Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.14.16.2 (tyrosine hydroxylase)
 14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Embryonic striatal grafts develop a modular organization in which patches of tissue enriched in many transmitter substances characteristic of striatum (P regions) are embedded in surrounds (NP regions) expressing only low levels of these substances. Catecholaminergic fibers from the host brain, identified by their expression of tyrosine hydroxylase (TH), grow into such grafts and selectively terminate in the striatum-like P regions. This terminal pattern suggests that cell-cell affinities between neurons of the substantia nigra and striatum may play a role either in the aggregation of the striatal cells into P regions, or in the targeting of the TH-positive fibers to the cell clusters. In the present study, we tested the first of these possibilities. Striatal grafts derived from embryonic day 15 striatal primordia were implanted into the ibotenate-damaged host striatum of rats previously treated with 6-hydroxydopamine (6-OHDA) to destroy TH-containing dopaminergic nigrostriatal afferents. The 6-OHDA lesions that eliminated nearly all TH-like immunostaining in the host striatum also resulted in disappearance of nearly all TH-positive fibers in the grafts. In this dopamine-depleted environment, the grafts nevertheless developed a clear modular organization. They contained striatum-like patches with neurons expressing many of the neurochemicals characteristic of striatum (ACh, ChAT, calbindin-D28KD, met-enkephalin, and dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein-32,000 or DARPP-32), and these patches were surrounded by graft tissue expressing few of these striatal markers. These observations suggest that the ingrowth of TH-positive fibers from the host is not obligatory for the sorting out of striatal from nonstriatal cells during the formation of P regions in embryonic striatal grafts. Despite the fact that dopaminergic denervation of the host striatum did not disrupt either the aggregation of grafted cells into P regions or the acquisition of striatal neurochemical phenotypes by cells in the P regions, there were clear differences between the staining patterns of these grafts and grafts placed into dopamine-innervated striatum. Most striking was a sharp increase of met-enkephalin-like immunostaining in the P zones of the denervated grafts. Upregulation of met-enkephalin is known to occur in the dopamine-depleted mature striatum, and was observed in the parts of host striatum surrounding the grafts on the side ipsilateral to the 6-OHDA lesions. This result suggests that functional interactions between dopaminergic and enkephalinergic systems can occur in the striatal circuits reconstructed by embryonic striatal grafting. More generally, our results suggest that TH-containing afferents from the host striatum, though not required for induction and maintenance of striatal phenotypy in striatal grafts, can chronically regulate neurotransmitter/neuromodulator expression in neurons of the striatum-like P zones in a manner similar to that found for the normal striatum.
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PMID:Influence of mesostriatal afferents on the development and transmitter regulation of intrastriatal grafts derived from embryonic striatal primordia. 127 38

Homotopic transplantation provides an interesting way to observe the relationships between developing cells and ingrowing host afferents. We have performed a complete and selective elimination of the mesostriatal dopaminergic system in adult rats to observe the influence of its absence on the development and chemical differentiation of embryonic striatal cells. Cell suspensions from striatal primordia of 14-15-day-old embryos were transplanted into host striata that were (i) neuron-depleted by kainic acid (control group) or (ii) deprived of dopamine by 6-hydroxydopamine prior to the neuronal depletion by kainic acid (experimental group). The expression of dopamine- and adenosine 3',5'-monophosphate-regulated phosphoprotein (DARPP-32) by transplanted cells was observed in correlation with their innervation by host dopaminergic afferents which in turn were identified by tyrosine hydroxylase immunohistochemistry. Observations were made between four days and three months after transplantation. Four days after transplantation, no immunoreactivity for DARPP-32 was observed in transplants of control animals despite the presence of tyrosine hydroxylase-immunopositive fibers growing from the host to discrete cell clusters in the transplant. DARPP-32-labeled cells appeared soon afterwards. Six days after transplantation they displayed varying intensities of immunoreaction, ranging from just detectable to normal levels and were specifically targeted by developing tyrosine hydroxylase-immunopositive fibers. The number of DARPP-32-labeled cells increased rapidly and they formed increasingly compact clusters. Fourteen days after transplantation and afterwards, all the DARPP-32-labeled cells displayed an intensity of immunoreaction and a distribution comparable to that observed in long-term transplants. Transplants in the experimental hosts displayed the same organization and developmental features as the control transplants with the exception of DARPP-32 labeling which was not detected before eight days after transplantation. Ten days after transplantation, the distribution and intensity of DARPP-32 labeling was similar to that observed at six days in the control group. The evolution of DARPP-32 labeling after 10 days in the experimental group paralleled that observed six days post-transplantation and beyond in the control group. Dopaminergic mesostriatal host afferents are able to provide developing cells in grafted striatal tissues with normal innervation very rapidly. Despite this rapidity, the innervation does not seem to have any trophic influence on the general development of the transplant but does affect the onset time of the expression of neurochemical markers that are directly related to its synaptic function.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Host dopaminergic afferents affect the development of DARPP-32 immunoreactivity in transplanted embryonic striatal neurons. 135 65

