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

GM1 ganglioside administration has previously been shown to increase striatal dopamine levels and to enhance the density of tyrosine hydroxylase-positive fibers in the striatum of monkeys made parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The present study examined the extent to which GM1 administration promotes recovery of dopamine terminals and reverses lesion-induced changes in postsynaptic receptors in the striatum of MPTP-treated monkeys. All MPTP-treated animals developed severe parkinsonism. GM1-treated monkeys exhibited significant functional recovery after 6 weeks of treatment, whereas saline-treated controls remained parkinsonian over the same time period. MPTP exposure resulted in profound decreases in [(3)H]-mazindol binding to dopamine transporters in the caudate and putamen and increased D1 and D2 receptor binding in several striatal regions. GM1 treatment resulted in significant increases in striatal [(3)H]-mazindol binding and decreases in D1 binding compared to control animals in many striatal regions. GM1 treatment did not significantly affect D2 binding. These results show that GM1 treatment can partially restore striatal dopaminergic terminals and partially reverse postsynaptic changes in dopamine receptors in a nonhuman primate model of parkinsonism.
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PMID:Effects of GM1 ganglioside treatment on pre- and postsynaptic dopaminergic markers in the striatum of parkinsonian monkeys. 1076 59

Cryopreservation may allow long-term storage of embryonic ventral mesencephalon (VM) for neural transplantation. We investigated whether the ganglioside GM1 or the lazaroid tirilazad mesylate (U-74006F) could improve survival of grafts derived from cryopreserved VM in a rat model of Parkinson's disease. VM was dissected from rat embryos (E14-E15), frozen and stored in liquid nitrogen under controlled conditions, thawed, dissociated, and then grafted into the 6-hydroxydopamine-lesioned rat striatum. In Experiment I, VM fragments were exposed in vitro either to GM1 (100 microM) or to lazaroid (0.3 microM) during all preparative steps. In Experiment II, rats receiving GM1-pretreated VM were, in addition, treated systematically with GM1 (30 mg/kg) daily for 3.5 weeks. Rats grafted with untreated cryopreserved or fresh VM were used as controls, respectively. Rats receiving fresh VM control grafts showed complete recovery from lesion-induced rotations after 6 weeks whereas rats grafted with cryopreserved VM (untreated or pretreated) did not recover. Cryografts contained significantly less (18%, control; 23%, GM1; and 12%, lazaroid) tyrosine hydroxylase-positive cells compared to fresh grafts (1415 +/- 153; mean +/- SEM). Graft volume was also significantly smaller after cryopreservation. In contrast, with additional systemic GM1 treatment cryografts contained almost the same number of tyrosine hydroxylase-positive cells (376 +/- 85) as fresh grafts (404 +/- 56), which was significantly more than that of untreated cryografts (147 +/- 20), showed a significantly larger volume (0.15 mm(3)) compared to that of untreated grafts (0.08 mm(3)) (fresh controls, 0.19 mm(3)), and induced significant and complete functional recovery in the rotation test. In conclusion, systemic treatment of rats with GM1 improved the low survival and functional inefficacy of grafts derived from cryopreserved VM whereas tissue pretreatment alone with either GM1 or lazaroid was not effective.
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PMID:Systemic treatment with GM1 ganglioside improves survival and function of cryopreserved embryonic midbrain grafted to the 6-hydroxydopamine-lesioned rat striatum. 1087 22

Adrenal autotransplantation is a widely used approach to investigate the potential for neural modulation of adrenal cortical function. It is believed that regenerating adrenal transplants are not reinnervated, thereby providing a model to investigate adrenal function in the absence of neural modulation. However, the hypothesis that adrenal transplants become reinnervated has not been directly tested. The purpose of the present study was to characterize the time course, extent, and nature of the reinnervation of the regenerating adrenal transplant and to assess whether the recovery of steroidogenic function and enzyme expression correlates temporally with the presence of innervation. Using immunohistofluorescent detection of tyrosine hydroxylase (TH), neuropeptide Y (NPY), calcitonin gene-related peptide (CGRP), and vasoactive intestinal peptide (VIP), the innervation of regenerating adrenals was assessed 14-30 days after transplantation of adrenal capsules beneath the kidney capsule in rats. Extensive reinnervation by TH-, NPY-, and VIP-positive fibres was present by 14 days after transplantation including regions of the adrenal capsule and cortex, with only minimal reinnervation by CGRP-positive fibres up to 30 days. TH- and NPY-positive chromaffin cells were also observed in the regenerating transplants. In addition, there was marked recovery of steroidogenic function and steroidogenic enzyme expression up to 30 days. The finding that nerve fibres are present in the transplants during the re-establishment of steroidogenic function and enzyme expression suggests that innervation may modulate the regeneration and functional recovery of adrenal transplants. In an attempt to prevent reinnervation of transplants, adrenal capsules were autotransplanted to denervated kidneys. Immunohistochemical analysis showed that, despite extensive denervation of the kidney tissue, the reinnervation and regeneration of the adrenal transplants still occurred. These data demonstrate the marked capacity of the regenerating adrenal to become reinnervated and reinforces the conclusion that adrenal transplants are an invalid model of denervated adrenal cortical tissue.
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PMID:Rat adrenal transplants are reinnervated: an invalid model of denervated adrenal cortical tissue. 1097 13

