Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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We examined the effects of electrical stimulation (ES) of right A1 noradrenergic cells on temporal changes in tyrosine hydroxylase (TH) mRNA levels in A1, A2 and locus ceruleus (LC) neurons by in situ hybridization histochemistry and quantitative image analysis methods. The stimulation parameters used previously have been shown to increase hypothalamic norepinephrine (NE) release. Within 1 h after beginning A1 stimulation, TH mRNA levels were significantly increased and they continued to rise to reach plateau by 6 h. TH message levels at 12 h were not difference from 6 h values. A1-ES did not affect TH mRNA levels in contralateral A1 or in A2 or locus ceruleus neurons. These data suggest that changes in TH mRNA levels may serve as an index of increased A1 neuronal activity in circumstances when increases in hypothalamic NE secretion occur.
Brain Res Mol Brain Res 1992 Mar
PMID:Temporal changes in tyrosine hydroxylase mRNA levels in A1, A2 and locus ceruleus neurons following electrical stimulation of A1 noradrenergic neurons. 134 22

Selegiline, a selective monoamine oxidase type B inhibitor, is beneficial in the treatment of Parkinson's disease. However, this beneficial effect is only transient, and patients must ultimately resort to treatment with standard levodopa therapy. We studied the effects of chronic selegiline treatment on the rat nigrostriatal pathway, to elucidate a neurochemical correlate for this adaptive clinical response. Selegiline treatment for 3, 7, 14, or 21 days decreased tyrosine hydroxylase (the enzyme that catalyzes the rate-limiting step in catecholamine biosynthesis) activity in the cell body regions (substantia nigra) of the nigrostriatal pathway. However, tyrosine hydroxylase activity measurements in the major terminal field region (corpus striatum) of the pathway did not correspond to those in the substantia nigra; in the corpus striatum, tyrosine hydroxylase activity was decreased at 3 and 7 days of treatment and recovered by 14 days. We tested whether the decrease in tyrosine hydroxylase activity was mediated by a decrease in tyrosine hydroxylase mRNA. Northern blot and RNA dot blot analyses (using a tyrosine hydroxylase-specific cDNA probe) of substantia nigra homogenates revealed a significant decrease in tyrosine hydroxylase mRNA at 3, 7, and 14 days of selegiline treatment, compared with controls. Conversely, after 21 days of selegiline, tyrosine hydroxylase mRNA levels were significantly higher (3-fold) than controls; this finding was not reflected in substantia nigra tyrosine hydroxylase activity. The 21-day increase in mRNA may be associated with the rebound in tyrosine hydroxylase activity observed in the corpus striatum. Thus, it is possible that the recovery in tyrosine hydroxylase activity in the corpus striatum is mediated through an increase in tyrosine hydroxylase protein transport from the substantia nigra to the corpus striatum and/or that the tyrosine hydroxylase enzyme exists in a more stabilized state during this period of time. These results demonstrate that monoamine oxidase type B-selective inhibitory doses of selegiline are capable of inducing transient decreases in tyrosine hydroxylase activity and tyrosine hydroxylase mRNA levels. Furthermore, these reversible effects may represent adaptive responses associated with pharmacological tolerance and the transient beneficial actions of this drug in Parkinson's disease.
Mol Pharmacol 1992 May
PMID:Chronic selegiline administration transiently decreases tyrosine hydroxylase activity and mRNA in the rat nigrostriatal pathway. 135 Mar 20

