA(B) receptor agonists in the treatment of akinesia in Parkinson's disease.
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PMID:GABA(B) receptor agonists reverse akinesia following intranigral or intracerebroventricular injection in the reserpine-treated rat. 1292 35

Loss of striatal dopaminergic innervation in Parkinson's disease (PD) is accompanied by widespread alterations in GABAergic activity within the basal ganglia and thalamus. Accompanying changes in GABA(B) receptor binding have been noted in some basal ganglia regions in parkinsonian primates, suggesting that plasticity of this receptor may also occur in PD. However, the molecular mechanisms underlying the changes in receptor binding and the manner and extent to which different GABA(B) receptor mRNA subunits and splice-variants are affected remain unknown. This study used in situ hybridisation to examine the full profile of changes in expression of the known rat GABA(B) receptor genes and gene variants in the basal ganglia and thalamus of rats, brought about by degeneration of the nigrostriatal tract. All of the GABA(B) mRNA species examined showed unique expression patterns throughout the basal ganglia and thalamus. In addition, all exhibited a marked loss of expression (between 46 and 80%) in the substantia nigra pars compacta of animals bearing a complete 6-hydroxydopamine-induced lesion of the nigrostriatal tract, confirming the presence of these variants in dopaminergic neurones in this region. Further analysis of autoradioagrams revealed additional changes only in GABA(B(1a)) mRNA in discrete anatomical regions. Expression of the GABA(B(1a)) variant was significantly increased in the substantia nigra pars reticulata (33+/-2%), entopeduncular nucleus (26+/-1%) and the subthalamic nucleus (16+/-1%). Since these regions all receive reduced GABAergic innervation following nigrostriatal tract lesioning, it is possible that the increased expression occurs as a compensatory measure. In conclusion, these data demonstrate that GABA(B) receptor genes exhibit regional- and subunit/variant-specific plasticity at the molecular level under parkinsonian conditions.
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PMID:Changes in GABA(B) receptor mRNA expression in the rodent basal ganglia and thalamus following lesion of the nigrostriatal pathway. 1292 8

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

The globus pallidus occupies a critical position in the 'indirect' pathway of the basal ganglia and, as such, plays an important role in the modulation of movement. In recent years, the importance of the globus pallidus in the normal and malfunctioned basal ganglia is emerging. However, the function and operation of various transmitter systems in this nucleus are largely unknown. GABA is the major neurotransmitter involved in the globus pallidus. By means of electrophysiological recording, immunohistochemistry and behavioral studies, new information on the distribution and functions of the GABAergic neurotransmission in the rat globus pallidus has been generated. Morphological studies revealed the existence of GABA(A) receptor, including its benzodiazepine binding site, and GABA(B) receptor in globus pallidus. At subcellular level, GABA(A) receptors are located at the postsynaptic sites of symmetric synapses (putative GABAergic synapses). However, GABA(B) receptors are located at both pre- and postsynaptic sites of symmetric, as well as asymmetric synapses (putative excitatory synapses). Consistent with the morphological results, functional studies showed that activation of GABA(B) receptors in globus pallidus reduces the release of GABA and glutamate by activating presynaptic auto- and heteroreceptors, and hyperpolarizes pallidal neurons by activating postsynaptic receptors. In addition to GABA(B) receptor, activation of GABA(A) receptor benzodiazepine binding site and blockade of GABA uptake change the activity of globus pallidus by prolonging the duration of GABA current. In agreement with the in vitro effect, activation of GABA(B) receptor, GABA(A) receptor benzodiazepine binding site and blockade of GABA uptake cause rotation in behaving animal. Furthermore, the GABA system in the globus pallidus is involved in the etiology of Parkinson's disease and regulation of seizures threshold. It has been demonstrated that the abnormal hypoactivity and synchronized rhythmic discharge of globus pallidus neurons associate with akinesia and resting tremor in parkinsonism. Recent electrophysiological and behavioral studies indicated that the new anti-epileptic drug, tiagabine, is functional in globus pallidus, which may present more information to understand the involvement of globus pallidus in epilepsy.
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PMID:GABAergic neurotransmission in globus pallidus and its involvement in neurologic disorders. 1532 74

Rats were injected (i.p.) once daily with either 1 mg/kg CGP 56999A, a gamma-aminobutyric acid(B) (GABA(B)) receptor antagonist, or an equivalent volume of saline beginning 7 days prior to, and continuing for 7 days following, a unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine (DA) pathway. At the end of the CGP 56999A treatment period the concentrations of DA and dihydroxyphenylacetic acid (DOPAC), as well as the expression of brain-derived neurotrophic factor (BDNF), were analyzed in corpus striatum ipsilateral and contralateral to the lesioning. No significant differences in these parameters were noted in the contralateral striatum between saline- and CGP 56999A-treated subjects. In contrast, as compared to animals receiving saline only, daily treatment with the GABA(B) receptor antagonist significantly attenuated the 6-hydroxydopamine-induced decline in DA and increased the expression of BDNF in the ipsilateral striatum. The results indicate that CGP 56999A enhances BDNF gene expression in the rat corpus striatum and prevents the decline in DA content that is a characteristic sequela of 6-hydroxydopapmine lesions of the nigrostraital dopamine pathway. These findings suggest that GABA(B) receptor antagonists may be of value in the treatment of Parkinson's disease and other conditions that would benefit from an enhanced production of neurotrophic factors in brain.
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PMID:CGP 56999A, a GABA(B) receptor antagonist, enhances expression of brain-derived neurotrophic factor and attenuates dopamine depletion in the rat corpus striatum following a 6-hydroxydopamine lesion of the nigrostriatal pathway. 1689 Mar 50