Delta enkephalin analogue [D-Ala(2),D-Leu(5)]enkephalin (DADLE) has been shown to protect dopamine transporters from methamphetamine-induced neurotoxicity. In the present study, we demonstrate that exposure of embryonic ventral mesencephalic cells to DADLE (0.01 g/ml), prior to intrastriatal transplantation, enhanced functional recovery and graft survival in 6-hydroxydopamine-induced hemiparkinsonian rats. At 6 and 8 weeks posttransplantation, animals that received DADLE-treated cell grafts exhibited significantly higher (near normal) spontaneous locomotor behaviors, as well as trends of greater reversal of motor asymmetrical behaviors compared with animals that received nontreated cell grafts. Histological examination revealed that animals transplanted with DADLE-treated cell grafts exhibited about twice the number of surviving tyrosine hydroxylase-immunoreactive grafted neurons compared with those animals that received nontreated cell grafts. These results suggest that DADLE should be considered as an adjunctive agent for neural transplantation therapy in Parkinson's disease.
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PMID:Delta opioid peptide augments functional effects and intrastriatal graft survival of rat fetal ventral mesencephalic cells. 1129 72

The present study was performed to investigate the influence of intrastriatal fetal mesencephalic grafts on dopaminergic mRNA expression in the non-lesioned substantia nigra pars compacta of unilaterally 6-hydroxydopamine-lesioned rats. The expression of dopamine transporter mRNA, synaptic vesicular monoamine transporter mRNA and tyrosine hydroxylase mRNA was assessed in adjacent cryostat sections using in situ hybridization. Rotational behavior induced by apomorphine and amphetamine as well as hybridization of striatal sections cut at the grafting coordinates were used to prove the functional recovery and the presence of grafted cells, respectively. After grafting, the number of rotations was decreased and hybridization signals overlying cells in the grafted striatum were detected. Mean grain densities overlying labeled neurons in the substantia nigra pars compacta of grafted rats were compared to those of shamgrafted rats and revealed differential expression of dopamine transporter mRNA, whereas synaptic vesicular monoamine transporter mRNA and tyrosine hydroxylase mRNA expression showed no difference. The results will be discussed in relation to previous in vitro and in vivo studies suggesting a reduction of functional dopamine transporter molecules in the contralateral striatum.
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PMID:Dopaminergic mRNA expression in the intact substantia nigra of unilaterally 6-OHDA-lesioned and grafted rats: an in situ hybridization study. 1131 69

One of the critical variables that influences the efficacy of clinical neural transplantation for Parkinson's disease (PD) is optimal graft placement. The current transplantation paradigm that focuses on ectopic placement of fetal grafts in the striatum (ST) fails to reconstruct the basal ganglia circuitry or normalize neuronal activity in important basal ganglia structures, such as the substantia nigra (SN) and the subthalamic nucleus (STN). The aim of this study was to investigate a multitarget neural transplantation strategy for PD by assessing whether simultaneous dopaminergic transplants in the ST, SN, and STN induce functional recovery in hemiparkinsonian rats. Forty-six female Wistar rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway were randomly divided into eight groups and received lesions only or injections of 900,000 embryonic rat ventral mesencephalic cells in the (1) ST, (2) SN, (3) STN, (4) ST and SN, (5) ST, SN, and STN, (6) ST and STN, or (7) SN and STN. The number of cells transplanted was equally divided among grafting sites. Animals with two grafts received 450,000 cells in each structure, and animals with three grafts received 300,000 cells per structure. Recovery was assessed by amphetamine-induced rotations and the stepping tests. Graft survival was assessed using tyrosine hydroxylase immunohistochemistry. At 8 weeks after transplantation, simultaneous dopaminergic transplants in the ST, SN, and STN induced significant improvement in rotational behavior and stepping test scores. Intrastriatal transplants were associated with significant recovery of rotational asymmetry, whereas SN and STN transplants were associated with improved forelimb function scores. These results suggest that restoration of dopaminergic activity to multiple basal ganglia targets, such as the ST and SN, or the ST and STN, promotes a more complete functional recovery of complex sensorimotor behaviors. A multitarget transplant strategy aimed at optimizing dopaminergic reinnervation of the basal ganglia may be crucial in improving clinical outcomes in PD patients.
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PMID:Enhancement of sensorimotor behavioral recovery in hemiparkinsonian rats with intrastriatal, intranigral, and intrasubthalamic nucleus dopaminergic transplants. 1133 81

