Background

Melanocortin 1 receptor (MC1R) is a key pigmentation gene, and loss-of-function of MC1R variants that produce red hair may be associated with Parkinson’s disease (PD). We previously reported compromised dopaminergic neuron survival in Mc1r mutant mice and dopaminergic neuroprotective effects of local injection of a MC1R agonist to the brain or a systemically administered MC1R agonist with appreciable central nervous system (CNS) permeability. Beyond melanocytes and dopaminergic neurons, MC1R is expressed in other peripheral tissues and cell types, including immune cells. The present study investigates the impact of NDP-MSH, a synthetic melanocortin receptor (MCR) agonist that does not cross BBB, on the immune system and the nigrostriatal dopaminergic system in mouse model of PD.

Methods

C57BL/6 mice were treated systemically with MPTP.HCl (20 mg/kg) and LPS (1 mg/kg) from day 1 to day 4 and NDP-MSH (400 µg/kg) or vehicle from day 1 to day 12 following which the mice were sacrificed. Peripheral and CNS immune cells were phenotyped and inflammatory markers were measured. The nigrostriatal dopaminergic system was assessed behaviorally, chemically, immunologically, and pathologically. To understand the role of regulatory T cells (Tregs) in this model, CD25 monoclonal antibody was used to deplete CD25 + Tregs.

Results

Systemic NDP-MSH administration significantly attenuated striatal dopamine depletion and nigral dopaminergic neuron loss induced by MPTP + LPS. It improved the behavioral outcomes in the pole test. Mc1r mutant mice injected with NDP-MSH in the MPTP and LPS paradigm showed no changes in striatal dopamine levels suggesting that the NDP-MSH acts through the MC1R pathway. Although no NDP-MSH was detected in the brain, peripheral, NDP-MSH attenuated neuroinflammation as observed by diminished microglial activation in the nigral region, along with reduced TNF-α and IL1β levels in the ventral midbrain. Depletion of Tregs was associated with diminished neuroprotective effects of NDP-MSH.

Conclusions

Our study demonstrates that peripherally acting NDP-MSH confers protection on dopaminergic nigrostriatal neurons and reduces hyperactivated microglia. NDP-MSH modulates peripheral immune responses, and Tregs may be involved in the neuroprotective effect of NDP-MSH.

中文翻译：

---

外周 MC1R 激活可调节免疫反应，并在帕金森病小鼠模型中具有神经保护作用

背景

黑皮质素 1 受体 ( MC1R ) 是一种关键的色素沉着基因，产生红发的MC1R变体功能丧失可能与帕金森病 (PD) 相关。我们之前报道了Mc1r突变小鼠的多巴胺能神经元存活受损，以及向大脑局部注射 MC1R 激动剂或全身给药具有明显中枢神经系统 (CNS) 通透性的 MC1R 激动剂的多巴胺能神经保护作用。除了黑素细胞和多巴胺能神经元之外，MC1R 还在其他外周组织和细胞类型中表达，包括免疫细胞。本研究探讨了 NDP-MSH（一种不穿过 BBB 的合成黑皮质素受体 (MCR) 激动剂）对 PD 小鼠模型中免疫系统和黑质纹状体多巴胺能系统的影响。

方法

C57BL/6 小鼠从第 1 天到第 4 天用 MPTP.HCl (20 mg/kg) 和 LPS (1 mg/kg) 进行全身治疗，并从第 1 天到第 12 天用 NDP-MSH (400 µg/kg) 或载体进行全身治疗小鼠被处死。对外周和中枢神经系统免疫细胞进行表型分析并测量炎症标志物。对黑质纹状体多巴胺能系统进行行为、化学、免疫学和病理学评估。为了了解调节性 T 细胞 (Treg) 在此模型中的作用，使用 CD25 单克隆抗体来消除 CD25 + Tregs。

结果

全身 NDP-MSH 给药显着减弱 MPTP + LPS 诱导的纹状体多巴胺耗竭和黑质多巴胺能神经元损失。它改善了杆测试中的行为结果。在 MPTP 和 LPS 范式中注射 NDP-MSH 的Mc1r突变小鼠显示纹状体多巴胺水平没有变化，表明 NDP-MSH 通过 MC1R 途径发挥作用。尽管在大脑中未检测到 NDP-MSH，但外周神经炎症可通过黑质区小胶质细胞激活的减少以及中脑腹侧 TNF-α 和 IL1β 水平的降低观察到。Tregs 的消耗与 NDP-MSH 神经保护作用的减弱有关。

结论

我们的研究表明，外周作用的 NDP-MSH 可以保护多巴胺能黑质纹状体神经元并减少过度活跃的小胶质细胞。NDP-MSH 调节外周免疫反应，Treg 可能参与 NDP-MSH 的神经保护作用。