Neuropeptide S Receptor as an Innovative Therapeutic Target for Parkinson Disease

Abstract

Parkinson disease (PD) is a neurodegenerative disease mainly characterized by the loss of nigral dopaminergic neurons in the substantia nigra pars compacta. Patients suffering from PD develop severe motor dysfunctions and a myriad of non-motor symptoms. The treatment mainly consists of increasing central dopaminergic neurotransmission and alleviating motor symptoms, thus promoting severe side effects without modifying the disease's progress. A growing body of evidence suggests a close relationship between neuropeptide S (NPS) and its receptor (NPSR) system in PD: (i) double immunofluorescence labeling studies showed that NPSR is expressed in the nigral tyrosine hydroxylase (TH)-positive neurons; (ii) central administration of NPS increases spontaneous locomotion in naïve rodents; (iii) central administration of NPS ameliorates motor and nonmotor dysfunctions in animal models of PD; (iv) microdialysis studies showed that NPS stimulates dopamine release in naïve and parkinsonian rodents; (v) central injection of NPS decreases oxidative damage to proteins and lipids in the rodent brain; and, (vi) 7 days of central administration of NPS protects from the progressive loss of nigral TH-positive cells in parkinsonian rats. Taken together, the NPS/NPSR system seems to be an emerging therapeutic strategy for alleviating motor and non-motor dysfunctions of PD and, possibly, for slowing disease progress.

Keywords: Parkinson disease; animal models; dopamine; neuropeptide S; oxidative stress.

Figure 1

The hyperlocomotor effects of Neuropeptide S (NPS) are impaired in mice pretreated with drugs able to block dopaminergic transmission. Pretreatment with (A,B) reserpine 2 mg/kg (sc, 24 h before NPS), an inhibitor of vesicular uptake of catecholamines and 5-HT, and (C,D) sulpiride 25 mg/kg (ip, 45 min before NPS), a D₂-like receptor antagonist, prevented the hyperlocomotor effects of NPS 1 nmol (icv, 15 min prior to the test) in male Swiss mice assessed in the open field (40 × 40 × 40 cm) test for 60 min. Data are presented as cumulative distance moved (m) and distance moved (m) in blocks of 5 min. * p < 0.05 vs. Control; # p < 0.05 vs. NPS. ANOVA, Dunnett’s post hoc test ((A); F (3,50) = 8.46; p < 0.05; (C); F (3,43) = 9.93; p < 0.05).

Figure 2

Putative mechanisms by which Neuropeptide S (NPS), activating Neuropeptide S receptor (NPSR), alleviates Parkinson Disease (PD)-induced motor and non-motor dysfunctions. NPS increases dopaminergic transmission in mesolimbic and nigral dopaminergic pathways by facilitating the dopamine transmission (left panel). NPS promotes neuroprotective effects on dopaminergic neurons possibly by counteracting reactive oxidative species (ROS)-induced damage to structural lipids and proteins (right panel).