Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calbindin-D 28kD is a calcium binding protein reported to protect neurons from degeneration by buffering intracellular calcium. It is expressed in midbrain dopaminergic neurons reported to be relatively resistant to degeneration in Parkinson's disease and certain of its animal models. Lesions of the nigrostriatal pathway produced in rats following injection of 6-hydroxydopamine result in a neurochemical profile similar to that seen in patients with Parkinson's disease. In the present study, brains were processed to exhibit tyrosine hydroxylase- and calbindin-D 28kD immunoreactivities in sections through the ventral mesencephalon at 3, 7, 10, 14 and 21 days after 6-hydroxydopamine had been injected into the medial forebrain bundle. Numbers of ventral mesencephalic calbindin-D 28kD immunoreactive neurons were significantly reduced ipsilateral to the lesions at 3 days post-lesion and, following slight recovery, remained significantly depleted through post-lesion day 21. The densities of calbindin-D 28kD and tyrosine hydroxylase immunoreactive neurons were different only at the 3 day post-lesion time point, when the apparent loss of calbindin-D 28 kD immunoreactive profiles was significantly greater. A lesion-induced increase in the proportion of neurons exhibiting both calbindin-D 28kD and tyrosine hydroxylase immunoreactivities, expected if calbindin-D 28kD is neuroprotective, was observed in the substantia nigra, pars compacta, but not in the ventral tegmental area. It is concluded that, while the observed losses of tyrosine hydroxylase and calbindin-D 28kD immunoreactivities do not necessarily reflect neuronal degeneration, they are not consistent with CB confering a neuroprotective advantage in the ventral tegmental area following 6-OHDA lesions as administered in this study.
 ...
PMID:On the altered expression of tyrosine hydroxylase and calbindin-D 28kD immunoreactivities and viability of neurons in the ventral tegmental area of Tsai following injections of 6-hydroxydopamine in the medial forebrain bundle in the rat. 1086 59

Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor for mesencephalic dopaminergic neurons. Subpopulations of these neurons express the calcium-binding proteins calbindin (CB) and calretinin (CR). Understanding the specific effects of GDNF on these neurons is important for the development of an optimal cell replacement therapy for Parkinson's disease. To investigate the effects of GDNF on the morphological complexity of mesencephalic tyrosine hydroxylase (TH)-immunoreactive (-ir), CB-ir, and CR-ir neurons, dissociated cultures of embryonic (E14) rat ventral mesencephalon were prepared. Chronic administration of GDNF (10 ng/ml) for 7 days promoted the survival of TH-ir and CB-ir neurons but did not alter the density of CR-ir neurons. Total fiber length/neuron and number of branching points/neuron of CB-ir and CR-ir cells were significantly increased after GDNF treatment (2x for CB-ir cells and 1.4x and 1.7x, respectively, for CR-ir cells), which resulted in a significantly larger size of neurite field/neuron (2.9x and 1.5x for CB-ir and CR-ir neurons, respectively). The number of primary neurites/neuron of CB-ir neurons was found to be 1.5x larger, while no difference could be detected for CR-ir cells. Assessment of the effects of GDNF on TH-ir neurons unveiled a similar outcome with an increased total fiber length/neuron (1.5x), an increased number of primary neurites/neuron (1.6x), and a twofold larger size of neurite field/neuron. In conclusion, our findings recognize GDNF as a neurotrophic factor that stimulates the morphological differentiation of ventral mesencephalic CB-ir and CR-ir neurons.
 ...
PMID:Glial cell line-derived neurotrophic factor stimulates the morphological differentiation of cultured ventral mesencephalic calbindin- and calretinin-expressing neurons. 1087 17

