Pridopidine activates neuroprotective pathways impaired in Huntington Disease.

Pridopidine has demonstrated improvement in Huntington Disease (HD) motor symptoms as measured by secondary endpoints in clinical trials. Originally described as a dopamine stabilizer, this mechanism is insufficient to explain the clinical and preclinical effects of pridopidine. This study therefore explored pridopidine's potential mechanisms of action. The effect of pridopidine versus sham treatment on genome-wide expression profiling in the rat striatum was analysed and compared to the pathological expression profile in Q175 knock-in (Q175 KI) vs Q25 WT mouse models. A broad, unbiased pathway analysis was conducted, followed by testing the enrichment of relevant pathways. Pridopidine upregulated the BDNF pathway (P = 1.73E-10), and its effect on BDNF secretion was sigma 1 receptor (S1R) dependent. Many of the same genes were independently found to be downregulated in Q175 KI mice compared to WT (5.2e-7 < P < 0.04). In addition, pridopidine treatment upregulated the glucocorticoid receptor (GR) response, D1R-associated genes and the AKT/PI3K pathway (P = 1E-10, P = 0.001, P = 0.004, respectively). Pridopidine upregulates expression of BDNF, D1R, GR and AKT/PI3K pathways, known to promote neuronal plasticity and survival, as well as reported to demonstrate therapeutic benefit in HD animal models. Activation of S1R, necessary for its effect on the BDNF pathway, represents a core component of the mode of action of pridopidine. Since the newly identified pathways are downregulated in neurodegenerative diseases, including HD, these findings suggest that pridopidine may exert neuroprotective effects beyond its role in alleviating some symptoms of HD.

Dopamine receptor DR2 expression in B cells is negatively correlated with disease activity in rheumatoid arthritis patients.

OBJECTIVE: Dopamine receptor (DR) signaling is involved in the pathogenesis of autoimmune diseases. We aimed to measure the expression levels of DR1-5 on B cells from patients with rheumatoid arthritis (RA) and to analyze the relationship between DRs and clinical manifestations, inflammatory biomarkers, functional status and disease activity. METHODS: A total of 29 patients with RA, 12 healthy donors and 12 patients with osteoarthritis (OA) were recruited in this study. Flow cytometry was used to measure the levels of DR1-5 expressed on B cells. The relationships between B cell DR expressions and clinical features in RA patients were analyzed using the Spearman correlation test. RESULTS: The expression levels of B cell DR1-5 in both the RA and OA groups were lower than those in healthy controls. After 3 months of medication, all five receptors were elevated in RA patients, with DR2 and DR3 being significantly increased from the baseline. DR2 expression on B cells was negatively correlated with inflammatory biomarkers and disease activity. CONCLUSION: RA patients had lower expression level of DR2 on B cells compared to the healthy controls, and the level of DR2 negatively correlated with the disease activity. DR2 and DR3 might be novel predictors of patient responses to disease modifying antirheumatic drug therapy.

Dopamine inhibits the effector functions of activated NK cells via the upregulation of the D5 receptor.

Several lines of evidence indicate that dopamine (DA) plays a key role in the cross-talk between the nervous and immune systems. In this study, we disclose a novel immune-regulatory role for DA: inhibition of effector functions of activated NK lymphocytes via the selective upregulation of the D5 dopaminergic receptor in response to prolonged cell stimulation with rIL-2. Indeed, engagement of this D1-like inhibitory receptor following binding with DA suppresses NK cell proliferation and synthesis of IFN-γ. The inhibition of IFN-γ production occurs through blocking the repressor activity of the p50/c-REL dimer of the NF-κB complex. Indeed, the stimulation of the D5 receptor on rIL-2-activated NK cells inhibits the binding of p50 to the microRNA 29a promoter, thus inducing a de novo synthesis of this miRNA. In turn, the increased levels of microRNA 29a were inversely correlated with the ability of NK cells to produce IFN-γ. Taken together, our findings demonstrated that DA switches off activated NK cells, thus representing a checkpoint exerted by the nervous system to control the reactivity of these innate immune effectors in response to activation stimuli and to avoid the establishment of chronic and pathologic inflammatory processes.

Stimulation of dopamine receptor D5 expressed on dendritic cells potentiates Th17-mediated immunity.

Dendritic cells (DCs) are responsible for priming T cells and for promoting their differentiation from naive T cells into appropriate effector cells. Emerging evidence suggests that neurotransmitters can modulate T cell-mediated immunity. However, the involvement of specific neurotransmitters or receptors remains poorly understood. In this study, we analyzed the role of dopamine in the regulation of DC function. We found that DCs express dopamine receptors as well as the machinery necessary to synthesize, store, and degrade dopamine. Notably, the expression of D5R decreased upon LPS-induced DC maturation. Deficiency of D5R on the surface of DCs impaired LPS-induced IL-23 and IL-12 production and consequently attenuated the activation and proliferation of Ag-specific CD4(+) T cells. To determine the relevance of D5R expressed on DCs in vivo, we studied the role of this receptor in the modulation of a CD4(+) T cell-driven autoimmunity model. Importantly, D5R-deficient DCs prophylactically transferred into wild-type recipients were able to reduce the severity of experimental autoimmune encephalomyelitis. Furthermore, mice transferred with D5R-deficient DCs displayed a significant reduction in the percentage of Th17 cells infiltrating the CNS without differences in the percentage of Th1 cells compared with animals transferred with wild-type DCs. Our findings demonstrate that by contributing to CD4(+) T cell activation and differentiation to Th17 phenotype, D5R expressed on DCs is able to modulate the development of an autoimmune response in vivo.

Dopamine receptors in human peripheral blood lymphocytes: changes in mRNA expression in opioid addiction.

Gradual adaptations of the brain to repeated drug exposure may induce addiction. Brain mesolimbic dopaminergic pathway is the site of the effect of addictive drugs. The dopamine receptors in peripheral blood lymphocytes may reflect the status of homologous brain receptors. In the present study, the effects of opioid addiction on mRNA expression of dopamine D(3), D(4) and D(5) receptors in human peripheral blood lymphocytes were investigated, using a real-time PCR method. Four groups each comprising 30 individuals were enrolled in the study: opioid addicted, methadone maintained, long-term abstinent and normal subjects. The results indicated that dopamine D(3) receptor mRNA expression was increased in addicted and methadone maintained subjects by a factor of 1.74 and 1.98, respectively, but no change was observed in the abstinent group. The dopamine D(4) receptor mRNA expression was reduced in abstinent and addicted subjects (but not in the methadone group) and reached 0.44 and 0.53 the amount of the control group, respectively. Expression of dopamine D(5) receptor mRNA showed a significant reduction in abstinent subjects (0.41 the amount of the control group). However, in the addicted and methadone maintained groups, the change of expression level was not statistically significant. It can be concluded that persisting deficiency of dopamine D(4) and D(5) receptors may be a risk factor urging individuals to addiction, and methadone may exert its therapeutic effects through normalizing mRNA expression of these receptors. The dopamine D(3) receptor may have a negative feedback role in addiction; however, we have no explanation for the persisting up-regulation of this receptor in methadone subjects.