Mutations in the LRRK2 gene cause autosomal dominant, late-onset parkinsonism, which presents with pleomorphic pathology including alpha-synucleopathy. To promote our understanding of the biological role of LRRK2 in the brain we examined the distribution of LRRK2 mRNA and protein in postmortem human brain tissue from normal and neuropathological subjects. In situ hybridization and immunohistochemical analysis demonstrate the expression and localization of LRRK2 to various neuronal populations in brain regions implicated in Parkinson's disease (PD) including the cerebral cortex, caudate-putamen and substantia nigra pars compacta. Immunofluorescent double labeling studies additionally reveal the prominent localization of LRRK2 to cholinergic-, calretinin- and GABA(B) receptor 1-positive, dopamine-innervated, neuronal subtypes in the caudate-putamen. The distribution of LRRK2 in brain tissue from sporadic PD and dementia with Lewy bodies (DLB) subjects was also examined. In PD brains, LRRK2 immunoreactivity localized to nigral neuronal processes is dramatically reduced which reflects the disease-associated loss of dopaminergic neurons in this region. However, surviving nigral neurons occasionally exhibit LRRK2 immunostaining of the halo structure of Lewy bodies. Moreover, LRRK2 immunoreactivity is not associated with Lewy neurites or with cortical Lewy bodies in sporadic PD and DLB brains. These observations indicate that LRRK2 is not a primary component of Lewy bodies and does not co-localize with mature fibrillar alpha-synuclein to a significant extent. The localization of LRRK2 to key neuronal populations throughout the nigrostriatal dopaminergic pathway is consistent with the involvement of LRRK2 in the molecular pathogenesis of familial and sporadic parkinsonism.
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PMID:Localization of Parkinson's disease-associated LRRK2 in normal and pathological human brain. 1751 2

Neurotransmitters have been shown to control CNS neurogenesis, and GABA-mediated signaling is thought to be involved in the regulation of nearly all key developmental stages. Generation of dopaminergic (DA) neurons from stem/precursor cells for cell therapy in Parkinson's disease has become a major focus of research. However, the possible effects of GABA on generation of DA neurons from proliferating neurospheres of mesencephalic precursors have not been studied. In the present study, GABA(A), and GABA(B) receptors were found to be located in DA cells. Treatment of cultures with GABA did not cause significant changes in generation of DA cells from precursors. However, treatment with the GABA(A) receptor antagonist bicuculline (10(-5) M) led to a significant increase in the number DA cells, and treatment with the GABA(B) receptor antagonist CGP 55845 (10(-5) M) to a significant decrease. Simultaneous treatment with bicuculline and CGP 55845 did not induce significant changes. Apoptotic cell death studies and bromodeoxyuridine immunohistochemistry indicated that the aforementioned differences in generation of DA neurons are not due to changes in survival or proliferation of DA cells, but rather to increased or decreased differentiation of mesencephalic precursors towards the DA phenotype. The results suggest that these effects are exerted via GABA receptors located on DA precursors, and are not an indirect consequence of effects on the serotonergic or glial cell population. Administration of GABA(A) receptor antagonists in the differentiation medium may help to obtain higher rates of DA neurons for potential use in cell therapy for Parkinson's disease.
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PMID:Effects of GABA and GABA receptor inhibition on differentiation of mesencephalic precursors into dopaminergic neurons in vitro. 1752 90

Changes in GABAergic transmission in the external and internal segments of the globus pallidus (GPe and GPi) contribute to the pathophysiology of the basal ganglia network in Parkinson's disease. Because GABA-B receptors are involved in the modulation of GABAergic transmission in GPe and GPi, it is possible that changes in the functions or localization of these receptors contribute to the changes in GABAergic transmission. To further examine this question, we investigated the anatomical localization of GABA-B receptors and the electrophysiologic effects of microinjections of GABA-B receptor ligands in GPe and GPi of MPTP-treated (parkinsonian) monkeys. We found that the pattern of cellular and ultrastructural localization of the GABA-BR1 subunit of the GABA-B receptor in GPe and GPi was not significantly altered in parkinsonian monkeys. However, the magnitude of reduction in firing rate of GPe and GPi neurons produced by microinjections of the GABA-B receptor agonist baclofen was larger in MPTP-treated animals than in normal monkeys. Injections of the GABA-B receptor antagonist CGP55845A were more effective in reducing the firing rate of GPi neurons in parkinsonian monkeys than in normal animals. In addition, the injections of baclofen in GPe and GPi, or of CGP55845A in GPi lead to a significant increase in the proportion of spikes in rebound bursts in parkinsonian animals, but not in normal monkeys. Thus, despite the lack of changes in the localization of GABA-BR1 subunits in the pallidum, GABA-B receptor-mediated effects are altered in the GPe and GPi of parkinsonian monkeys. These changes in GABA-B receptor function may contribute to bursting activities in the parkinsonian state.
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PMID:Localization and pharmacological modulation of GABA-B receptors in the globus pallidus of parkinsonian monkeys. 2203 48

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