Dopamine Agonists Exert Nurr1-inducing Effect in Peripheral Blood Mononuclear Cells of Patients with Parkinson's Disease

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.

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.

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.

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 μmol/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).