Pramipexole, a Dopamine D2/D3 Receptor-Preferring Agonist, Prevents Experimental Autoimmune Encephalomyelitis Development in Mice

Lieberknecht, Vicente; Junqueira, Stella Célio; Cunha, Maurício P.; Barbosa, Tatiane Muniz; Souza, Luiz Felipe de; Coelho, Igor S.; Santos, Adair R.S.; Rodrigues, Ana Lúcia S.; Dafré, Alcir Luiz; Dutra, Rafael C.

doi:10.1007/s12035-016-9717-5

Cited by 49 publications

(35 citation statements)

References 67 publications

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“…Drd2 agonist was first reported to suppress nitric oxide and tumor necrosis factor-α in peripheral neutrophils two decades ago [32]. Since then, more studies have showed that Drd2 is a potential candidate for amelioration of inflammatory diseases [33][34][35][36] and NDDs [22,[37][38][39]. Nevertheless, to date there are no reports on whether Drd2 participates in the suppression of inflammasome activation.…”

Section: Discussionmentioning

confidence: 99%

Dopamine D2 receptor restricts astrocytic NLRP3 inflammasome activation via enhancing the interaction of β-arrestin2 and NLRP3

et al. 2018

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Astrocytes are involved in the neuroinflammation of neurodegenerative diseases, such as Parkinson's disease (PD). Among the numerous inflammatory cytokines, interleukin-1β (IL-1β) produced by astrocytic Nod-like receptor protein (NLRP) inflammasome is crucial in the pathogenesis of PD. β-arrestin2-mediated dopamine D2 receptor (Drd2) signal transduction has been regarded as a potential anti-inflammatory target. Our previous study revealed that astrocytic Drd2 suppresses neuroinflammation in the central nervous system. However, the role of Drd2 in astrocytic NLRP3 inflammasome activation and subsequent IL-1β production remains unclear. In the present study, we used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mouse model to investigate whether Drd2 could suppress astrocytic NLRP3 inflammasome activation. We showed that Drd2 agonist inhibited NLRP3 inflammasome activation, evidenced by decreased caspase-1 expression and reduced IL-1β release in the midbrain of wild type mice. The anti-inflammasome effect of Drd2 was abolished in β-arrestin2 knockout and β-arrestin2 small interfering RNA-injected mice, suggesting a critical role of β-arrestin2 in Drd2-regulated NLRP3 inflammasome activation. We also found that Drd2 agonists suppressed the upregulation of caspase-1 and IL-1β expression in primary cultured mouse astrocytes in response to the activation of NLRP3 inflammasome induced by lipopolysaccharide plus adenosine triphosphate. Furthermore, we demonstrated that β-arrestin2 mediated the inhibitory effect of Drd2 on NLRP3 inflammasome activation via interacting with NLRP3 and interfering the inflammasome assembly. Collectively, our study illustrates that astrocytic Drd2 inhibits NLRP3 inflammasome activation through a β-arrestin2-dependent mechanism, and provides a new strategy for treatment of PD.

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Section: Discussionmentioning

confidence: 99%

Dopamine D2 receptor restricts astrocytic NLRP3 inflammasome activation via enhancing the interaction of β-arrestin2 and NLRP3

et al. 2018

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“…Inflammation is also associated with changes in brain dopamine metabolism (Felger, 2016); dopamine in turn affects immune system, especially immune response mediated by interleukin 17 producing Th cells (labelled Th17) that are distinct from Th1 and Th2 cells (Lieberknecht et al, 2016; Melnikov et al, 2016). Bupropion, a non-serotonergic antidepressant, inhibits dopamine reuptake, increases brain extracellular dopamine concentration (Ascher et al, 1995; Cremers et al, 2016), and has been shown to reduce inflammation mediated by both Th1 (by reducing IL-1 beta, IFNγ, and TNFα) and Th17 cells (Brustolim et al, 2006; Ebbinghaus et al, 2012; Warner-Schmidt et al, 2011).…”

Section: 0 Introductionmentioning

confidence: 99%

Can C-reactive protein inform antidepressant medication selection in depressed outpatients? Findings from the CO-MED trial

