Pubmed Parkinsons Mirapex


Impact Factor for 2014 is 1.053 Click here to view optimized website for mobile devices Journal is indexed with MEDLINE/Index Medicus, PubMed and Science Citation Index Expanded
Share on facebookShare on twitter Share on citeulike Share on googleShare on linkedin More Sharing Services

Table of Contents
ORIGINAL ARTICLE
Year : 2015 | Volume : 128 | Issue : 13 | Page : 1755-1760
Dopamine Agonists Exert Nurr1-inducing Effect in Peripheral Blood Mononuclear Cells of Patients with Parkinson’s Disease

Li-Min Zhang1, Cong-Cong Sun2, Ming-Shu Mo1, Luan Cen1, Lei Wei3, Fei-Fei Luo4, Yi Li5, Guo-Fei Li6, Si-Yun Zhang7, Li Yi8, Wei Huang9, Zhuo-Lin Liu1, Wei-Dong Le10, Ping-Yi Xu11
1 Department of Neurology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
2 Department of Neurology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080; Department of Neurology, Qilu Affiliated Hospital of Shandong University, Jinan, Shandong 250001, China
3 Department of Neurology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080; Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510000, China
4 Department of Neurology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080; Department of Neurology, The Second Affiliated Hospital of Chengdu, Chongqing Medical University/The Third People’s Hospital of Chengdu, Chengdu, Sichuan 610031, China
5 Department of Neurology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080; Department of Neurology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, Guangdong 510000, China
6 Department of Neurology, Huaihe Hospital of Henan University, Kaifeng, Henan 470080, China
7 Department of Neurology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080; Department of Neurology, Shenzhen Hospital of Beijing University, Shenzhen, Guangdong 518036, China
8 Department of Neurology, Shenzhen Hospital of Beijing University, Shenzhen, Guangdong 518036, China
9 Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 360006, China
10 Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025; Center for Translational Research of Neurology Disease, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, China
11 Department of Neurology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080; Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangdong 510120, China

Date of Submission 04-Nov-2014
Date of Web Publication 25-Jun-2015

Correspondence Address:
Ping-Yi Xu
Department of Neurology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080
China
Login to access the Email id

Source of Support: This work was supported by grants from the National High Technology Research and Development Program of China (No. 2007AA02Z460), the State Key Development Program for Basic Research of China (No. 2011CB510001), the National Natural Science Foundation of, Conflict of Interest: None
DOI: 10.4103/0366-6999.159349

Get Permissions

Abstract
Background: Nurr1 plays an essential role in the development, survival, and function maintenance of midbrain dopaminergic (DA) neurons, and it is a potential target for Parkinson’s disease (PD). Nurr1 mRNA can be detected in peripheral blood mononuclear cells (PBMCs), but whether there is any association of altered Nurr1 expression in PBMC with the disease and DA drug treatments remains elusive. This study aimed to measure the Nurr1 mRNA level in PBMC and evaluate the effect of Nurr1 expression by DA agents in vivo and in vitro.
Methods: The mRNA levels of Nurr1 in PBMC of four subgroups of 362 PD patients and 193 healthy controls (HCs) using real-time polymerase chain reaction were measured. The nonparametric Mann-Whitney U-test and Kruskal-Wallis test were performed to evaluate the differences between PD and HC, as well as the subgroups of PD. Multivariate linear regression analysis was used to evaluate the independent association of Nurr1 expression with Hoehn and Yahr scale, age, and drug treatments. Besides, the Nurr1 expression in cultured PBMC was measured to determine whether DA agonist pramipexole affects its mRNA level.
Results: The relative Nurr1 mRNA levels in DA agonists treated subgroup were significant higher than those in recent-onset cases without any anti-PD treatments (de novo) (P < 0.001) and HC groups (P < 0.010), respectively. Furthermore, the increase in Nurr1 mRNA expression was seen in DA agonist and L-dopa group. Multivariate linear regression showed DA agonists, L-dopa, and DA agonists were independent predictors correlated with Nurr1 mRNA expression level in PBMC. In vitro, in the cultured PBMC treated with 10 μmol/L pramipexole, the Nurr1 mRNA levels were significantly increased by 99.61%, 71.75%, 73.16% in 2, 4, and 8 h, respectively (P < 0.001).
Conclusions: DA agonists can induce Nurr1 expression in PBMC, and such effect may contribute to DA agonists-mediated neuroprotection on DA neurons.