To evaluate the development of striatal ischemic cell damage in relation to alterations in dopamine (DA) transmission, one year old male Wistar rats underwent a 15 min incomplete cerebral ischemia (ICI) induced by occlusion of the common carotid arteries and by hypovolemic hypotension. The animals were divided into the following experimental groups: sham operated rats, rats with ICI without reperfusion, and rats with ICI followed by 60 min, 24 h, 72 h and 144 h of recirculation. The ischemia induced striatal lesions were investigated in serial coronal brain sections, stained with cresylviolet or immunostained for dopamine and cAMP regulated phosphoprotein (DARPP-32), for tyrosine hydroxylase (TH) and for glial fibrillary acidic protein (GFAP) immunoreactivities (IR). Measurements of striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels were made on analogous experimental groups using HPLC methods. Signs of degeneration in small to medium sized neurons were already seen after 60 min of postischemic reperfusion together with slight decreases of DARPP-32 IR and increases of GFAP IR. The damage continued to increase up to 144 h, and after 24 h of recirculation there were clearly defined areas of reduced DARPP-32 IR, overlapping with increased TH IR and increased GFAP IR. The levels of DA, DOPAC and HVA increased sharply after 60 min (151%, 462% and 201%, respectively) remained high after 24 h and normalized after 72 h of recirculation. The DA metabolism was high after 60 min and had already normalized after 24 h of recirculation. The increased DA metabolism in striatal nerve terminals in response to ischemic injury may reflect an early degenerative change in the DA terminals. The long-lasting increase in TH IR may to some extent represent an adaptive change in response to the disappearance of DA receptor-containing nerve cells. Based on the present findings it is possible that an increased D1 transmission in neostriatum immediately following the ischemic injury may contribute to striatal nerve cell degeneration in which an enhancement of NMDA receptor transduction may be implicated.
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PMID:Changes in striatal dopamine neurohistochemistry and biochemistry after incomplete transient cerebral ischemia in the rat. 166 38

Cocaine, a catecholamine agonist, has been shown to produce a transient induction of the immediate-early gene c-fos and its protein product Fos in the striatum of normal rats. In the present study we report that the expression of Fos can be induced by cocaine challenge in intrastriatal grafts derived from cell suspensions of embryonic striatal primordia. Fos-like immunoreactivity in the nuclei of grafted neurons was detected 2 hr after the injection of 50 mg/kg cocaine into the host rats. Neurons with Fos-immunoreactive nuclei tended to form clusters in the striatal grafts. The Fos-rich clusters were aligned with acetylcholinesterase (AChE)-rich and tyrosine hydroxylase (TH)-rich patches demonstrated in adjoining sections. Previous studies have shown that presynaptic and postsynaptic cellular markers of the dopaminergic system in the striatum, including immunostaining for TH and dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein (DARPP-32), and binding for high affinity dopamine uptake sites and for dopamine D1 and D2 receptor sites, are all concentrated in the AChE-rich patch regions (P regions) of such embryonic striatal grafts. The preferential expression of Fos in neurons of the P regions of the grafts thus implies that the induction of Fos was cell-type specific in being concentrated in the parts of the grafts that express striatal phenotype and that are innervated by catecholamine-containing fibers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intrastriatal grafts derived from fetal striatal primordia. III. Induction of modular patterns of fos-like immunoreactivity by cocaine. 168 Jul 35

