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)

The present study evaluates the cytoarchitecture of midbrain dopaminergic regions in baboons using similar methodology to that recently applied to compare humans and rats. This information is relevant for the interpretation of nonhuman primate models of Parkinson's disease (PD). The midbrains of four alpha male baboons were serially sectioned into 10 evenly spaced series of 50 microm sections. Series were stained with either cresyl violet or immunohistochemically reacted for tyrosine hydroxylase, substance P, calbindin-D28k, or parvalbumin. The organization of dopaminergic cell groups and the distribution of proteins within these groups were found to be very similar to that previously described in humans [McRitchie et al., J. Comp. Neurol. 364:121-150; 1996]. Dorsal and ventral tiers of the A9 substantia nigra (SN) pars compacta and all divisions of the A8 and A10 cell groups were identified revealing a high degree of homology in the arrangement of chemically distinct midbrain neurons between primates. The major difference between the organization of human and baboon midbrain dopaminergic neurons is the anteroposterior extent of the dense cell clusters within the SN pars compacta. In baboons the dorsomedial cell cluster is absent at posterior levels. The ventral tier cell clusters, which are targeted by PD in humans, are restricted to the posterior and ventral regions of the SN pars compacta of the baboon. In humans these cell clusters are found throughout the rostrocaudal extent of the SN. These ventral cell clusters have been previously shown to have reciprocal connections with sensorimotor regions of the putamen.
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PMID:The midbrain dopaminergic cell groups in the baboon Papio ursinus. 1007 18

Among the dopaminergic neurons in substantia nigra pars compacta and in the ventral tegmental area, subpopulations express the calcium-binding proteins calbindin (CB) and calretinin (CR), and the CB-containing neurons are supposed to be less prone to degeneration in Parkinson's disease. Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for nigrostriatal dopaminergic neurons. Using free-floating roller-tube (FFRT) cultures derived from fetal rat (E14) ventral mesencephalon we found that GDNF (10 ng/ml) significantly increased the number of surviving tyrosine hydroxylase (TH)-immunoreactive neurons. The possible effects of GDNF treatment on CB-immunoreactive (CB-ir) and CR-ir neurons in such cultures were examined in the present study. The neuronal cell densities were measured by quantifying the numbers of CB-ir and CR-ir neurons in areas of sections through the most extensive parts of the spherical cultures. In 4-day-old and 8-day-old cultures GDNF treatment increased the density of CB-ir neurons by 50% and 59%, respectively. Partial co-existence of TH and CB was shown using the method of double immunolabeling. The density of CR-containing neurons was unaffected by GDNF treatment as confirmed by Western blotting for CR. Parallel effects of GDNF treatment were obtained for cultures of human fetal ventral mesencephalon (8 weeks postconception). In conclusion, our findings identify GDNF as a potent factor for fetal rat and human nigral CB-ir neurons able to promote their survival in culture. Referring to a suggested neuroprotective role of CB, the results may be of relevance in the context of neuronal transplantation of patients suffering from severe Parkinson's disease.
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PMID:GDNF increases the density of cells containing calbindin but not of cells containing calretinin in cultured rat and human fetal nigral tissue. 1033 73

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

In contrast to the well-established dopaminergic innervation of the neostriatum, the existence of dopaminergic innervation of the subthalamic nucleus and globus pallidus is controversial. In the present study, tyrosine hydroxylase (TH)-immunoreactive elements were observed by light microscopy after antigen retrieval in the subthalamic nucleus and in the internal and external segments of the globus pallidus in postmortem human brain. Small islands of apparent neostriatal tissue with abundant arborization of fine, TH-immunoreactive axons in the vicinity of calbindin-positive small neurons resembling neostriatal medium spiny neurons were present in the external segment of the globus pallidus. Large numbers of medium-large, TH-immunoreactive axons were observed passing above and through the subthalamic nucleus and through both pallidal segments; these are presumed to be axons of passage on their way to the neostriatum. In addition, fine, TH-immunoreactive axons with meandering courses, occasional branches, and irregular outlines, morphologically suggestive of terminal axon arborizations with varicosities, were seen in both pallidal segments, including the ventral pallidum, and the subthalamic nucleus, consistent with a catecholaminergic (probably dopaminergic) innervation of these nuclei. This finding suggests that, in Parkinson's disease and in animal models of this disorder, loss of dopaminergic innervation might contribute to abnormal neuronal activation in these three nuclei.
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PMID:Tyrosine hydroxylase-immunoreactive elements in the human globus pallidus and subthalamic nucleus. 1037 26