Keywords: Dopamine Agonists; Nurr1; Parkinson′s Disease
How to cite this article:
Zhang LM, Sun CC, Mo MS, Cen L, Wei L, Luo FF, Li Y, Li GF, Zhang SY, Yi L, Huang W, Liu ZL, Le WD, Xu PY. Dopamine Agonists Exert Nurr1-inducing Effect in Peripheral Blood Mononuclear Cells of Patients with Parkinson’s Disease. Chin Med J 2015;128:1755-60

How to cite this URL:
Zhang LM, Sun CC, Mo MS, Cen L, Wei L, Luo FF, Li Y, Li GF, Zhang SY, Yi L, Huang W, Liu ZL, Le WD, Xu PY. Dopamine Agonists Exert Nurr1-inducing Effect in Peripheral Blood Mononuclear Cells of Patients with Parkinson’s Disease. Chin Med J [serial online] 2015 [cited 2015 Jul 4];128:1755-60. Available from: http://www.cmj.org/text.asp?2015/128/13/1755/159349
Introduction
Top
Nurr1 also known as NR4A2, belongs to the nuclear receptor superfamily of transcription factors, is highly expressed in midbrain dopaminergic (DA) neurons, and plays an essential role in the development, survival and function maintenance of midbrain DA neurons. [1],[2],[3],[4] Nurr1 is a potential target for Parkinson’s disease (PD), which is the second common neurodegenerative disease and both genetic and environmental neurotoxin are important causes. [5],[6] Nurr1 can activate the transcription of tyrosine hydroxylase and enhance the expression of DA transporter. [7],[8],[9] It was reported that homozygous Nurr1 knockout mice failed to develop DA neurons, and heterozygotes reduced their brain DA and developed age-dependent locomotor deficits including impaired horizontal and vertical movement, difficultly performance on rotarod test compared to age-matched wild-type mice. [3],[10],[11],[12],[13],[14] Reduction of Nurr1 in the adult brain may increase the vulnerability of DA neurons to stress and participate in the pathogenesis of PD. [11]

Several polymorphisms of Nurr1 gene including −291Tdel and −245T–>G have been reported to result in a marked decrease of Nurr1 mRNA levels in transfected cell lines and lymphocytes of affected individuals. [15] Furthermore, Le et al. [16] reported a decreased Nurr1 gene expression in peripheral blood mononuclear cells (PBMCs) of PD patients, which anticipated Nurr1 as a potential biomarker for PD diagnosis. But to date, little has been done to investigate the association among Nurr1 expression in PBMC, disease progression of PD, and DA agents. This study was to measure the Nurr1 mRNA level in PBMC and evaluate the effect of Nurr1 expression by DA agents in vivo and in vitro.
Methods
Top
Study population

The 362 PD patients at Department of Neurology, the First Affiliated Hospital of Sun Yet-Sen University between January 2012 and August 2014 were recruited. The diagnosis was made in accordance with the United Kingdom PD Society Brain Bank Criteria. [17] Besides recent-onset PD patients without any anti-PD treatments (de novo), each patient reported to have taken anti-PD medicines at least 2 years and all patients were assessed according to the Hoehn and Yahr (H and Y) scale. [18],[19] They participated voluntarily and provided written informed consents before enrollment. Meantime, 193 healthy controls (HCs) were enrolled either from Physical Examination Center of Sun Yat-Sen University or the spouses of the patients. Exclusion criteria for HC were based on our previous published criteria. [20] The study was approved by the Ethics Committee of Sun Yat-Sen University.