Jha

Minhajuddin

Gadad

et al. 2017

Psychoneuroendocrinology

155

113

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Objective Currently, no valid measures inform treatment selection for depressed patients. Whether C-reactive protein (CRP) in particular and two other acute phase reactants (inflammatory markers) could differentiate between patients responding to either of two treatments with different mechanisms of action was assessed. Method Subjects included Combining Medications to Enhance Depression Outcomes (CO-MED) trial participants randomly assigned to either escitalopram plus placebo (SSRI monotherapy, n=51) or bupropion plus escitalopram combination (bupropion-SSRI combination, n=55) with baseline plasma samples. CRP, serum amyloid P component, and alpha-2-macroglobulin were measured using the Bioplex Pro™ human acute-phase 4-plex panel. We conducted mixed model analyses of depressive symptom (Quick Inventory of Depressive Symptomatology Self-Report) and side-effect burden (Frequency, Intensity, and Burden of Side-Effects Rating Scale) obtained weekly or every other week over the 12-week acute-phase of CO-MED trial to evaluate the relationship between these outcomes and baseline CRP and other acute-phase reactants. Results The treatment arms did not differ in depressive symptom or side effect outcomes. Most participants (69.8%, 74/106) had baseline CRP levels greater than 1 mg/L (indicative of systemic inflammatory activity). Higher baseline CRP levels were associated lower depression severity (correlation coefficient=−0.63) with bupropion-SSRI combination but not with SSRI monotherapy (correlation coefficient=0.40). The overall remission rate was 41.5%. The estimated remission rate with CRP threshold based assignment (SSRI monotherapy for <1 mg/L and Bupropion-SSRI for ≥1 mg/L) was 53.1%, with a number needed to treat of 8.6. Side effect burden was unrelated to any baseline inflammatory marker. Conclusions Baseline CRP levels relate differentially to antidepressant treatment outcomes in persons with major depressive disorder.

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“…Dopamine D2 receptor (Drd2) has been regarded as a potential anti-inflammatory target in the therapy of NDDs [ 19 – 21 ]. Drd2 expresses both in neurons and astrocytes [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

α-Synuclein disrupts the anti-inflammatory role of Drd2 via interfering β-arrestin2-TAB1 interaction in astrocytes

Zhou

Xia

et al. 2018

J Neuroinflammation

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Backgroundα-Synuclein (α-Syn)-induced neuroinflammation plays a crucial role in the pathogenesis of Parkinson’s disease (PD). Dopamine D2 receptor (Drd2) has been regarded as a potential anti-inflammatory target in the therapy of neurodegenerative diseases. However, the effect of astrocytic Drd2 in α-Syn-induced neuroinflammation remains unclear.MethodsThe effect of Drd2 on neuroinflammation was examined in mouse primary astrocyte in vitro and A53T transgenic mice in vivo. The inflammatory responses of astrocyte were detected using immunofluorescence, ELISA, and qRT-PCR. The details of molecular mechanism were assessed using Western blotting and protein-protein interaction assays.ResultsWe showed that the selective Drd2 agonist quinpirole suppressed inflammation in the midbrain of wild-type mice, but not in α-Syn-overexpressed mice. We also found that Drd2 agonists significantly alleviated LPS-induced inflammatory response in astrocytes, but failed to suppress α-Syn-induced inflammatory response. The anti-inflammation effect of Drd2 was dependent on β-arrestin2-mediated signaling, but not classical G protein pathway. α-Syn reduced the expression of β-arrestin2 in astrocytes. Increased the β-arrestin2 expression restored in the anti-inflammation of Drd2 in α-Syn-induced inflammation. Furthermore, we demonstrated that α-Syn disrupted the anti-inflammation of Drd2 via inhibiting the association of β-arrestin2 with transforming growth factor-beta-activated kinase 1 (TAK1)-binding protein 1 (TAB1) and promoting TAK1-TAB1 interaction in astrocytes.ConclusionsOur study illustrates that astrocytic Drd2 inhibits neuroinflammation through a β-arrestin2-dependent mechanism and provides a new strategy for treatment of PD. Our findings also reveal that α-Syn disrupts the function of β-arrestin2 and inflammatory pathways in the pathogenesis of PD.

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Pramipexole, a Dopamine D2/D3 Receptor-Preferring Agonist, Prevents Experimental Autoimmune Encephalomyelitis Development in Mice

Cited by 49 publications

References 67 publications

Dopamine D2 receptor restricts astrocytic NLRP3 inflammasome activation via enhancing the interaction of β-arrestin2 and NLRP3

Dopamine D2 receptor restricts astrocytic NLRP3 inflammasome activation via enhancing the interaction of β-arrestin2 and NLRP3

Can C-reactive protein inform antidepressant medication selection in depressed outpatients? Findings from the CO-MED trial

α-Synuclein disrupts the anti-inflammatory role of Drd2 via interfering β-arrestin2-TAB1 interaction in astrocytes

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