The catecholaminergic cell groups in the human brain, denominated from A1 to A17, display some striking anatomical differences with those described in the rodent. These differences are essentially observed in the extent of the dopaminergic neurons and especially their axonal fields in the telencephalon. Immunocytochemistry for tyrosine-hydroxylase and dopamine-ss-hydroxylase allowed the visualization of the precocious human catecholaminergic groups as early as 4.5 postovulatory weeks. Maps of tyrosine-hydroxylase positive neurons generated in the different rhombomeres, midbrain, and prosomeres are shown following the prosomeric model introduced by Puelles and Rubenstein [(1993) Trends Neurosci. 16:472-476]. Such a description is convenient to compare catecholaminergic systems in different mammalian species and provide clear anatomical landmarks of the embryonic substantia nigra (midbrain and prosomeres 1 and 2), that are necessary for transplantation of neural tissue in Parkinson's disease. The development and early specification of the dopaminergic neurons expressing calbindin D28K phenotype in the substantia nigra and in the ventral tegmental area are described. The catecholaminergic axons enter the anlage of the cerebral cortex just after the formation of the cortical plate, from 7 postovulatory weeks on. They invade the subplate layer where they wait for 4 weeks before penetrating the cortical plate. At midgestation, the different areas and layers of the frontal cerebral wall are invaded by the catecholaminergic axons, before the layering of the cortex is completed, in a pattern of fiber distribution similar to that described in the adult human brain. The early pattern of development of the catecholamine systems appeared to be phylogenetically well preserved in mammals, but specific features emerging during the differentiation period are unique to humans.
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PMID:Distribution of the catecholaminergic neurons in the central nervous system of human embryos and fetuses. 1040 70

Parkinson's disease is characterized by massive degeneration of dopamine-containing neurons in the midbrain. However, the vulnerability of these neurons is heterogeneous both across different midbrain dopamine-containing cell groups and within the substantia nigra, the brain structure most affected in this disease. To determine the exact pattern of cell loss and to map the cellular distribution of candidate pathogenic molecules, it is necessary to have landmarks independent of the degenerative process by which to subdivide the substantia nigra. We have developed a protocol for this purpose based on immunostaining for calbindin D(28K), a protein present in striatonigral afferent fibres. We used it to examine post-mortem brain samples from seven subjects who had had no history of neurological or psychiatric disease. We found intense immunostaining for calbindin D(28K) associated with the neuropil of the ventral midbrain. Within the calbindin-positive region, there were conspicuous calbindin-poor zones. Analysed in serial sections, many of the calbindin-poor zones seen in individual sections were continuous with one another, forming elements of larger, branched three-dimensional structures. Sixty per cent of all dopamine-containing neurons in the substantia nigra pars compacta were located within the calbindin-rich zone, which we named the nigral matrix, and 40% were packed together within the calbindin-poor zones, which we named nigrosomes. We identified five different nigrosomes. This organization was consistent from one control brain to another. We propose that subdivision of the human substantia nigra based on patterns of calbindin immunostaining provides a key tool for analysing the organization of the substantia nigra and offers a new approach to analysing molecular expression patterns in the substantia nigra and the specific patterns of nigral cell degeneration in Parkinson's disease.
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PMID:The substantia nigra of the human brain. I. Nigrosomes and the nigral matrix, a compartmental organization based on calbindin D(28K) immunohistochemistry. 1043 Aug 27

To achieve accuracy in studying the patterns of loss of midbrain dopamine-containing neurons in Parkinson's disease, we used compartmental patterns of calbindin D(28K) immunostaining to subdivide the substantia nigra with landmarks independent of the degenerative process. Within the substantia nigra pars compacta, we identified dopamine-containing neurons in the calbindin-rich regions ('matrix') and in five calbindin-poor pockets ('nigrosomes') defined by analysis of the three-dimensional networks formed by the calbindin-poor zones. These zones were recognizable in all of the brains, despite severe loss of dopamine-containing neurons. The degree of loss of dopamine-containing neurons in the substantia nigra pars compacta was related to the duration of the disease, and the cell loss followed a strict order. The degree of neuronal loss was significantly higher in the nigrosomes than in the matrix. Depletion was maximum (98%) in the main pocket (nigrosome 1), located in the caudal and mediolateral part of the substantia nigra pars compacta. Progressively less cell loss was detectable in more medial and more rostral nigrosomes, following the stereotyped order of nigrosome 1 > nigrosome 2 > nigrosome 4 > nigrosome 3 > nigrosome 5. A parallel, but lesser, caudorostral gradient of cell loss was observed for dopamine-containing neurons included in the matrix. This pattern of neuronal loss was consistent from one parkinsonian substantia nigra pars compacta to another. The spatiotemporal progression of neuronal loss related to disease duration can thus be drawn in the substantia nigra pars compacta for each Parkinson's disease patient: depletion begins in the main pocket (nigrosome 1) and then spreads to other nigrosomes and the matrix along rostral, medial and dorsal axes of progression.
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PMID:The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson's disease. 2876 33