Chronic (8- to 10-week) administration of the selective, potent, and irreversible monoamine oxidase B inhibitor (R)-deprenyl has been shown to increase the tyrosine hydroxylase immunoreactivity in the substantia nigra of mice that had been treated three days earlier with a neurotoxic dose of the parkinsonian-inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This reported rescuing of lesioned nigrostriatal cell bodies by (R)-deprenyl prompted us to investigate if this (R)-deprenyl treatment also could restore neostriatal dopamine levels that are depleted by MPTP. The results of these experiments show that long term (8 or 10 weeks) treatment with (R)-deprenyl beginning three days post MPTP administration did not result in restoration of depleted neostriatal dopamine levels in C57BL/6 mice. We conclude that, although (R)-deprenyl may rescue MPTP-injured nigrostriatal neurons, it does not lead to functional recovery of these neurons as measured by the restoration of neostriatal dopamine levels.
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PMID:Rescue of dying neurons by (R)-deprenyl in the MPTP-mouse model of Parkinson's disease does not include restoration of neostriatal dopamine. 1146 89

1-Methyl-4-phenyl-1,2,3,6-tetrahyrdropyridine (MPTP)-exposed cats develop severe Parkinsonism that spontaneously resolves in 4-6 weeks. The present study examined the extent to which compensatory changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) gene and protein expression may underlie this behavioral recovery. In normal cats, TH and DAT protein levels were higher in the dorsal vs. ventral striatum. Expression of DAT and TH mRNA was higher in substantia nigra pars compacta (SNc) than in the ventral tegmental area (VTA). In symptomatic parkinsonian animals, DAT and TH protein levels were significantly decreased in all striatal areas studied. TH and DAT mRNA expression in residual SNc neurons were decreased a mean 32% and 38%, respectively. DAT gene expression in residual VTA neurons in symptomatic animals was decreased 30% whereas TH gene expression was unaffected. In spontaneously recovered cats, TH protein levels were significantly higher than the levels in symptomatic cats only in the ventral striatum, whereas no increase in DAT protein levels were observed in any striatal area. Residual neurons in most ventral mesencephalic regions of recovered cats had increased TH mRNA expression but not increased DAT gene expression, compared with symptomatic animals. Thus, increased TH protein and mRNA and suppression of DAT protein and mRNA expression in the striatum and ventral mesencephalon were associated with functional recovery from MPTP-induced parkinsonism.
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PMID:Tyrosine hydroxylase and dopamine transporter expression in residual dopaminergic neurons: potential contributors to spontaneous recovery from experimental Parkinsonism. 1149 60

Clinical and experimental grafting in Parkinson's disease has shown the need for enhanced survival of dopamine neurons to obtain improved functional recovery. In addition, it has been suggested that a limited number of surviving dopamine neurons project to the dopamine-denervated host striatum. The aim of this study was to investigate if subpopulations of ventral mesencephalic dopamine neurons project to their normal targets, i.e., dorsal vs. ventral striatum. Following implantation of human ventral mesencepahlic tissue into the lateral ventricle of dopamine-depleted rats, human-derived dopamine reinnervation was achieved both in dorsal and ventral striatum. Treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) resulted in a degeneration of tyrosine hydroxylase (TH)-immunoreactive nerve fibers in dorsal striatum but not in ventral areas in some animals, while MPTP was without effect in other animals. TH-immunoreactive neurons were small and appeared shrunken in animals carrying grafts affected by the MPTP treatment. In conclusion, grafted dopamine neurons projected nerve fibers into areas that they normally innervate. Thus, when searching for factors that may enhance survival of grafted dopamine neurons it is important to study which subpopulation(s) of ventral mesencephalic dopamine neurons is affected, such that a proper reinnervation may be achieved.
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PMID:Evidence for target-specific outgrowth from subpopulations of grafted human dopamine neurons. 1151 85

Adult C57BL/6 mice were injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Intrastriatal transplantation of bone marrow stromal cells (MSCs) was performed 1 week after MPTP administration. MSCs were harvested from donor adult mice, and then cultured and prelabeled with bromodeoxyuridine (BrdU). MPTP-Parkinson's disease (PD) mice treated with intrastriatal injection of phosphate-buffered saline (PBS), and normal non-MPTP mice were used as controls. MPTP-PD mice with MSC intrastriatal transplantation exhibit significant improvement on the rotarod test (P<0.05) at day 35 compared with PBS controls. Immunohistochemistry shows that BrdU reactive cells survive in the transplanted areas in the MPTP-PD striatum at least 4 weeks after administration. Scattered BrdU reactive cells express tyrosine hydroxylase (TH) immunoreactivity. Our findings suggest that MSCs injected intrastriatally survive, express dopaminergic protein TH immunoreactivity, and promote functional recovery.
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PMID:Intracerebral transplantation of bone marrow stromal cells in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. 1174 17


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