neuropeptide-y and Parkinson-Disease

Previous research has demonstrated that dopamine and Neuropeptide Y (NPY) promote motivated behavior, and there is evidence to suggest that they interact within neural circuitry involved in motivation. NPY and dopamine both modulate appetitive motivation towards food through direct actions in the nucleus accumbens (NAc), although how they interact in this region to promote motivation is presently unclear. In this study, we sought to further elucidate the relationship between NAc NPY and dopamine and their effects on motivated behavior. Specifically, we examined whether NAc injections of NPY might reverse behavioral deficits caused by reduced dopamine signaling due to systemic dopamine receptor antagonism. Appetitive motivation was measured using a progressive ratio-2 paradigm. Male Sprague Dawley rats were treated with systemic injections of the dopamine antagonist, α-flupenthixol or a saline vehicle. Two hours following injections, they were administered infusions of NPY (at 0, 156, or 235 pmol) into either the NAc shell (n = 12) or the NAc core (n = 10) and were placed in operant chambers. In both groups, α-flupenthixol impaired performance on the PR-2 task. NPY receptor stimulation of the NAc shell significantly increased both breakpoint and active lever presses during the PR-2 task, and dose-dependently increased responding following systemic dopamine receptor blockade. NPY did not affect appetitive motivation when injected into the NAc core. These data demonstrate that NPY in the NAc shell can improve motivational impairments that result from dopamine antagonism, and that these effects are site specific. These results also suggest that upregulation of NPY in neurodegenerative diseases may possibly buffer early motivational deficits caused by dopamine depletion in Parkinson's and Huntington's disease patients, both of which show increased NPY expression after disease onset.

Topics: Animals; Dopamine; Dopamine Antagonists; Flupenthixol; Huntington Disease; Male; Motivation; Neuropeptide Y; Nucleus Accumbens; Parkinson Disease; Rats; Rats, Sprague-Dawley; Receptors, Dopamine

Parkinson's disease (PD) is an aging disorder related to vesicle transport dysfunctions and neurotransmitter secretion. Secretory granules (SGs) are large dense-core vesicles for the biosynthesis of neuropeptides and hormones. At present, the involvement of SGs impairment in PD remains unclear. In the current study, we found that the number of SGs in tyrosine hydroxylase-positive neurons and the marker proteins secretogranin III (Scg3) significantly decreased in the substantia nigra and striatum regions of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) exposed mice. Proteomic study of SGs purified from the dopaminergic SH-sy5Y cells under 1-methyl-4-phenylpyridinium (MPP+) treatments (ProteomeXchange PXD023937) identified 536 significantly differentially expressed proteins. The result indicated that disabled lysosome and peroxisome, lipid and energy metabolism disorders are three characteristic features. Protein-protein interaction analysis of 56 secretory proteins and 140 secreted proteins suggested that the peptide processing mediated by chromogranin/secretogranin in SGs was remarkably compromised, accompanied by decreased candidate proteins and peptides neurosecretory protein (VGF), neuropeptide Y, apolipoprotein E, and an increased level of proenkephalin. The current study provided an extensive proteinogram of SGs in PD. It is helpful to understand the molecular mechanisms in the disease.

Topics: Animals; Apolipoproteins E; Chromogranins; Dopaminergic Neurons; Humans; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Parkinson Disease; Proteins; Proteomics; Secretory Vesicles

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the nigro-striatal pathway. Interestingly, it has already been shown that an intracerebral administration of neuropeptide Y (NPY) decreases the neurodegeneration induced by 6-hydroxydopamine (6-OHDA) in rodents and prevents loss of dopamine (DA) and DA transporter density. The etiology of idiopathic PD now suggest that chronic production of inflammatory mediators by activated microglial cells mediates the majority of DA-neuronal tissue destruction. In an animal experimental model of PD, the present study shows that NPY inhibited the activation of microglia evaluated by the binding of the translocator protein (TSPO) ligand [3H]PK11195 in striatum and substantia nigra of 6-OHDA rats. These results suggest a potential role for inflammation in the pathophysiology of the disease and a potential treatment by NPY in PD.