Preparation of peripheral blood mononuclear cell both from Parkinson’s disease patients and healthy controls

Peripheral blood samples (5 ml) of PD patients and HCs were drawn from antecubital venous and put into natrium citricum-containing tubes. PBMC from venous blood of PD patients and HCs were prepared by Ficoll-Hypaque density gradient centrifugation. After centrifugation at 2200 r/min for 20 min, buffy coats were collected and washed three times with phosphate-buffered saline (PBS), then centrifuged at 1800 r/min for 10 min to collect PBMC cells. Then PBMC were lysed by adding 1 ml TRIzol reagent (Invitrogen, Carlsbad, CA, USA) and stored at −80°C until used.

In order to further explore the pattern of Nurr1 expression, an in vitro analysis on cultured human PBMC was conducted. PBMC from venous blood of 10 HCs was prepared by Ficoll-Hypaque density gradient centrifugation through centrifuging at 2200 r/min for 20 min. The buffy coats were collected and washed twice with PBS, then washed once with complete RPMI 1640 medium (Gibco, German) containing 2 mmol/L L-glutamine, 100 U/ml penicillin, 100 μg/ml streptomycin, and 10% fetal bovine serum and suspended at a concentration of 2 × 10 6 cells/ml with complete RPMI 1640 medium. PBMC was delivered in 3.5 cm diameter dishes with 2 × 10 6 cells separately with complete RPMI 1640 medium. After 12 h cultured, the cells were treated with 10 μmol/L pramipexole (Sigma, St. Louis, MO, USA) for 2, 4, 8, 12 and 24 h and cultured at 37°C under the humidified 5% CO 2 atmosphere. All the PBMC from 10 HCs were treated similarly. At each selected time, the PBMC cells were collected for RNA extraction.

Reverse transcription polymerase chain reaction analysis of Nurr1 expression on peripheral blood mononuclear cell

Then total RNA was isolated using TRIzol (Invitrogen) according to the manufacturer’s protocol. The 1 μg of total RNA was reverse transcribed into first-strand complementary DNA (cDNA) using a reverse transcription (RT) kit (Takara, Japan) according to the manufacturer’s protocol in a final volume of 20 μl. For analysis, on Nurr1 expression with quantitative real-time RT-polymerase chain reaction (RT-PCR), human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as internal control, and the sequences of primers as follows: Nurr1 forward: 5′-TCCAACGAGGGGCTGTGCG-3′; Nurr1 reverse: 5′- CACTGTGCGCTTAAAGAAGC-3′; and GAPDH forward: 5′- GAAGGTGAAGG TCGGAGTC-3′; GAPDH reverse: 5′- GAAGATGGTGATGGGATTTC-3′. The 2 μl of the synthesized cDNA were used in all real-time PCR together with the SYBR Green I Master Mix (SYBR ® Premix Ex Taq™, Takara, Japan) on MJ Research Opticon2 real-time thermocycler (Bio-Rad, Hercules, CA, USA). Fluorescent reading from real-time PCR reaction was quantitatively analyzed by determining the difference of Ct (delta Ct) between Ct of Nurr1 and its internal GAPDH, and the Nurr1 gene expression was determined by the formation of 2−delta Ct . In addition, for all the analyzed samples, only triplicates with a standard deviation of the Ct < 0.20 were accepted.

Statistical analysis

Quantitative data (age, H and Y scale, the relative Nurr1 mRNA relative level) were shown as mean ± standard error (SE) or median and interquartile range, depending on the distribution of the data. Categorical variables (gender) were shown as a percentage. The Chi-square test was used to analyze the differences of gender between PD and HCs or among the subgroups of PD. The nonparametric Mann-Whitney U-test and Kruskal-Wallis test were performed to evaluate the differences between PD and HC or among the subgroups of PD. The multivariate linear regression models were used to simultaneously evaluate the cross-sectional association of dependent variables (the Nurr1 mRNA relative level) and independent variables (H and Y scale, age, and the different drug treatments). After adjustment of H and Y scale and age, the covariance analysis was utilized to test the differences of Nurr1 mRNA relative level among different drug treatments. One-way analysis of variance was used to analyze the difference of Nurr1 mRNA level among the different hours treated with pramipexole. Data were analyzed with statistical software SPSS 21.0 (SPSS Inc., Chicago, IL, USA). P < 0.05 (two sides) was considered as statistically significant.
Results
Top
Clinical characteristics of the subjects