The morphological maturation of cell suspension grafts of fetal striatal tissue (obtained from 14-15-day-old rat fetuses) was followed from two days to eight weeks after implantation into intact and ibotenic acid-lesioned striata of adult rats. The development of host afferent innervation of the grafts from the substantia nigra (tyrosine hydroxylase immunoreactive), mesencephalic raphe (serotonin immunoreactive), and the frontal cortex (anterogradely labelled with Phaseolus vulgaris leucoagglutinin) were revealed by immunohistochemistry. During the first weeks post-grafting, the striatal implants consisted of a mixture of mature- and immature-looking cell clusters. Grafts implanted into ibotenic acid-lesioned striatum grew rapidly (about five-fold) in volume over the first week. The areas of immature (probably proliferating) cells gradually disappeared, and by six to eight weeks the grafts had a fully mature appearance with patches of neurons which stained densely for DARPP-32 (i.e. were striatum-like) embedded within areas of essentially DARPP-32-negative (i.e. non-striatum-like) tissue. Peripheral clusters of grafted cells gradually intermingled with nearby areas of the surrounding lesioned host, and already by two to four days after implantation, coarse and densely immunoreactive host fibres from the substantia nigra, mesencephalic raphe and frontal cortex were present within the grafts. By four to five days the first DARPP-32-immunoreactive neurons appeared in patches within the mature portions of the grafts, and one to two days later the tyrosine hydroxylase-positive fibres began to sprout thin axons selectively within the DARPP-32-positive patches. Similarly, the serotonergic and cortical fibres in the grafts increased in number over the next two weeks, but they showed no preference for the DARPP-32-positive regions. Rich terminal networks were established by two to three weeks post-grafting, and by six to eight weeks the nigral, raphe and cortical afferents had reached terminal densities similar to those seen previously in long-term surviving grafts. Grafts implanted into dopamine-denervated hosts showed a normal morphological maturation of both DARPP-32-positive and -negative areas, although no tyrosine hydroxylase-positive innervation appeared within the grafts. Grafts implanted into non-lesioned striata did not grow beyond their initial size. The implanted cells showed less intermingling with the surrounding host striatum, thus resulting in sharply delineated graft-host borders. DARPP-32-positive patches developed, but they were smaller in size and generally present only in the most peripheral graft portions.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Development of intrastriatal striatal grafts and their afferent innervation from the host. 171 46

The distribution and morphology of neurons containing the dopamine- and cyclic AMP-regulated phosphoprotein, DARPP-32, were investigated in the bed nucleus of the stria terminalis (BST) and the central nucleus of the amygdala (CeA). DARPP-32 immunoreactive neurons are numerous in both regions, but are restricted to the lateral dorsal and the lateral juxtacapsular subdivisions of the BST, and the central lateral and lateral capsular subdivisions of the CeA. Immunoreactive neurons in the lateral dorsal BST, and the central lateral and lateral capsular CeA are similar morphologically, while those in the juxtacapsular BST appear to be a subpopulation of striatal medium-sized spiny neurons. The distribution of DARPP-32 immunoreactive neurons in the BST and CeA overlaps considerably with axonal plexuses containing tyrosine hydroxylase (TH), vasoactive intestinal polypeptide (VIP), and calcitonin gene-related peptide (CGRP). These studies provide further evidence of the close relationship between the CeA and BST, and also provide anatomical evidence for possible interactions between neurotransmitters, neuropeptides, and phosphoproteins.
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PMID:Localization of DARPP-32 immunoreactive neurons in the bed nucleus of the stria terminalis and central nucleus of the amygdala: co-distribution with axons containing tyrosine hydroxylase, vasoactive intestinal polypeptide, and calcitonin gene-related peptide. 197 Dec 24

DARPP-32, a dopamine- and adenosine 3':5'-monophosphate regulated neuronal phosphoprotein, Mr 32 kDa, is a phenotypic marker of the medium-size spiny neurons of the mammalian caudate-putamen. In the present study, we examined the ontogeny of DARPP-32 protein and mRNA, and compared it to the ontogeny of tyrosine hydroxylase and synapsin I, a synaptic-vesicle phosphoprotein. In vivo, the amount of DARPP-32 protein per mg total protein increased throughout the first three postnatal weeks, and then declined to plateau at adult levels. The mRNA level closely paralleled the protein, except that its rise preceded that of the protein. Tyrosine hydroxylase levels rose throughout the first 4 postnatal weeks, and synapsin I levels rose steadily during the same period. Primary reaggregate cultures containing cells from the caudate-putamen expressed DARPP-32 with a time course similar to that seen in vivo. The level of expression was not altered by coculturing with dopaminergic neurons from the rostral mesencephalic tegmentum. Thus, the postnatal increase in DARPP-32 levels in the caudate-putamen appears to be independent of transsynaptic or end-organ influences from the substantia nigra.
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PMID:DARPP-32 development in the caudate nucleus is independent of afferent input from the substantia nigra. 197 75

