背景:黑皮质素1受体(MC1R)是一个关键的色素沉着基因,产生红发的MC1R变体的功能丧失可能与帕金森病(PD)有关。我们先前报道了Mc1r突变小鼠中多巴胺能神经元的存活受损,以及向大脑局部注射MC1R激动剂或全身给药的具有明显中枢神经系统(CNS)渗透性的MC1R激动剂的多巴胺能神经保护作用。除了黑色素细胞和多巴胺能神经元,MC1R在其他外周组织和细胞类型中表达,包括免疫细胞。本研究调查了NDP-MSH的影响,一种不穿过BBB的合成黑皮质素受体(MCR)激动剂,对PD小鼠模型免疫系统和黑质纹状体多巴胺能系统的影响。
方法:用MPTP系统处理C57BL/6小鼠。从第1天至第4天的HCl(20mg/kg)和LPS(1mg/kg)和从第1天至第12天的NDP-MSH(400μg/kg)或载体,随后处死小鼠。对外周和CNS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了行为评估,化学,免疫学,和病态。为了了解调节性T细胞(Tregs)在该模型中的作用,CD25单克隆抗体用于消耗CD25+Treg。
结果:全身NDP-MSH给药显著减弱了MPTP+LPS诱导的纹状体多巴胺耗竭和黑质多巴胺能神经元丢失。它改善了极点测试中的行为结果。在MPTP和LPS范例中注射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途径起作用。尽管在大脑中没有检测到NDP-MSH,外围,NDP-MSH减弱了神经炎症,如在黑色区域的小胶质细胞活化减少所观察到的,腹侧中脑中TNF-α和IL1β水平降低。Tregs的消耗与NDP-MSH的神经保护作用减弱有关。
结论:我们的研究表明,外周作用的NDP-MSH可保护多巴胺能黑质纹状体神经元,并减少过度活化的小胶质细胞。NDP-MSH调节外周免疫应答,Tregs可能参与NDP-MSH的神经保护作用。
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.
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.
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.
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.