The 362 PD patients (209 males, 153 females) were enrolled in this study. Among these 362 patients, 136 patients were recent-onset cases and did not receive any anti-PD treatment before blood drawing (de novo); 83 patients were administrated with L-dopa, 38 patients received D2/D3 agonists (piribedil or pramipexole), 105 patients took both L-dopa and DA agonists. These patients were divided into four subgroups according to the different drug treatments: De novo, L-dopa, DA agonist, and L-dopa and DA agonist. The demographic and clinical characteristics of PD patients and HCs are summarized in [Table 1], showing no significant differences (P = 0.683) in gender between PD patients and HCs and among the four subgroups of PD patients. The average age of PD patients in L-dopa and L-dopa and DA agonist subgroups was older than that of de novo subgroup or HCs (P < 0.05). Furthermore, the median scale of PD was 2.0 of H and Y stage in all three subgroups (L-dopa, DA agonists and L-dopa and DA agonist), which was significantly higher than de novo subgroup (P < 0.05).
Table 1: Demographic and clinical characteristics of the subjects

Click here to view
The association of dependent variables (the Nurr1 mRNA relative level) and independent variables (Hoehn and Yahr, age, and the different drug treatments)

Generalized estimating equations in linear regression models were performed on the data from all subjects. H and Y scale, age and different drug treatments of PD patients were identified to be independently associated with Nurr1 mRNA relative level. In both the stepwise model and inclusive model, the independent predictors of Nurr1 mRNA relative level were DA agonists, L-dopa, and DA agonists. The formulae for Nurr1 mRNA relative level were created based on the regression coefficients (β): In stepwise model, for DA agonists, β = 4.551 (95% confidence interval [CI], 2.200-6.903; P < 0.001); for L-dopa and DA agonists, β = 4.398 (95% CI, 2.883-5.912; P < 0.001); and in inclusive model, for age, β = −0.024 (95% CI, −0.069-0.022; P = 0.311); for H and Y scale, β = −0.120 (95% CI, −1.092-0.852; P = 0.809); for de novo, β = −0.633 (95% CI, −2.739-1.473; P = 0.555); for L-dopa, β = −0.672 (95% CI, −2.058-3.402; P = 0.629); for DA agonists, β = 4.657 (95% CI, 1.552-7.762; P = 0.003); for L-dopa and DA agonists, β = 4.561 (95% CI, 1.973-7.147; P = 0.001). The Nurr1 mRNA relative level was made using the following formulas: Nurr1 mRNA level = 2.973 + 4.551 × DA agonists + 4.398 × L-dopa and DA agonists, or Nurr1 mRNA level = 4.545 + 4.657 × DA agonists + 4.561 × L-dopa and DA agonists.