These studies examined the effects of reserpine on concentrations of norepinephrine (NE), dopamine (DA) and epinephrine (EPI) and on levels of tyrosine hydroxylase (TH) mRNA in locus coeruleus (LC) and medullary A1 and A2 neurons. Noradrenergic neurons in these regions first were identified by immunocytochemistry and, thereafter, by in situ hybridization histochemistry. Levels of TH mRNA were measured by quantitative image analysis methods. Changes in catecholamine concentrations in micropunches of these brain regions were analyzed by HPLC. Epinephrine was not detected in any of the nuclei examined. Twenty-four hours after reserpine treatment, NE concentrations declined in A1, A2 and LC neurons by 46, 69 and 34% respectively while DA declined only in the region of A2 neurons. This reserpine-induced depletion of NE was accompanied by a 2- to 3-fold increase in TH mRNA levels in LC and A1 neurons but no change in message levels occurred in A2 cells 24 h after reserpine. Forty eight hours later, message levels in A1 and LC neurons did not differ significantly from the elevated 24 h values but TH mRNA levels in A2 neurons now were significantly elevated compared to 24 h values. TH mRNA levels 72 h after reserpine did not differ from 48 h values in A1, A2 and LC neurons. Thus, TH gene expression in A1 neurons increases after reserpine treatment in a manner equivalent to that observed in LC, adrenal medulla and superior cervical ganglia. The reason why it required 48 h for TH mRNA to increase in A2 neurons remains unclear.
Brain Res Mol Brain Res 1992 Apr
PMID:Effects of reserpine on tyrosine hydroxylase mRNA levels in locus coeruleus and medullary A1 and A2 neurons analyzed by in situ hybridization histochemistry and quantitative image analysis methods. 135 Jun 53

Temporal changes in tyrosine hydroxylase (TH) mRNA levels in medullary A1 and A2 neurons and locus coeruleus (LC) cells were studied 6, 12 and 24 h following orchidectomy in rats. Brains from intact controls and sham castrated rats also were evaluated at these same time periods. In situ hybridization histochemistry and quantitative image analysis techniques were used to quantitate levels of cytoplasmic TH mRNA. Neither the time of day nor the stress of sham castration affected TH mRNA levels in A1, A2 and LC neurons. In contrast, 6 h following castration, TH mRNA levels in A1 neurons had declined significantly. Thereafter, there was a linear increase in A1 message levels such that, by 24 h, TH mRNA values were significantly higher than those obtained in intact controls. Placement of Silastic estrogen capsules immediately after castration prevented the 6 h decline in A1 message levels. At 12 h, TH mRNA levels in A1 neurons were significantly higher in estrogen-treated rats compared to those of the castrate or intact control groups. By 24 h, message levels in A1 neurons of steroid-treated rats were comparable to the intact control. Neither castration nor estrogen treatment altered TH mRNA levels in A2 neurons. TH mRNA levels in LC neurons increased significantly 6 h after castration and estrogen produced a further significant increase in message levels. Six hours later (12 h), TH mRNA values were still higher than controls but, in the estrogen-treated group, these levels had declined to those observed in the 12 h castrate group.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1992 Apr
PMID:Changes in tyrosine hydroxylase mRNA levels in medullary A1 and A2 neurons and locus coeruleus following castration and estrogen replacement in rats. 135 Jun 54

Both aging and exercise are associated with alterations in circulating levels of catecholamines. To determine the interactions of age and exercise on tyrosine hydroxylase (TH) activity and TH mRNA, Fischer-344 female rats aged 5 months (young) and 25 months (old) were trained by treadmill running for 10 weeks. The elevation in maximum oxygen consumption in both groups was equivalent following exercise, indicating that training had occurred. In control rats, both TH activity and TH mRNA were greater in the older groups when compared with the younger animals. In young rats, exercise decreased TH activity by 25% and TH mRNA by 27%. In older rats, exercise was not associated with a decrease in TH activity and TH mRNA. Choline acetyltransferase activity (ChAT) was decreased and glutamic acid decarboxylase activity (GAD) was increased by exercise in young rats. The decrease in ChAT activity and increase in GAD activity suggest that trans-synaptic mechanisms play a role in the exercise-induced alteration of TH gene expression. Neither ChAT nor GAD was altered by exercise in older groups. Our data suggest that the previously reported diminution in catecholamines associated with exercise may be due to a decrease in TH mRNA and a resulting decrease in TH activity. There was no effect of exercise in the old rats, supporting previous observations that the plasticity of the sympathoadrenal system diminishes with age.
Brain Res Mol Brain Res 1992 Jun
PMID:Modulation of tyrosine hydroxylase gene expression in the rat adrenal gland by exercise: effects of age. 135 55