A subset of tyrosine-hydroxylase (TH) neurons of the substantia nigra (A9) containing calbindin D28K (CaBP) appeared to be less vulnerable to cell death induced by Parkinson's disease than the subset containing dopamine (DA) alone. Because grafting procedures of fetal human neurons are increasingly used in the therapy of Parkinson's disease, it is important to study the development of DA neurons coexpressing CaBP. In humans, the genesis of TH immunoreactivity of A9, of the ventral tegmental area (A10), and of the retrorubral area (A8) occurred during a 2-week period from the 4. 5th gestational week (g.w.) in the ventricular zone of the floor plate and the contiguous basal plate of the mesencephalon and diencephalon, i.e., the prosomeres p1-p3. Double-immunolabeled TH-CaBP neurons were detected from 5.5 g.w. on, in the first wave of DA neuron's migration, and were observed in their final residence in the dorsal A9 by 10.5 g.w. Calretinin immunoreactivity was expressed in TH-immunoreactive (IR) neurons from 10.5 g.w. on. Ascending TH-CaBP-IR axons were observed toward the telencephalon from 6-7 g.w. , reaching the anlage of the nucleus accumbens and amygdaloid complex at 10.5 g.w., but were not detected in the ganglionic eminence at this latter stage. Dopaminergic patches were detected at 13 g.w. in the anlage of the putamen, but no TH-CaBP-IR fibers were observed in the matrix at this stage. In conclusion, even if CaBP immunoreactivity was detected in TH-IR cell bodies during the embryonic period, the TH-CaBP-IR axonal terminal was observed earlier in some limbic-related areas than in the matrix compartment of the basal ganglia in humans.
 ...
PMID:Expression of calbindin D28K in the dopaminergic mesotelencephalic system in embryonic and fetal human brain. 1108 88

Cynomolgus monkeys (Macaca fascicularis) were chronically treated with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) until stable parkinsonism was reached. Two months later, monkeys were sacrificed and monoamine content was measured in different brain regions of the lesioned monkeys and of age-matched controls. 5-HT(1A) serotonin receptor density was measured in coronal sections labeled with [(3)H]8-OH-DPAT. As expected, dopamine was virtually nonexistent in the caudate nucleus and putamen of MPTP-treated monkeys. Serotonin levels were significantly reduced in different brain regions, particularly in the raphe nuclei. 5-HT(1A) receptor density of control animals was high in the hippocampus, notably in the CA1 field and also in the raphe nuclei, and much lower in the striatum, where 5-HT(1A) receptors showed a patchy distribution which corresponded to striosomes with poor calbindin immunostaining. 5-HT(1A) receptor density was reduced in hippocampal fields and in the raphe nuclei of parkinsonian monkeys. Conversely, in the severely lesioned striatal nuclei 5-HT(1A) receptor density was increased at caudal levels of the striatum, particularly in the putamen. The results tend to support the possibility of an increased synthesis of 5-HT(1A) receptors in brain regions with higher neuronal cell death. Upregulation of this 5-HT receptor subtype in the limbic compartment of the striatum may represent a compensatory event for the serotonergic dysfunction and associated mental disorders in neurodegenerative diseases such as Parkinson disease.
 ...
PMID:Serotonin 5-HT(1A) receptor expression is selectively enhanced in the striosomal compartment of chronic parkinsonian monkeys. 1116 78

This paper summarises the results of some of our recent tyrosine hydroxylase (TH) immunohistochemical studies of the dopaminergic innervation of the human basal ganglia. It also reports new findings on the presence of TH-immunoreactive (ir) neurons in the striatum. Our data show the existence of nigrostriatal TH-ir axons that provide collaterals arborizing in the globus pallidus and subthalamic nucleus. These thin and varicose collaterals emerge from thick and smooth axons that course along the main output pathways of the basal ganglia, including the ansa lenticularis, the lenticular fasciculus and Wilson's pencils. We postulate that this extrastriatal innervation, which allows nigral dopaminergic neurons to directly affect the pallidum and subthalamic nucleus, plays a critical role in the functional organisation of human basal ganglia. The TH-ir fibres that reach the striatum arborize according to a highly heterogeneous pattern. At rostral striatal levels, numerous small TH-poor zones embedded in a TH-rich matrix correspond to calbindin-poor striosomes and calbindin-rich extrastriosomal matrix, respectively. At caudal striatal levels, in contrast, striosomes display a TH immunostaining that is more intense than that of the matrix. A significant number of small, oval, aspiny TH-ir neurons scattered throughout the rostrocaudal extent of the caudate nucleus and putamen, together with a few larger, multipolar, spiny TH-ir neurons lying principally within the ventral portion of the putamen, were disclosed in human. This potential source of intrinsic striatal dopamine might play an important role in the functional organisation of the human striatum, particularly in case of Parkinson's disease.
 ...
PMID:Dopaminergic innervation of human basal ganglia. 1120 19