Nurr1 gene expression in subgroups of Parkinson’s disease and health controls

According to different drug treatments, the PD patients were divided into 4 subgroups. As shown in [Figure 1], the relative levels of Nurr1 mRNA in de novo subgroup and HCs were 2.38 ± 0.42 versus 3.18 ± 0.42, respectively (P = 0.307), a slight decrease but no statistical significance in de novo subgroup without any DA agonists, L-dopa or other anti-PD drugs. The relative level of Nurr1 mRNA in L-dopa PD group was 3.37 ± 0.57 versus 3.18 ± 0.42 in HC (P = 0.841), which showed no statistical significance. However, the relative Nurr1 mRNA level in DA agonist subgroup was 7.52 ± 1.82, significant higher than those both in de novo group (P < 0.001) and HC (P = 0.001). The Nurr1 mRNA level in DA agonist and L-dopa subgroup was up to 7.37 ± 1.07, which was significantly increased versus de novo subgroup or L-dopa subgroup (P < 0.001). There were no significant differences of Nurr1 mRNA level between DA agonist and DA agonist and L-dopa subgroups.
Figure 1: Scatter plots of Nurr1 mRNA relative levels in peripheral blood mononuclear cells of subgroups of PD patients. Fluorescent reading from real-time polymerase chain reaction was quantitatively analyzed by determining the difference of Ct (delta Ct) between Ct of Nurr1 and internal control. Glyceraldehyde-3-phosphate dehydrogenase and the Nurr1 gene expression was determined by the formation of 2−delta Ct. Horizontal bars represented mean ± standard error. HC: Healthy control; PD: Parkinson’s disease; de novo: PD without any anti-PD treatment; DA agonists: PD treated with DA agonists; L-dopa: PD treated with L-dopa; L-dopa and DA agonists: PD treated with L-dopa and DA agonists; DA: Dopaminergic.

Click here to view
The Nurr1 mRNA level in de novo subgroup before and after treatments

In 136 recent-onset cases, 25 were treated with L-dopa and 19 were treated with DA agonists. Their Nurr1 mRNA relative levels pre and posttreatment were detected [Figure 2]. The Nurr1 mRNA level in 25 patients was 7.87 ± 1.70 before L-dopa treatment, and 7.59 ± 1.59 after L-dopa taken, but no significant difference (P = 0.905). The Nurr1 mRNA levels in 19 patients before and after DA agonist treatment were 5.92 ± 1.42 and 8.47 ± 2.52, respectively, indicating a slight but nonsignificant increase after DA agonist treatment (P = 0.066).
Figure 2: Scatter plots of Nurr1 mRNA relative levels in peripheral blood mononuclear cells before and after treatment of L-dopa (a) (n = 25) or DA agonist (b) (n = 19) in de novo subgroup. There were no obvious changes before and after L-dopa treatment neither for the whole group nor for each individual, while there were three individuals showed obvious increase of Nurr1 mRNA levels though there was no significance between before and after DA agonist treatment as a whole group. DA: Dopaminergic.

Click here to view
The Nurr1 mRNA level in peripheral blood mononuclear cell treated with pramipexole

To further explore whether DA agonists have effect on Nurr1 expression, we measured the Nurr1 mRNA level in PBMC from 10 healthy volunteers with 10 μmol/L pramipexole [Figure 3]. Compared with control, the Nurr1 mRNA relative levels in PBMC by DA agonist were significantly increased to 199.61 ± 13.17%, 171.75 ± 11.33%, 173.16 ± 11.42% in 2, 4 and 8 h, respectively (P < 0.001). In vitro experiment, the Nurr1 mRNA levels of PBMC treated by DA agonist for 12 h and 24 h were 95.30 ± 6.26% and 104.60 ± 4.32%, respectively, and there were no significant differences compared with control (P > 0.05), which was in accord with the half-life of 8-12 h.
Figure 3: Nurr1 mRNA relative levels in vitro measured by real-time polymerase chain reaction treated with pramipexole. Peripheral blood mononuclear cells from health volunteers were treated with 10 ìmol/L pramipexole for 0-24 h. Glyceraldehyde-3-phosphate dehydrogenase was monitored as internal control. Nurr1 mRNA level was compared with control. All experiments were performed at least three independent times (*P < 0.001).

