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Dopaminergic Receptors as Neuroimmune Mediators in Experimental Autoimmune Encephalomyelitis
Molecular Neurobiology ( IF 4.6 ) Pub Date : 2021-08-25 , DOI: 10.1007/s12035-021-02507-6
E C D Gonçalves 1, 2 , V Lieberknecht 1, 2 , V V Horewicz 3, 4 , B D Rabelo 1 , F A Felipetti 1 , A L S Rodrigues 2, 5 , D F Martins 3, 4 , R C Dutra 1, 2
Affiliation  

The dopaminergic system plays an essential role in maintaining homeostasis between the central nervous system (CNS) and the immune system. Previous studies have associated imbalances in the dopaminergic system to the pathogenesis of multiple sclerosis (MS). Here, we examined the protein levels of dopaminergic receptors (D1R and D2R) in different phases of the experimental autoimmune encephalomyelitis (EAE) model. We also investigated if the treatment with pramipexole (PPX)—a dopamine D2/D3 receptor-preferring agonist—would be able to prevent EAE-induced motor and mood dysfunction, as well as its underlying mechanisms of action. We report that D2R immunocontent is upregulated in the spinal cord of EAE mice 14 days post-induction. Moreover, D1R and D2R immunocontents in lymph nodes and the oxidative damage in the spinal cord and striatum of EAE animals were significantly increased during the chronic phase. Also, during the pre-symptomatic phase, axonal damage in the spinal cord of EAE mice could already be found. Surprisingly, therapeutic treatment with PPX failed to inhibit the progression of EAE. Of note, PPX treatment inhibited EAE-induced depressive-like while failed to inhibit anhedonic-like behaviors. We observed that PPX treatment downregulated IL-1β levels and increased BNDF content in the spinal cord after EAE induction. Herein, we show that a D2/D3 receptor-preferred agonist mitigated EAE-induced depressive-like behavior, which could serve as a new possibility for further clinical trials on treating depressive symptoms in MS patients. Thus, we infer that D2R participates in the crosstalk between CNS and immune system during autoimmune and neuroinflammatory response induced by EAE, mainly in the acute and chronic phase of the disease.



中文翻译:

多巴胺能受体作为实验性自身免疫性脑脊髓炎的神经免疫介质

多巴胺能系统在维持中枢神经系统 (CNS) 和免疫系统之间的体内平衡方面发挥着重要作用。以前的研究已将多巴胺能系统的失衡与多发性硬化症 (MS) 的发病机制联系起来。在这里,我们在实验性自身免疫性脑脊髓炎 (EAE) 模型的不同阶段检查了多巴胺能受体 (D1R 和 D2R) 的蛋白质水平。我们还研究了普拉克索 (PPX)(一种多巴胺 D2/D3 受体优先激动剂)治疗是否能够预防 EAE 诱导的运动和情绪功能障碍,以及其潜在的作用机制。我们报告说,诱导后 14 天,EAE 小鼠脊髓中 D2R 免疫含量上调。而且,EAE动物的淋巴结中D1R和D2R免疫含量以及脊髓和纹状体的氧化损伤在慢性期显着增加。此外,在症状前阶段,已经发现 EAE 小鼠脊髓中的轴突损伤。令人惊讶的是,PPX 治疗未能抑制 EAE 的进展。值得注意的是,PPX 治疗抑制了 EAE 诱导的抑郁样行为,而未能抑制快感样行为。我们观察到 PPX 治疗在 EAE 诱导后下调 IL-1β 水平并增加脊髓中的 BNDF 含量。在这里,我们展示了 D2/D3 受体首选的激动剂减轻了 EAE 诱导的抑郁样行为,这可以作为进一步临床试验治疗 MS 患者抑郁症状的新可能性。因此,

更新日期:2021-08-26
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