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.

Relationship of Neuropeptide S with Clinical and Metabolic Parameters of Patients during Rehabilitation Therapy for Schizophrenia

“…The NPS central activity was highlighted as the model of ‘arousal without anxiety’, which gives hope for the ability to improve fundamental deficits in schizophrenia, often even further exacerbated by using sedative anti-psychotics and anti-cholinergic drugs [ 50 ]. Finally, NPS is directly related to the most classic dopaminergic hypothesis of schizophrenia through stimulating dopamine release [ 3 ]. An experimental 7-day NPS administration to substantia nigra protected dopaminergic neurons from degeneration, possibly by reducing oxidative damage to lipids and proteins.…”

“…NPS is bound specifically to the G-protein-coupled receptor (NPSR1), which stimulates the intracellular Ca 2+ and cAMP signaling. The NPS peptide precursor mRNA is found only in limited regions of the brain (trigeminal nucleus, lateral parabrachial nucleus, locus coeruleus, and amygdala), and in contrast, NPSR1 mRNA is widely expressed in the entire central nervous system (CNS) [ 2 , 3 ]. NPS fibers project to limbic and thalamic areas such as the amygdala, hypothalamus, and paraventricular thalamic nucleus [ 4 ].…”

“…While NPS may have a beneficial effect on anxiety, no direct effect on depression has yet been demonstrated in animal models [ 20 ]. The NPS/NPSR1 system could be the platform for drug development on wakefulness–sleep disorders [ 8 ], to alleviate motor and non-motor dysfunctions of Parkinsonian diseases [ 3 ], to improve learning and memory, e.g., in Alzheimer’s disease [ 21 ], and to treat substance abuse disorders [ 22 , 23 ].…”

Commentary: Dopamine-Dependent Early Synaptic and Motor Dysfunctions Induced by α-Synuclein in the Nigrostriatal Circuit

“…Parkinson’s disease (PD) is a neurodegenerative illness that causes severe motor dysfunction in individuals. Symptoms of PD include motor retardation, uncontrollable tremors at rest, postural problem, and stiffness ( Surmeier, 2018 ; Ganguly et al, 2021 ), as well as a variety of non-motor symptoms ( Holanda et al, 2021 ). The predominant neuropathologic hallmarks are synaptic damage and loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) ( Trudler et al, 2021 ).…”