Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Sympathetic neurons in the superior cervical ganglion (SCG) of adult rats depend on target-derived nerve growth factor (NGF) for maintenance of tyrosine hydroxylase (TH) levels and the noradrenergic neurotransmitter system. Axotomy of a SCG results in NGF deprivation, causing a decline in TH activity; continuous local application of NGF can prevent this decline in TH activity. We now report that injection of a defective herpes simplex virus 1 vector that expresses NGF (pHSVngf) into a SCG can prevent the decline in TH activity that follows axotomy. SCG of adult rats were injected with either pHSVngf virus or pNFlac virus, which expresses Escherichia coli beta-galactosidase. Analysis of RNA from pHSVngf-infected SCG indicated that the NGF gene was efficiently transcribed and processed. Furthermore, 4 days after pHSVngf injection animals underwent axotomy of the virus-injected SCG. After another 10 days, animals were sacrificed and both the injected-axotomized and contralateral control ganglia were assayed for TH activity. Axotomy of SCG injected with pNFlac virus produced a 50% decline in TH activity relative to control ganglia (P = 0.02). In contrast, SCG injected with pHSVngf virus did not show a decline in TH activity following axotomy; instead, these ganglia manifested an 18% increase in TH levels relative to control ganglia. These data demonstrate that herpes simplex virus 1 vectors can be used to modify neuronal physiology in vivo; specifically, expression of a critical gene product by neural cells that do not normally produce it has potential applications for gene therapy.
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PMID:Expression of nerve growth factor in vivo from a defective herpes simplex virus 1 vector prevents effects of axotomy on sympathetic ganglia. 131 46

We combined Phaseolus vulgaris leucoagglutinin anterograde tracing and Herpes simplex virus transneuronal retrograde tracing to determine whether neurons in the vasodepressor region of the rabbit caudal ventrolateral medulla project to brainstem neurons containing the virus after its transneuronal transport from the adrenal medulla. Five days after adrenal injection of virus, 764 +/- 159 virus-positive neurons were found bilaterally in the brainstem: 61% in the C1 sympathoexcitatory region of the rostral ventrolateral medulla, 30% in the A5 region, 5% in the parapyramidal region, and 3% in the paraventricular nucleus of the hypothalamus. Many of the virus-positive neurons in the C1 and A5 areas also contained tyrosine hydroxylase and, in the parapyramidal area, many contained 5-hydroxytryptamine. After iontophoretic deposit of leucoagglutinin into the vasodepressor region of the caudal ventrolateral medulla, brain regions containing varicose processes labeled with leucoagglutinin included the regions containing virus-positive neurons. We examined the C1 and A5 regions following injections of both tracers in the same rabbits, leucoagglutinin into the caudal ventrolateral medulla and virus into the adrenal gland. Varicosities containing leucoagglutinin were seen in contiguity with perikarya and dendritic branches of neurons containing HSV1, in both the C1 and A5 regions. Studies also revealed labeled varicosities in contiguity with TH-containing C1 and A5 neurons. The projection from the caudal medulla to presumed sympathetic premotor neurons in the C1 area, including some C1 cells, represents a potential pathway whereby activity of neurons in the caudal medulla could reduce blood pressure by inhibiting sympathoexcitatory neurons in the rostral medulla.
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PMID:Projections from rabbit caudal medulla to C1 and A5 sympathetic premotor neurons, demonstrated with phaseolus leucoagglutinin and herpes simplex virus. 134 16

Several neurological diseases which affect the corpus striatum are candidates for gene therapy. We have developed a defective Herpes Simplex Virus (HSV-1) vector system to introduce genes into postmitotic cells, such as neurons. The prototype vector, pHSVlac, contains a transcription unit which places the E. coli Lac Z gene under the control of the HSV-1 immediate early (IE) 4/5 promoter, a constitutive promoter. We now demonstrate that a HSV-1 vector can deliver a gene into striatal neurons. Infection of cultured rat striatal neurons with pHSVlac virus resulted in stable expression of beta-galactosidase for at least two weeks, without cell death. The potential to replace the Lac Z gene with other genes of interest, such as the gene responsible for Huntington's Disease, once it is isolated, may lead to insights about the pathogenesis of this genetic neurodegenerative disease, and may provide a method for performing gene therapy on this disease. Similarly, introduction of the tyrosine hydroxylase gene, which encodes the rate-limiting enzyme in the conversion of tyrosine to dopamine, into striatal neurons might provide a novel gene therapy approach towards treating Parkinson's Disease.
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PMID:Infection of cultured striatal neurons with a defective HSV-1 vector: implications for gene therapy. 166 13