Topics: Animals; Corpus Striatum; Disease Models, Animal; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Inflammation; Male; Microglia; Nerve Degeneration; Neuropeptide Y; Neuroprotection; Oxidopamine; Parkinson Disease; Rats; Rats, Wistar; Substantia Nigra

This study was aimed to investigate the potential neuroprotective effect of neuropeptide Y (NPY) on the survival of dopaminergic cells in both in vitro and in animal models of Parkinson's disease (PD). NPY protected human SH-SY5Y dopaminergic neuroblastoma cells from 6-hydroxydopamine-induced toxicity. In rat and mice models of PD, striatal injection of NPY preserved the nigrostriatal dopamine pathway from degeneration as evidenced by quantification of (1) tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta, levels of (2) striatal tyrosine hydroxylase and dopamine transporter, (3) dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) as well as (4) rotational behavior. NPY had no neuroprotective effects in mice treated with Y(2) receptor antagonist or in transgenic mice deficient for Y(2) receptor suggesting that NPY effects are mediated through this receptor. Stimulation of Y(2) receptor by NPY triggered the activation of both the ERK1/2 and Akt pathways but did not modify levels of brain derived neurotrophic factor (BDNF) or glial cell line-derived neurotrophic factor. These results open new perspectives in neuroprotective therapies using NPY and suggest potential beneficial effects in PD.

Topics: Adrenergic Agents; Analysis of Variance; Animals; Animals, Newborn; Arginine; Autoradiography; Cell Line, Tumor; Cell Survival; Chromatography, High Pressure Liquid; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Enzyme Inhibitors; Female; Functional Laterality; Humans; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuroblastoma; Neurodegenerative Diseases; Neuropeptide Y; Neuroprotective Agents; Nortropanes; Oligopeptides; Oxidopamine; Parkinson Disease; Protein Binding; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Substantia Nigra; Tyrosine 3-Monooxygenase

The exact mechanism of weight gain (WG) after deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with idiopathic Parkinson's disease remains unknown.. To investigate a possible involvement of ghrelin, neuropeptide Y (NPY) and leptin in WG after DBS.. Twenty-three Parkinson patients were submitted for body composition measurements and blood sampling 3 days before, and 3 and 6 months after STN DBS. Peripheral concentrations of ghrelin, NPY, and leptin were determined, as well as the L-dopa equivalent daily dose. Patients were clinically evaluated using the Unified Parkinson's Disease Rating Scale.. Three months after surgery, a significant WG was observed (3.09 ± 5.00 kg; p = 0.007) with no further increase at 6 months. Three months postoperatively, NPY circulating levels increased significantly (p = 0.05), while the increase of ghrelin levels reached statistical significance at 6 months (p = 0.001). WG was significantly associated with changes of ghrelin and leptin levels at 3 and 6 months, respectively.. STN DBS seems to temporarily dysregulate the hypothalamic secretion of NPY and ghrelin. The variation of weight may be attributed to an increased production of ghrelin and leptin. A possible neuroprotective role of DBS, exerted through the increase of ghrelin levels, should be further studied.

Topics: Aged; Body Composition; Deep Brain Stimulation; Female; Ghrelin; Humans; Leptin; Male; Middle Aged; Neuropeptide Y; Parkinson Disease; Subthalamic Nucleus; Treatment Outcome; Weight Gain