Click here to view

Discussion
Top
Nurr1 is highly expressed in the developing and adult ventral midbrain and required for the acquisition and maintenance of the DA phenotype in nigrostriatal neurons. [1],[2],[3],[4] It has been reported that besides central nervous system, Nurr1 is also an expression in many tissues including bone, endothelial cells, and PBMC. [21],[22],[23] The key point for clinical evacuation of Nurr1 is whether the alteration of Nurr1expression is secondary to anti-PD drug effects. Using RT-PCR, we analyzed the Nurr1 mRNA level in PBMC from 362 sporadic PD patients and 193 HCs from Southern China, and found that the Nurr1 expression level in de novo subgroup with a tendency of nonsignificant decrease compared to HCs, but a statistically significant increase in both DA agonist or DA agonist and L-dopa subgroups, which indicated that DA agonists may exert an up-regulation effect on the expression of Nurr1 in PBMC.

As a transcription factors, the expression of Nurr1 can be affected by many factors including growth factors, neurotransmitters, and drugs. [24],[25],[26] For example, injection of 6-hydroxydopamine into the striatum produced an increase in the number of cells expressing Nurr1 in both substantia nigra compacta (SNc) and substantia nigra reticulate. [27] Similar to our data, a series of evidence indicated that DA receptor agonists may play an active role on the Nurr1 expression. For instance, ropinirole has been documented to prevent the progression of PD in Nurr1 deficient mouse, and Pan et al. [28] reported that SH-SY5Y cells treated with D3 receptor agonist pramipexole enhanced the expression of Nurr1 mRNA and protein in vitro.

Studies on postmortem brains have been found that an age-related decline of DA phenotypic markers was associated with down-regulation of Nurr1 expression in human SN. [29] Chu et al. [30] reported the optical density of Nurr1 immunofluorescence was significantly decreased in nigral neurons containing α-synuclein-immunoreactive inclusions in PD patients. In addition, recent studies showed a significant decreased of Nurr1 mRNA in SNc of D2 dopamine receptor −/− mice (D2R−/−). [31] However, our data showed that the expression of Nurr1 mRNA in PBMC was affected by drugs like DA agonist, but was no significant correlation with the disease severity (H and Y scale) or age of onset of PD. For further exploring the pattern of Nurr1 expression in vitro, we found that Nurr1 mRNA relative levels in PBMC increased significantly after treated with 10 μmol/L pramipexole for 2, 4, and 8 h, which in accordance with our clinical investigation from blood cells of PD patients, demonstrating DA agonist plays an active effect on Nurr1 gene in PBMC. Similarly, Pan et al. [28] reported that levels of Nurr1 mRNA and protein in SH-SY5Y increased after pramipexole treatment, indicating that the biological pattern of Nurr1 expression in PBMC might be different from the changes in degeneration of DA neurons in midbrain.

In summary, we observed that Nurr1 mRNA level in PBMC from our PD patients was significantly influenced by antiparkinsonism drugs DA agonists but not L-dopa, and such effect may contribute to DA agonists-mediated neuroprotection on DA neurons. Furthermore, we found a slight insignificant reduction of Nurr1 level in our de novo PD patients, which might present a correlation with the disease. A larger sample of de novo PD patients may be needed to evaluate whether reduced expression of Nurr1 in PBMC can be used as a biomarker for early PD.
References
Top

1.
Zetterström RH, Williams R, Perlmann T, Olson L. Cellular expression of the immediate early transcription factors Nurr1 and NGFI-B suggests a gene regulatory role in several brain regions including the nigrostriatal dopamine system. Brain Res Mol Brain Res 1996;41:111-20. Back to cited text no. 1

2.
Bäckman C, Perlmann T, Wallén A, Hoffer BJ, Morales M. A selective group of dopaminergic neurons express Nurr1 in the adult mouse brain. Brain Res 1999;851:125-32. Back to cited text no. 2

3.
Zetterström RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T. Dopamine neuron agenesis in Nurr1-deficient mice. Science 1997;276:248-50. Back to cited text no. 3

4.
Saucedo-Cardenas O, Quintana-Hau JD, Le WD, Smidt MP, Cox JJ, De Mayo F, et al. Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons. Proc Natl Acad Sci U S A 1998;95:4013-8. Back to cited text no. 4