Previous studies have demonstrated that the sympathetic hypogastric ganglia (HG) are dependent upon the continued presence of testosterone for normal development and maintenance of tyrosine hydroxylase (TH) activity. The regulation of TH by testosterone has been examined further to determine whether the reduction in TH activity following castration is associated with changes in levels of TH protein and mRNA. TH protein was measured by immunotitration of HG homogenates using a TH-specific antibody, and TH-specific mRNA was detected by hybridization of dot blots of total RNA isolated from HG with a cDNA probe coding for TH. The results show that tyrosine hydroxylase activity, protein and mRNA are coordinately reduced in a graded fashion at 1, 2 and 4 weeks following castration. Testosterone replacement therapy immediately following castration prevents the decrease in TH levels. The results indicate that gonadal steroids regulate the biosynthesis of TH in the HG. Testosterone may control TH either directly by interacting with neurons of the HG, or indirectly by altering levels of trophic factors in the target tissues.
Brain Res Mol Brain Res 1992 Jun
PMID:Molecular aspects of the regulation of tyrosine hydroxylase by testosterone. 135 56

Injectable local drug delivery formulations-so-called microspheres have recently been developed, in which drugs are microencapsulated within biocompatible and biodegradable copolymer excipients like poly[DL-lactide-co-glycolide]. In view of its potential therapeutical usefulness, we have studied the microsphere methodology as a means to substitute for experimentally induced subnormal levels of endogenous dopamine (DA). Administration of 6-hydroxydopamine (6-OH-DA) unilaterally in the medial forebrain bundle of rats results in an up-regulation of postsynaptic receptors in the denervated striatum, functionally manifested as contralateral rotational behavior after apomorphine. DA microspheres were implanted in the denervated striatum. The majority of the rats displayed an attenuation of the contralateral rotational behavior induced by apomorphine up to 8 wk postimplantation. Immunocytochemical observations unexpectedly demonstrated growth of DA and tyrosine hydroxylase immunoreactive fibers in the denervated striatum. Interestingly, there was an apparent correlation between functional recovery and the degree of growth of DA fibers. The present results suggest that implantation of DA microspheres may promote DA fiber growth and extended recovery of surviving DA neurons, and, therefore, could be of therapeutic usefulness in Parkinson's disease.
Mol Chem Neuropathol
PMID:Dopamine fiber growth induction by implantation of synthetic dopamine-containing microspheres in rats with experimental hemi-parkinsonism. 135 53

