Background:Melanocortin 1 receptor (MC1R) is a key pigmentation gene, and loss-of-function ofMC1Rvariants that produce red hair may be associated with Parkinson’s disease (PD). We previously reported compromised dopaminergic neuron survival inMc1rmutant mice and dopaminergic neuroprotective effects of local injection of a MC1R agonist to the brain or a systemically administered MC1R agonist with appreciable 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.Mc1rmutant 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 limited the 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.