In an attempt to find a convenient rat model to study cell vulnerability in Parkinson's disease, we have investigated the cell-loss profile in different midbrain dopaminergic nuclei and subnuclei of rats injected with 6-hydroxydopamine (6-OHDA) in the third ventricle. Following administration of different doses (5-1000 microgram) of 6-OHDA, motor behavior was evaluated and tyrosine hydroxylase-immunostained neurons were counted in the A8 group and different subdivisions of A9 and A10 groups. Animals developed hypokinesia, repetitive chewing movements, and catalepsia. Signs of cell degeneration were evident from the first day after injection, reaching the definitive pattern at the end of the first week. There was a similar degeneration in both brain sides, the A9 group showing the highest degree of cell-loss, followed by A8 and A10 groups. In the A9 group, the degeneration mostly affected those subgroups located in its ventral, lateral, and posterior regions. In the A10 group the degeneration mainly affected the parabrachial pigmented nucleus, the paranigral nucleus and the ventral tegmental area. This topographic pattern of degeneration is very similar to that previously described in Parkinson's disease, suggesting that this model may be a useful tool in the study of the cell vulnerability mechanisms in this neurodegenerative disorder. In addition, our results also showed that small dopaminergic neurons are more resistant to degeneration than the large ones. In some DA subgroups, the cells that contained calbindin but not calretinin were less vulnerable to the neurotoxic effect of 6-OHDA.
 ...
PMID:Dopamine cell degeneration induced by intraventricular administration of 6-hydroxydopamine in the rat: similarities with cell loss in parkinson's disease. 1131 69

Efforts have been made to counteract the symptoms of Parkinson's disease by substituting the loss of dopaminergic neurons with fetal ventral mesencephalic grafts. One of the postulated limiting factors in this treatment is the relatively poor cell survival and limited graft-derived fiber outgrowth. Recent results documenting enhanced survival of grafted dopaminergic neurons showed no positive correlation to enhanced innervation of the striatal target. Therefore this study was undertaken to investigate whether all surviving grafted dopaminergic neurons projected to the striatal target. Hence, fetal ventral mesencephalic tissue was implanted adjacent to mature versus immature striatal tissue using in oculo and intraventricular grafting techniques. In in oculo grafting, fetal ventral mesencephalon was implanted simultaneously with fetal lateral ganglionic eminence (immature striatal target) or to already matured striatal in oculo grafts (mature striatal target). Furthermore, fetal ventral mesencephalon was implanted into the lateral ventricle adjacent to mature dopamine-depleted striatum. The retrograde tracer fluorogold was injected into the striatal portion of the in oculo cografts and into reinnervated areas of the adult brain. Immunohistochemistry revealed that a significantly larger proportion of tyrosine hydroxylase-positive neurons in the ventral mesencephalic graft was innervating in oculo immature striatal tissue, and hence was fluorogold-positive, in comparison with the number of tyrosine hydroxylase-positive neurons innervating mature striatal tissue. Moreover, intracranial transplantations showed that tyrosine hydroxylase-positive neurons were distributed within the grafts in dense clusters of cells. In most clusters tyrosine hydroxylase-positive cells were fluorogold-negative but calbindin-positive. In a few tyrosine hydroxylase-positive cell clusters, neurons were coexpressing fluorogold but were calbindin-negative. In conclusion, significantly more dopamine neurons projected to immature than to mature striatal tissue and thus, a subpopulation of grafted dopaminergic neurons was not projecting into adult striatum. Thus, the results from this study show that further attempts to enhance survival of grafted dopamine neurons in purpose to enhance graft-derived fiber outgrowth and efficacy should also consider different subtypes of dopamine neurons.
 ...
PMID:Evidence for target-specific nerve fiber outgrowth from subpopulations of grafted dopaminergic neurons: a retrograde tracing study using in oculo and intracranial grafting. 1135 46