Tyrosine hydroxylase mRNA is induced in rat pheochromocytoma PC18 cells by cAMP analogs and glucocorticoids. Previous studies have shown that these increases in tyrosine hydroxylase mRNA are due at least in part to stimulation of the tyrosine hydroxylase gene. However, the involvement of post-transcriptional mechanisms in the regulation of tyrosine hydroxylase mRNA by these inducing agents has not been investigated. In the present study, using nuclear run-on assays we show that the relative transcription rate of the tyrosine hydroxylase gene is stimulated 2-5-fold within 20 min after treatment of PC18 cells with cAMP analogs or dexamethasone and that the rate of transcription remains elevated 2-3-fold for at least 24 hr in the continual presence of these inducing agents. Pulse-labeling experiments using 4-thiouridine indicate that the rate of synthesis of tyrosine hydroxylase mRNA is increased approximately 3-fold or 10-fold after treatment with either a cyclic AMP analog or dexamethasone, respectively. These increases in rates of synthesis agree well with the fold increases in tyrosine hydroxylase mRNA levels after treatment with these inducers. Treatment of the cells with cycloheximide lowers the basal relative transcription rate of the tyrosine hydroxylase gene 2-3-fold; however, the relative transcription rate of the tyrosine hydroxylase gene is still elevated in cells treated with either dexamethasone or cAMP analogs in the presence of cycloheximide, compared with the transcription rate of the gene in cells treated with cycloheximide alone. These results indicate that protein synthesis is not required for the short term regulation of the gene by these inducing agents. The apparent t1/2 for tyrosine hydroxylase mRNA has been estimated by two different procedures, approach to steady state kinetics and pulse-chase analysis. Both procedures yield an estimated apparent t1/2 of approximately 6-9 hr for tyrosine hydroxylase mRNA under basal culture conditions. Dexamethasone does not substantially alter this apparent t1/2 value; however, cAMP appears to lower this apparent t1/2 value transiently. Our results suggest that cAMP and glucocorticoid regulate tyrosine hydroxylase mRNA levels primarily by stimulating the transcription rate of the tyrosine hydroxylase gene; however, cAMP may also regulate the stability of the mRNA for a short period of time, such that it is induced more rapidly in the cells.
Mol Pharmacol 1992 Nov
PMID:Regulation of tyrosine hydroxylase gene transcription rate and tyrosine hydroxylase mRNA stability by cyclic AMP and glucocorticoid. 135 99

1. With respect to the mesostriatal projection, the mesencephalon is composed of two dopaminergic (DA) cell populations, called dorsal tier and ventral tier. Strong evidence suggests differences in both the spatial and the temporal sequence of the innervation of the striatum between the two groups, with the ventral tier neurons innervating striatal patches prenatally and dorsal tier cells innervating striatal matrix postnatally. 2. Using in situ hybridization, we have examined the expression of the gene coding for tyrosine hydroxylase (TH) in mesencephalic DA neurons with respect to their postnatal development. Two ontogenic patterns of expression were observed: (a) dorsal tier neurons of the medial mesencephalon exhibited a sharp increase in expression beginning after birth, peaking on day 14, then decreasing and, finally, stabilizing; and (b) ventral tier neurons and dorsal tier cells from the lateral and the medial-dorsal mesencephalon showed only a slight increase in TH mRNA, reaching a plateau at P10. 3. The time course of the observed increase in TH gene expression in the first group, generally parallels the innervation of their target cells in the striatal matrix, suggesting that TH gene expression in these cells may be influenced by their postsynaptic cells or by the innervation process.
Cell Mol Neurobiol 1992 Dec
PMID:Differential expression of tyrosine hydroxylase mRNA in the developing rat mesencephalon. 136 92

Our earlier work demonstrated that certain populations of brain neurons which do not synthesize catecholamine (CA) neurotransmitters in vivo, will, when grown in culture with muscle-derived differentiation factor (MDF), unexpectedly express the gene for the CA biosynthetic enzyme tyrosine hydroxylase (TH). In this paper, we sought to determine whether MDF could also regulate TH expression in those neurons which normally synthesize CA neurotransmitters. Incubation of cultured dopamine neurons from the ventral midbrain with MDF elevated the levels of TH mRNA and TH enzyme activity 5- to 40-fold higher than that measured in control cultures. Sympathetic neurons were unaffected by a similar MDF treatment. Unlike the 2-day critical period for MDF-responsivity in non-CA neurons. CA neurons remained susceptible to MDF's influence over an extended developmental interval (E14-18), suggesting that MDF may be important for TH gene regulation in brain CA neurons even differentiation is complete. Because of these unique properties, MDF may provide a unique opportunity to explore ways in which the TH gene might be directly manipulated in these cell populations in order to correct the CA imbalances that occur in certain neurological diseases and disorders.
Brain Res Mol Brain Res 1992 Dec
PMID:Muscle-derived differentiation factor increases expression of the tyrosine hydroxylase gene and enzyme activity in cultured dopamine neurons from the rat midbrain. 136 26


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