OBJECTIVES - Determine whether bilateral subthalamic nucleus stimulation (STN-DBS) in Parkinson's disease (PD) is associated with an increase in neuropeptide Y (NPY) and/or resistance to inhibition by leptin in relation to post-surgery weight gain. MATERIALS AND METHODS - This prospective study included 20 patients who underwent bilateral STN-DBS and 17 who refused surgery. Data were obtained at baseline, 3 and 6 months on neurological and nutritional status, including determination of body mass index (BMI) and serum NPY and leptin levels. RESULTS -  NPY and leptin levels changed over time, with a distinct pattern. The BMI increase at 6 months was greater in the surgical group (5.5 ± 6.3% vs 0.5 ± 3.5%; P = 0.035). Medical group exhibited a reduction in leptin level (-2.0 ± 4.3 ng/ml) and a consequent increase in NPY level (72.4 ± 58.7 pmol/ml). However, STN-DBS patients showed an increase in leptin (3.1 ± 5.0 ng/ml; P = 0.001 vs medical group) and also in NPY (12.1 ± 53.6 pmol/ml; P = 0.022 vs medical group) levels, which suggests resistance to inhibition by leptin. Rise in NPY level correlated with higher stimulation voltages. CONCLUSIONS -  Bilateral STN-DBS causes disruption of the melanocortin system, probably related to diffusion of the electric current to the hypothalamus. This mechanism may in part explain the weight gain of patients with PD after surgery.

Topics: Aged; Body Mass Index; Electric Stimulation Therapy; Female; Humans; Leptin; Male; Melanocortins; Middle Aged; Neuropeptide Y; Parkinson Disease; Prospective Studies; Subthalamic Nucleus; Treatment Outcome; Weight Gain

High levels of neuropeptide Y (NPY) are found in basal ganglia where it is co-localised with somatostatin (SOM) and nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH/d) in a population of striatal GABA containing interneurones. Although alterations occur in the levels of various neuropeptides in basal ganglia in Parkinson's disease (PD), it is not known whether NPY is affected. Using in situ hybridisation immunohistochemistry, we have examined the distribution of NPY mRNA in the caudate nucleus, putamen and nucleus accumbens of normal individuals and patients with PD. NPY mRNA was weakly expressed in the caudate nucleus, putamen and nucleus accumbens in normal individuals with a scattered labelling of neurones. However, there was no regional localisation within any brain area and no obvious differences between brain regions. In PD, the number of NPY mRNA-expressing cells was increased as was the density of the silver grains overlying each positive cell. The increase was more pronounced in the nucleus accumbens and in the ventral part of the caudate nucleus. The increase in NPY mRNA expression observed in patients with PD may reflect the loss of dopaminergic tone on striatal NPY containing interneurones, although a role for chronic L-DOPA therapy cannot be ruled out.

Topics: Aged; Caudate Nucleus; Corpus Striatum; Female; Gene Expression Regulation; Humans; Interneurons; Male; Middle Aged; Neuropeptide Y; Nucleus Accumbens; Parkinson Disease; Putamen; RNA, Messenger

Neuropeptide Y, one of the most abundant polypeptides within the nervous system, is co-stored with catecholamines, especially norepinephrine (NE), thus suggesting its possible involvement in pathologies characterized by a noradrenergic impairment. In Parkinson's disease (PD), as well as in multiple system atrophy (MSA), a central noradrenergic deficit has been demonstrated, and in the dementia of Alzheimer type (DAT) an impaired noradrenergic transmission has been postulated. In this study we determined CSF NE and MHPG levels in 29 PD, 15 MSA, 22 DAT patients and in 36 controls, while CSF NPY-immunoreactivity (NPY-ir) levels were measured in 10 PD, 7 MSA, 10 DAT patients and 20 controls. PD, MSA, and DAT patients showed a significant reduction in CSF NPY-ir and NE levels compared with controls, while CSF MHPG levels resulted in a reduction in only the MSA group. Furthermore, an inverse correlation between either NE or MHPG levels and the duration of the orthostatic hypotension was found in MSA patients while for DAT patients the MHPG levels were directly correlated to the severity of cognitive impairment, and inversely to the duration of illness.