5.
Singh NK, Banerjee BD, Bala K, Chhillar M, Chhillar N. Gene-gene and gene-environment interaction on the risk of Parkinson’s disease. Curr Aging Sci 2014;7:101-9. Back to cited text no. 5

6.
Pan-Montojo F, Reichmann H. Considerations on the role of environmental toxins in idiopathic Parkinson’s disease pathophysiology. Transl Neurodegener 2014;3:10. Back to cited text no. 6

7.
Sakurada K, Ohshima-Sakurada M, Palmer TD, Gage FH. Nurr1, an orphan nuclear receptor, is a transcriptional activator of endogenous tyrosine hydroxylase in neural progenitor cells derived from the adult brain. Development 1999;126:4017-26. Back to cited text no. 7

8.
Schimmel JJ, Crews L, Roffler-Tarlov S, Chikaraishi DM. 4.5 kb of the rat tyrosine hydroxylase 5′ flanking sequence directs tissue specific expression during development and contains consensus sites for multiple transcription factors. Brain Res Mol Brain Res 1999;74:1-14. Back to cited text no. 8

9.
Sacchetti P, Mitchell TR, Granneman JG, Bannon MJ. Nurr1 enhances transcription of the human dopamine transporter gene through a novel mechanism. J Neurochem 2001;76:1565-72. Back to cited text no. 9

10.
Le W, Conneely OM, Zou L, He Y, Saucedo-Cardenas O, Jankovic J, et al. Selective agenesis of mesencephalic dopaminergic neurons in Nurr1-deficient mice. Exp Neurol 1999;159:451-8. Back to cited text no. 10

11.
Le W, Conneely OM, He Y, Jankovic J, Appel SH. Reduced Nurr1 expression increases the vulnerability of mesencephalic dopamine neurons to MPTP-induced injury. J Neurochem 1999;73:2218-21. Back to cited text no. 11

12.
Eells JB, Lipska BK, Yeung SK, Misler JA, Nikodem VM. Nurr1-null heterozygous mice have reduced mesolimbic and mesocortical dopamine levels and increased stress-induced locomotor activity. Behav Brain Res 2002;136:267-75. Back to cited text no. 12

13.
Bäckman C, You ZB, Perlmann T, Hoffer BJ. Elevated locomotor activity without altered striatal dopamine contents in Nurr1 heterozygous mice after acute exposure to methamphetamine. Behav Brain Res 2003;143:95-100. Back to cited text no. 13

14.
Jiang C, Wan X, He Y, Pan T, Jankovic J, Le W. Age-dependent dopaminergic dysfunction in Nurr1 knockout mice. Exp Neurol 2005;191:154-62. Back to cited text no. 14

15.
Le WD, Xu P, Jankovic J, Jiang H, Appel SH, Smith RG, et al. Mutations in NR4A2 associated with familial Parkinson disease. Nat Genet 2003;33:85-9. Back to cited text no. 15

16.
Le W, Pan T, Huang M, Xu P, Xie W, Zhu W, et al. Decreased NURR1 gene expression in patients with Parkinson’s disease. J Neurol Sci 2008;273:29-33. Back to cited text no. 16

17.
Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: A clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181-4. Back to cited text no. 17

18.
Goetz CG, Poewe W, Rascol O, Sampaio C, Stebbins GT, Counsell C, et al. Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: Status and recommendations. Mov Disord 2004;19:1020-8. Back to cited text no. 18

19.
Hoehn MM, Yahr MD. Parkinsonism: Onset, progression and mortality. Neurology 1967;17:427-42. Back to cited text no. 19

20.
Sun CC, Luo FF, Wei L, Lei M, Li GF, Liu ZL, et al. Association of serum uric acid levels with the progression of Parkinson’s disease in Chinese patients. Chin Med J 2012;125:583-7. Back to cited text no. 20

21.
Tetradis S, Bezouglaia O, Tsingotjidou A. Parathyroid hormone induces expression of the nuclear orphan receptor Nurr1 in bone cells. Endocrinology 2001;142:663-70. Back to cited text no. 21