We used the dopaminergic neurotoxicant, 1-methyl-1,2,3,6-tetrahydropyridine (MPTP), as a tool to characterize the origins of astroglial response to injury. Radioimmunoassay of the astrocyte protein, glial fibrillary acidic protein (GFAP), was used to quantify the astrocyte reaction to MPTP. Assays of neuron-localized proteins and of dopamine were used to assess neuronal damage caused by MPTP. A single administration of MPTP (12.5 mg/kg, s.c.) to the C57BL/6J mouse resulted in more than a 3-fold increase in striatal GFAP within 48 h, followed by a decline to baseline at 3 weeks. A decrease in the amount of striatal tyrosine hydroxylase (TH), a marker of dopaminergic neurons, preceded the rise in GFAP. The concentration of striatal DARPP-32, a phosphoprotein enriched in neurons receiving dopaminergic input, was not affected by MPTP. Protecting the dopaminergic neurons from the neurotoxic metabolite of MPTP, 1-methyl-4-phenylpyridinium (MPP+), either by blocking its formation or by preventing its uptake into dopaminergic neurons, completely blocked the increase in GFAP. MPTP did not appear to disrupt the blood-brain barrier, therefore, blood-borne elements probably did not mediate the increase in GFAP. In addition, immunoblot data indicated that brain-derived interleukin 1, an astrocyte growth factor, also did not play a role in MPTP-induced gliosis. Together, these findings suggest that diffusible factors derived from damaged dopaminergic neurons initiate the astrocyte response to MPTP and that large increases in GFAP can be induced without the participation of serum-derived growth factor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of the origins of astrocyte response to injury using the dopaminergic neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 197 16

Newborn male Sprague-Dawley rats were treated neonatally with an intracisternal injection of 75 micrograms 6-hydroxydopamine (6-OHDA) following desipramine pretreatment in order to induce a permanent selective dopamine (DA) lesion. At 60-70 days of age a massive loss of tyrosine hydroxylase (TH) immunoreactive (IR) cells was seen in substantia nigra. The TH-IR terminal density was reduced by 92% in striatum, 77% in nucleus accumbens and by 72% in tuberculum olfactorium. Quantitative autoradiography using 3H-SCH-23390 and 3H-spiperone did not reveal any alteration of DA D1 and D2 receptor binding in the denervated regions studied. Furthermore, no change in the Bmax or Kd of 3H-SCH-23390 or 3H-spiperone in vitro binding was observed in membrane preparations of striatum following the neonatal DA lesion. Basal and DA-stimulated accumulation of cAMP was increased in striatal membrane preparations of the neonatally DA-lesioned rats. No alteration of the immunoreactivity of the D1 receptor associated phosphoprotein dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein (DARPP-32), was observed as visualized using quantitative immunohistochemistry. Thus, neonatal DA lesions seem to induce a selective functional supersensitivity reflected by an enhanced activity of D1 receptor-coupled adenylate cyclase, without any alteration in the number of affinity of D1 and D2 receptor sites. Furthermore, the appearance of DARPP-32 seems to be independent of intact DA input during development.
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PMID:Neonatal dopamine lesion in the rat results in enhanced adenylate cyclase activity without altering dopamine receptor binding or dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein (DARPP-32) immunoreactivity. 198 64

Antibodies to tyrosine hydroxylase and DARPP-32 were used to examine the spatial arrangement between mesostriatal dopamine projections and the reciprocal pathway from DARPP-32-containing neurons in the basal forebrain. Use of a double-labeling immunocytochemical procedure demonstrated that the mesostriatal and striatonigral pathways run in close proximity throughout the rostral mesencephalon and basal forebrain. The majority of descending axons immunoreactive for DARPP-32 appear to originate in the striatum, including the nucleus accumbens, and run through the internal capsule to innervate the globus pallidus, entopeduncular nucleus, and all subdivisions of the substantia nigra. The ventral tegmental area is sparsely invested with DARPP-32-immunoreactive axons. At all levels, there are also fascicles of DARPP-32-containing fibers which run ventromedial to the internal capsule in the medial forebrain bundle, and which are coextensive with ascending axons of the mesencephalic dopamine the internal capsule in the medial forebrain bundle, and which are coextensive with ascending axons of the mesencephalic dopamine cell groups. Tyrosine hydroxylase-immunoreactive axons are coextensive with DARPP-32-immunoreactive axons in the internal capsule entopeduncular nucleus, and globus pallidus, as well as much of the remainder of the basal forebrain. Although the main source of descending DARPP-32 immunoreactive axons would appear to be the striatum, other possible sources are also discussed.
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PMID:Spatial relationship of the striatonigral and mesostriatal pathways: double-label immunocytochemistry for DARPP-32 and tyrosine hydroxylase. 256 11


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