Topics: Adult; Aged; Alzheimer Disease; Female; Humans; Male; Methoxyhydroxyphenylglycol; Middle Aged; Neuropeptide Y; Norepinephrine; Parkinson Disease; Peripheral Nervous System Diseases; Severity of Illness Index; Shy-Drager Syndrome; Spinal Cord Diseases

Topics: Aged; Aged, 80 and over; Brain Mapping; Computer Simulation; Female; Galanin; Humans; Locus Coeruleus; Male; Models, Neurological; Nerve Degeneration; Neurons; Neuropeptide Y; Norepinephrine; Parkinson Disease; Peptide Fragments; Peptides

For diagnostic purposes, a differentiation can be made between the locus coeruleus (LC) in normal brain and the LC, in senile dementia of the Alzheimer's type (SDAT) and Parkinson's disease (PD). The differentiation is based on findings concerning the morphological alterations of the TH-immunoreactive; neurons, on the topographical distribution of neuron loss within the length of the LC, and on the total reduction in cell number.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Cell Count; Dopamine beta-Hydroxylase; Female; Galanin; Humans; Immunoenzyme Techniques; Locus Coeruleus; Male; Middle Aged; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Parkinson Disease; Peptides; Tyrosine 3-Monooxygenase

The levels in lumbar cerebrospinal fluid (CSF) of neuropeptide Y (NPY), methionine enkephalin (Enk), and Enk contained in amino- and carboxy-terminus extended forms (X-Enk) were examined in nine control patients undergoing elective surgical procedures and in eight patients with advanced Parkinson's disease, before and after the autologous transplantation of adrenal medullary fragments into the right caudate nucleus. The levels of CSF Enk and X-Enk before surgery in patients with Parkinson's disease were significantly less than those observed in control patients (Enk, 166 +/- 38 vs 264 +/- 44 pg/ml; X-Enk, 794 +/- 416 vs 1497 +/- 153 pg/ml). NPY levels did not differ (221 +/- 25 vs 193 +/- 23 pg/ml). After surgery, lumbar CSF samples were taken at 6 weeks, 12 weeks, 6 months, and 9 months. Placement of adrenal medullary fragments into the striatum had no effect on the levels of NPY or Enk at any time point. The levels of X-Enk were significantly enhanced only at 12 weeks (1138 +/- 140 pg/ml) but were at presurgical levels again by 6 months. These data suggest that the transplant was not functionally contributing to the CSF levels of these peptides.

Topics: Adrenal Medulla; Adult; Aged; Caudate Nucleus; Enkephalin, Methionine; Humans; Male; Middle Aged; Neuropeptide Y; Parkinson Disease; Spinal Puncture; Time Factors; Transplantation, Autologous

Topics: Alzheimer Disease; Brain; Brain Mapping; Corticotropin-Releasing Hormone; Humans; Neuropeptide Y; Parkinson Disease; Radioimmunoassay; Receptors, Nicotinic

Somatostatin-like immunoreactivity (SLI) and neuropeptide Y-like immunoreactivity (NPYLI) were measured in postmortem brain tissue from 12 control patients and 13 demented Parkinsonian patients who had Alzheimer-type cortical pathology. Twenty-two cortical regions were examined. Significant reductions in cortical SLI were found in 17 regions, while significant reductions in cortical NPYLI were found in nine regions. The reductions in SLI were typically 50-60%, while NPYLI reductions were 20-30%. These findings are similar to those in Alzheimer's disease (AD) and are consistent with a previous report of a dissociation between reductions in SLI and NPYLI in Parkinson's disease (PD) with dementia.

Topics: Aged; Alzheimer Disease; Female; Humans; Male; Middle Aged; Neuropeptide Y; Parkinson Disease; Somatostatin

The concentration of neuropeptide Y has been determined in the cortex and hippocampus of subjects with Parkinson's disease and compared to changes of activity of dopamine beta-hydroxylase and concentration of somatostatin. Despite a marked reduction in the concentration of somatostatin in the severely demented subject, in both cortex and hippocampus, no significant change in concentration of NPY was found in either region. This finding therefore suggests that the majority of NPY within the cortex is independent of somatostatin. This study provides some further evidence of neurochemical similarities between the dementia of Parkinson's disease and Alzheimer's disease.

Topics: Brain Chemistry; Cerebral Cortex; Dopamine beta-Hydroxylase; Hippocampus; Humans; Nerve Tissue Proteins; Neuropeptide Y; Parkinson Disease; Retrospective Studies; Somatostatin