Herpes simplex virus type 1 (HSV1) was injected into either the aortic depressor nerve or the vagus nerve in the rabbit. Four or 5 days after injection of virus, the rabbit brain was processed immunohistochemically to demonstrate viral antigen. After injection into the aortic nerve HSV1 positive cells were found principally ipsilaterally within the nucleus tractus solitarius, area postrema, caudal and rostral ventrolateral medulla oblongata, the spinal trigeminal complex, raphe nuclei, A5 area, locus coeruleus, parabrachial nucleus, periaqueductal gray, ventrolateral hypothalamic area, paraventricular nucleus, amygdala, bed nucleus of the stria terminalis and insular cortex. Double labeling studies indicated that approximately 85% of the virus-containing neurons in the ventrolateral medulla, and virtually all the HSV-positive neurons in the A5 area and locus coeruleus also contained tyrosine hydroxylase. In the raphe nuclei and parapyramidal region approximately 33% of virus-containing cells reacted positively with PH8 antibody, a marker for serotonin synthesis. After injection of HSV1 into the vagus nerve labeled cells were found in similar brain areas, with a more bilateral distribution. The HSV-positive neurons may be involved in the processing of baroreceptor-derived information.
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PMID:Transneuronal labeling of neurons in rabbit brain after injection of herpes simplex virus type 1 into the aortic depressor nerve. 168 33

Herpes simplex virus type 1 (HSV1) was injected into the rat adrenal gland. After 3 days the rat CNS was processed immunohistochemically to demonstrate viral antigen. In the lower thoracic spinal cord viral antigen was found in neurons in the intermediolateral column. In the medulla oblongata HSV1-positive neurons were found in the raphe pallidus and in the C1 and C3 regions of the rostral medulla. Approximately 50% of HSV1-positive neurons in the C1 and all the HSV1-positive neurons in the C3 area also contained phenylethanolamine N-methyltransferase (PNMT) and were thus identified as C1 and C3 cells. The HSV1-positive neurons in the C1 region which did not contain PNMT were also negative for tyrosine hydroxylase and were therefore not catecholamine-synthesizing neurons. The HSV1-positive neurons in the medulla oblongata were presumably transsynaptically labelled from the adrenal gland and our study therefore provides neuroanatomical evidence supporting the view that some C1 neurons are involved in controlling the function of the adrenal gland.
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PMID:PNMT-containing neurons in the rostral medulla oblongata (C1, C3 groups) are transneuronally labelled after injection of herpes simplex virus type 1 into the adrenal gland. 255 51

During infection with herpes simplex virus type 1 (HSV-1) the activity of tyrosine hydroxylase (TH) in PC12 pheochromocytoma cells was initially depressed reaching a nadir at 6 hours post-inoculation, but recovered rapidly with a return to baseline activity by 8 to 9 hours post-inoculation. Subsequently, TH activity again fell with a second more variable rise in activity occurring at 24 hours post-inoculation. Studies with metabolic inhibitors and 2 temperature-sensitive viral mutants indicated that these alterations of TH activity were dissociated from morphological cytopathology and likely required expression of "late" viral gene products. Immunotitration using anti-TH antibody suggested that early depression of TH activity resulted principally from loss of enzyme protein rather than simple enzyme inactivation, and that reconstitution of activity at 9 hours was related to augmented enzyme synthesis. These observations illustrate the complexity of perturbed cellular metabolism during HSV-1 infection and suggest involvement of two unexpected processes: alteration of a specialized cell function as a result of viral genes expressed late in the replicative cycle, and augmented synthesis of a cell-coded gene product during the course of infection.
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PMID:Alteration of tyrosine hydroxylase activity in PC12 cells infected with herpes simplex virus type 1. 285 60