Transplantation of embryonic dopaminergic neurons is an experimental therapy for Parkinson's disease, but limited tissue availability and suboptimal survival of grafted dopaminergic neurons impede more widespread clinical application. Glial cell line-derived neurotrophic factor (GDNF) and neurotrophin-4/5 (NT-4/5) exert neurotrophic effects on dopaminergic neurons via different receptor systems. In this study, we investigated possible additive or synergistic effects of combined GDNF and NT-4/5 treatment on rat embryonic (embryonic day 14) nigral explant cultures grown for 8 days. Contrary to cultures treated with GDNF alone, cultures exposed to NT-4/5 and GDNF+NT-4/5 were significantly larger than controls (1.6- and 2.0-fold, respectively) and contained significantly more protein (1.6-fold). Treatment with GDNF, NT-4/5 and GDNF+NT-4/5 significantly increased dopamine levels in the culture medium by 1.5-, 2.5- and 4.7-fold, respectively, compared to control levels, and the numbers of surviving tyrosine hydroxylase-immunoreactive neurons increased by 1.7-, 2.1-, and 3.4-fold, respectively. Tyrosine hydroxylase enzyme activity was moderately increased in all treatment groups compared to controls. Counts of nigral neurons containing the calcium-binding protein, calbindin-D28k, revealed a marked increase in these cells by combined GDNF and NT-4/5 treatment. Western blots for neuron-specific enolase suggested an enhanced neuronal content in cultures after combination treatment, whereas the expression of glial markers was unaffected. The release of lactate dehydrogenase into the culture medium was significantly reduced for GDNF+NT-4/5-treated cultures only. These results indicate that combined treatment with GDNF and NT4/5 may be beneficial for embryonic nigral donor tissue either prior to, or in conjunction with, intrastriatal transplantation in Parkinson's disease.
 ...
PMID:Additive effect of glial cell line-derived neurotrophic factor and neurotrophin-4/5 on rat fetal nigral explant cultures. 1173 60

Dopaminergic (DA) midbrain neurons in the substantia nigra (SN) and ventral tegmental area (VTA) are involved in various brain functions such as voluntary movement and reward and are targets in disorders such as Parkinson's disease and schizophrenia. To study the functional properties of identified DA neurons in mouse midbrain slices, we combined patch-clamp recordings with either neurobiotin cell-filling and triple labeling confocal immunohistochemistry, or single-cell RT-PCR. We discriminated four DA subpopulations based on anatomical and neurochemical differences: two calbindin D28-k (CB)-expressing DA populations in the substantia nigra (SN/CB+) or ventral tegmental area (VTA/CB+), and respectively, two calbindin D28-k negative DA populations (SN/CB-, VTA/CB-). VTA/CB+ DA neurons displayed significantly faster pacemaker frequencies with smaller afterhyperpolarizations compared with other DA neurons. In contrast, all four DA populations possessed significant differences in I(h) channel densities and I(h) channel-mediated functional properties like sag amplitudes and rebound delays in the following order: SN/CB- --> VTA/CB- --> SN/CB+ --> VTA/CB+. Single-cell RT-multiplex PCR experiments demonstrated that differential calbindin but not calretinin expression is associated with differential I(h) channel densities. Only in SN/CB- DA neurons, however, I(h) channels were actively involved in pacemaker frequency control. In conclusion, diversity within the DA system is not restricted to distinct axonal projections and differences in synaptic connectivity, but also involves differences in postsynaptic conductances between neurochemically and topographically distinct DA neurons.
 ...
PMID:I(h) channels contribute to the different functional properties of identified dopaminergic subpopulations in the midbrain. 1185 Apr 57

Using a rat brain slice preparation, we investigated the role of energy impairment on the selective loss of dopamine neurons in the substantia nigra (SN). Brain slices (400 microm) were incubated at 35 degrees C for 2 h in the presence or absence of mitochondrial complex inhibitors, rotenone, MPP+, 3-nitropropionic acid, and antimycin A. Slices were also incubated in rotenone with excitatory amino acid (EAA) receptor antagonists, MK-801 and CNQX, to determine whether rotenone-induced damage was mediated by EAAs. The slices were then fixed, recut into 30-microm sections, and immunolabeled for tyrosine hydroxylase (TH) to identify catecholamine neurons and to quantify loss of TH-labeled dendrites after treatment. Quantitative comparison was made between SN dopamine neurons, in which rotenone-induced dendrite loss was severe, and hypothalamic A11 dopamine neurons, which were spared. Adjacent sections that were immunolabeled for calbindin or stained with cresyl violet also revealed a striking dendritic degeneration of SN neurons in rotenone-exposed slices, whereas noncatecholamine neurons, such as those in the perifornical nucleus (PeF), were more resistant. Preferential damage to SN dopamine neurons was also evident with other mitochondrial complex inhibitors, MPP+ and antimycin A. EAA receptor antagonists provided partial protection to SN neurons in slices incubated with rotenone (3 microM). The particular vulnerability of SN dopamine neurons in the slice is consistent with the vulnerability of SN in Parkinson's disease. The selective effect of mitochondrial complex inhibition in SN dopamine neurons implies a fundamental deficit in the capacity of these neurons to defend against toxic insult.
 ...
PMID:Mitochondrial complex inhibitors preferentially damage substantia nigra dopamine neurons in rat brain slices. 1250 67


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>