22.
Martínez-González J, Badimon L. The NR4A subfamily of nuclear receptors: New early genes regulated by growth factors in vascular cells. Cardiovasc Res 2005;65:609-18. Back to cited text no. 22

23.
Mages HW, Rilke O, Bravo R, Senger G, Kroczek RA. NOT, a human immediate-early response gene closely related to the steroid/thyroid hormone receptor NAK1/TR3. Mol Endocrinol 1994;8:1583-91. Back to cited text no. 23

24.
Zhao D, Desai S, Zeng H. VEGF stimulates PKD-mediated CREB-dependent orphan nuclear receptor Nurr1 expression: Role in VEGF-induced angiogenesis. Int J Cancer 2011;128:2602-12. Back to cited text no. 24

25.
Myers SA, Eriksson N, Burow R, Wang SC, Muscat GE. Beta-adrenergic signaling regulates NR4A nuclear receptor and metabolic gene expression in multiple tissues. Mol Cell Endocrinol 2009;309:101-8. Back to cited text no. 25

26.
Maheux J, Ethier I, Rouillard C, Lévesque D. Induction patterns of transcription factors of the nur family (nurr1, nur77, and nor-1) by typical and atypical antipsychotics in the mouse brain: Implication for their mechanism of action. J Pharmacol Exp Ther 2005;313:460-73. Back to cited text no. 26

27.
Ojeda V, Fuentealba JA, Galleguillos D, Andrés ME. Rapid increase of Nurr1 expression in the substantia nigra after 6-hydroxydopamine lesion in the striatum of the rat. J Neurosci Res 2003;73:686-97. Back to cited text no. 27

28.
Pan T, Xie W, Jankovic J, Le W. Biological effects of pramipexole on dopaminergic neuron-associated genes: Relevance to neuroprotection. Neurosci Lett 2005;377:106-9. Back to cited text no. 28

29.
Chu Y, Kompoliti K, Cochran EJ, Mufson EJ, Kordower JH. Age-related decreases in Nurr1 immunoreactivity in the human substantia nigra. J Comp Neurol 2002;450:203-14. Back to cited text no. 29

30.
Chu Y, Le W, Kompoliti K, Jankovic J, Mufson EJ, Kordower JH. Nurr1 in Parkinson’s disease and related disorders. J Comp Neurol 2006;494:495-514. Back to cited text no. 30

31.
Kim SY, Choi KC, Chang MS, Kim MH, Kim SY, Na YS, et al. The dopamine D2 receptor regulates the development of dopaminergic neurons via extracellular signal-regulated kinase and Nurr1 activation. J Neurosci 2006;26:4567-76. Back to cited text no. 31
Figures

[Figure 1], [Figure 2], [Figure 3]

Tables

[Table 1]
Top

Search

Similar in PUBMED
Search Pubmed for
Zhang LM
Sun CC
Mo MS
Cen L
Wei L
Luo FF
Li Y
Li GF
Zhang SY
Yi L
Huang W
Liu ZL
Le WD
Xu PY
Search in Google Scholar for
Zhang LM
Sun CC
Mo MS
Cen L
Wei L
Luo FF
Li Y
Li GF
Zhang SY
Yi L
Huang W
Liu ZL
Le WD
Xu PY
Related articles
Dopamine Agonists
Nurr1
Parkinson’s Disease
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)
In this article
Abstract
Introduction
Methods
Results
Discussion
References
Article Figures
Article Tables

Article Access Statistics
Viewed 31
Printed 0
Emailed 0
PDF Downloaded 22
Comments [Add]

Recommend this journal
[TAG2]
[TAG3]
[TAG4]

Advertisements

About garyskeete

ASHWORTH MEDICINE-Professional Medical Assisting, Doctor of Science,Legal Assistant Diploma BSc Criminal Justice
This entry was posted in Uncategorized. Bookmark the permalink.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s