The activity of tyrosine hydroxylase (TH) was measured in the superior cervical ganglion (SCG) of the mouse during herpes simplex virus (HSV) infection. TH activity remained at control levels or actually increased during acute infection at a time when viral titers of SCG homogenates were at their peak and viral antigen was detected in from one-third to one-half of ganglionic neurons. A rapid decline in TH activity followed and coincided with falling viral titers, disappearance of viral antigen and replacement of neurons by inflammatory cells. Immunization partially prevented this reduction of TH activity. In addition, when mice were immunosuppressed by cyclophosphamide, TH activity was relatively preserved early in the course of infection despite high viral titers in the ganglion and the presence of viral antigen and histopathological alterations in nearly 100% of neurons. These results suggest that a cellular 'luxury function', in this case TH activity, can be preserved and perhaps even augmented during neuronal HSV infection. Indeed, activity of this enzyme may persist until late into the acute phase of infection, perhaps up to the point of cell death induced either by immune-mediated or direct virus-induced cell lysis.
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PMID:Tyrosine hydroxylase activity in the superior cervical ganglion during herpes simplex virus infection: correlation with viral titers and viral antigen. 611 38

Stereotactic intracerebral inoculation of a non-neuroadapted strain of herpes simplex virus type 1 into the left neostriatum of Sprague-Dawley rats induced clinical acute encephalitis within 3 to 5 days postinoculation, with microscopic evidence of inflammation in brain parenchyma, but with no gross areas of tissue destruction. Viral presence in brain was unequivocally confirmed by tissue culture, immunofluorescence and electron microscopy. Levels of activity of neurotransmitter synthesizing enzymes tyrosine hydroxylase (TH), glutamate decarboxylase (GAD), and choline acetyltransferase (ChAT) in the substantia nigra, caudate-putamen and frontal cortex of acutely encephalitic animals were not significantly different from those of PBS-inoculated controls; neither were there significant differences between the inoculated and non-inoculated sides of the individual animals. Our results show that locally injected herpes simplex virus may spread in brain causing neurological symptoms and death without major local structural changes or loss of neurotransmitter synthesizing enzymes. The degree and distribution of cell dysfunction and cell loss in viral encephalitis basically determine any alterations of enzyme activities specific to the involved cell population. The literature on neurotransmitter enzymes and experimental viral encephalitis is reviewed.
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PMID:Neurotransmitter synthesizing enzymes in experimental viral encephalitis. 613 11

One therapeutic approach to treating Parkinson's disease is to convert endogenous striatal cells into levo-3,4-dihydroxyphenylalanine (L-dopa)-producing cells. A defective herpes simplex virus type 1 vector expressing human tyrosine hydroxylase was delivered into the partially denervated striatum of 6-hydroxydopamine-lesioned rats, used as a model of Parkinson's disease. Efficient behavioral and biochemical recovery was maintained for 1 year after gene transfer. Biochemical recovery included increases in both striatal tyrosine hydroxylase enzyme activity and in extracellular dopamine concentrations. Persistence of human tyrosine hydroxylase was revealed by expression of RNA and immunoreactivity.
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PMID:Long-term behavioral recovery in parkinsonian rats by an HSV vector expressing tyrosine hydroxylase. 763 5

We mapped the distribution of virus-labelled neurons in the brain after injection of Herpes simplex virus type 1 (HSV1) into the rabbit renal nerve. Seven days after injection, labelled neurons were observed in four brain regions, the rostral ventrolateral medulla (47 +/- 3% of neurons), the A5 area of the lower pons (38 +/- 4%), the caudal raphe nuclei and the parapyramidal area of the medulla (13 +/- 2%), and the paraventricular nucleus of the hypothalamus (1 +/- 1%). In the rostral ventrolateral medulla approximately one half of the HSV1-labelled neurons also contained tyrosine hydroxylase, characterizing them as C1 neurons. In the A5 area virtually all HSV1-labelled neurons also contained tyrosine hydroxylase. In the raphe nuclei and the parapyramidal area 47% of HSV1-positive neurons contained serotonin. The distribution of labelled neurons was similar to that observed after injection of HSV1 into the adrenal gland.
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PMID:Transneuronal labelling of neurons in rabbit brain after injection of herpes simplex virus type 1 into the renal nerve. 767 86


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