The phenotype of substantia nigra (SN) neurons in homozygous weaver (wv/wv) mice was studied by combining patch-clamp and single-cell RT-multiplex PCR techniques in midbrain slices of 14-d-old mice. In contrast to GABAergic SN neurons, which were unaffected in homozygous weaver mice (wv/wv), dopaminergic SN neurons possessed a dramatically altered phenotype with a depolarized membrane potential and complete loss of spontaneous pacemaker activity. The gain-of-function phenotype was mediated by a large, nonselective membrane conductance exclusively present in (wv/wv) dopaminergic SN neurons. This constitutively activated conductance displayed a sensitivity to external QX-314 (IC(50) = 10.6 microM) very similar to that of heterologously expressed wvGirk2 channels and was not further activated by G-protein stimulation. Single-cell Girk1-4 expression profiling suggested that homomeric Girk2 channels were present in most dopaminergic SN neurons, whereas Girk2 was always coexpressed with other Girk family members in GABAergic SN neurons. Surprisingly, acute QX-314 inhibition of wvGirk2 channels did not induce wild-type-like pacemaker activity but instead caused membrane hyperpolarization. Additional application of a blocker of ATP-sensitive potassium channels (100 microM tolbutamide) induced wild-type-like pacemaker activity. We conclude that the gain-of-function weaver phenotype of dopaminergic substantia nigra neurons is mediated by coactivation of wvGirk2 and SUR1/Kir6. 2-mediated ATP-sensitive K(+) channels. We also show that in contrast to wild-type neurons, all (wv/wv) dopaminergic SN neurons expressed calbindin, a calcium-binding protein that marks dopaminergic SN neurons resistant to neurodegeneration. The identification of two ion channels that in concert determine the weaver phenotype of surviving calbindin-positive dopaminergic SN neurons will help to understand the molecular mechanisms of selective neurodegeneration of dopaminergic SN neurons in the weaver mouse and might be important in Parkinson's disease.
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PMID:The weaver mouse gain-of-function phenotype of dopaminergic midbrain neurons is determined by coactivation of wvGirk2 and K-ATP channels. 1051 3

This study was carried out in order to examine the effects of acute or chronic L-DOPA treatment on striatally expressed FosB- and JunB-like proteins in a rat model of Parkinson's disease. Rats with a unilateral, near-total 6-hydroxydopamine lesion of the ascending mesostriatal projection received either an acute challenge or a one-week treatment with 10 mg/kg/day methyl L-DOPA (combined with 15 mg/mg benserazide), and were killed at either 3 h or two days post-injection. Both acute and chronic L-DOPA treatment caused a pronounced, persistent increase in the number of FosB-like immunoreactive cells in the dopamine-denervated striata (five- and seven-fold increase, respectively, above the levels found in lesioned but non-drug-treated controls), but the two treatment groups differed markedly with respect to both the average amount of staining per cell, which was two-fold larger in the chronic L-DOPA cases, and the anatomical distribution of the labeled cells. After an acute injection of L-DOPA, FosB-positive cells were distributed rather uniformly across all striatal subregions, whereas chronic L-DOPA treatment induced discrete clusters of strongly FosB-like immunoreactive cells within medial and central striatal subregions, as well as in a large, yet sharply defined portion of the lateral caudate-putamen. Strongly labeled cell clusters that appeared in the medial and central caudate-putamen were preferentially located within calbindin-poor, mu-opioid receptor-rich striosomes, whereas the lateral area displaying FosB activation encompassed both striosomal and matrix domains. In both the medial and the lateral striatum a near-total overlap was found between strongly FosB-like immunoreactive cell groups and areas showing pronounced dynorphin expression. NADPH-diaphorase-positive striatal interneurons did not express FosB-like immunoreactivity after a 6-hydroxydopamine lesion alone, a negligible proportion of them did after an acute L-DOPA challenge, but about 8% of these interneurons were FosB positive following chronic L-DOPA treatment. Like FosB, JunB was induced in the DA-denervated striatum by both acute and chronic L-DOPA treatment, and exhibited similar distribution patterns. However, JunB did not exhibit prolonged expression kinetics, and was somewhat down-regulated in the chronically compared with the acutely L-DOPA-treated rats. The present results show that L-DOPA administration produces a long-lasting increase in the levels of FosB-, but not JunB-like immunoreactivity in the dopamine-denervated striatum. More importantly, these data show that striatal induction of FosB- and JunB-like proteins by chronic L-DOPA treatment exhibits both regional and compartmental specificity.
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PMID:Changes in the regional and compartmental distribution of FosB- and JunB-like immunoreactivity induced in the dopamine-denervated rat striatum by acute or chronic L-dopa treatment. 1057 13

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