neuropeptide-y and Neurodegenerative-Diseases

Neuropeptide Y (NPY), a 36 amino acid peptide, is widely expressed in the mammalian brain. Changes in NPY levels in different brain regions and plasma have been described in several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and Machado-Joseph disease. The changes in NPY levels may reflect the attempt to set up an endogenous neuroprotective mechanism to counteract the degenerative process. Accumulating evidence indicates that NPY can function as an anti-apoptotic, anti-inflammatory, and pro-phagocytic agent, which may be used effectively to halt or to slow down the progression of the disease. In this review, we will focus on the neuroprotective roles of NPY in several neuropathological conditions, with a particular focus on the anti-inflammatory properties of NPY.

Topics: Animals; Brain; Humans; Huntington Disease; Mammals; Neurodegenerative Diseases; Neuropeptide Y; Neuroprotective Agents

Microglial cells are responsible for immune surveillance within the CNS. They respond to noxious stimuli by releasing inflammatory mediators and mounting an effective inflammatory response. This is followed by release of anti-inflammatory mediators and resolution of the inflammatory response. Alterations to this delicate process may lead to tissue damage, neuroinflammation, and neurodegeneration. Chronic pain, such as inflammatory or neuropathic pain, is accompanied by neuroimmune activation, and the role of glial cells in the initiation and maintenance of chronic pain has been the subject of increasing research over the last two decades. Neuropeptides are small amino acidic molecules with the ability to regulate neuronal activity and thereby affect various functions such as thermoregulation, reproductive behavior, food and water intake, and circadian rhythms. Neuropeptides can also affect inflammatory responses and pain sensitivity by modulating the activity of glial cells. The last decade has witnessed growing interest in the study of microglial activation and its modulation by neuropeptides in the hope of developing new therapeutics for treating neurodegenerative diseases and chronic pain. This review summarizes the current literature on the way in which several neuropeptides modulate microglial activity and response to tissue damage and how this modulation may affect pain sensitivity.

Topics: Adrenomedullin; Animals; Calcitonin Gene-Related Peptide; Ghrelin; Humans; Inflammation; Inflammation Mediators; Leptin; Macrophage Activation; Microglia; Neuralgia; Neurodegenerative Diseases; Neuroglia; Neuropeptide Y; Neuropeptides; Pain; Pro-Opiomelanocortin; Tachykinins; Vasoactive Intestinal Peptide

Neuropeptide Y (NPY) and NPY receptors are widely expressed in the mammalian central nervous system. Studies in both humans and rodent models revealed that brain NPY levels are altered in some neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Machado-Joseph disease. In this review, we will focus on the roles of NPY in the pathological mechanisms of these disorders, highlighting NPY as a neuroprotective agent, as a neural stem cell proliferative agent, as an agent that increases trophic support, as a stimulator of autophagy and as an inhibitor of excitotoxicity and neuroinflammation. Moreover, the effect of NPY in some clinical manifestations commonly observed in Alzheimer's disease, Parkinson's disease, Huntington's disease and Machado-Joseph disease, such as depressive symptoms and body weight loss, are also discussed. In conclusion, this review highlights NPY system as a potential therapeutic target in neurodegenerative diseases.

Topics: Animals; Brain; Cell Survival; Humans; Neurodegenerative Diseases; Neuropeptide Y; Neuroprotective Agents; Receptors, Neuropeptide Y

Topics: Animals; Central Nervous System Diseases; Emotions; Hippocampus; Humans; Neurodegenerative Diseases; Neuropeptide Y; Pain; Seizures; Stress, Psychological; Synapses

Topics: Animals; Chronic Disease; Humans; Neurodegenerative Diseases; Neuropeptide Y

Neuropeptide Y (NPY) is one of the most abundant and widely distributed neuropeptides in the mammalian central nervous system (CNS). An overview of the distribution of the G-protein coupled NPY receptor family (Y(1), Y(2), Y(4), Y(5) receptors) in the brain is described. The coexistence of NPY with other neurotransmitters and its wide distribution in several brain areas predict the high importance of NPY as a neuromodulator. Thus, the effect of NPY on the release of several neurotransmitters such as glutamate, gamma-aminobutyric acid (GABA), norepinephrine (NE), dopamine, somastotatin (SOM), serotonin (5-HT), nitric oxide (NO), growth hormone (GH) and corticotropin releasing factor (CRF) is reviewed. A neuroprotective role for NPY under physiological conditions and during hyperactivity such as epileptic-seizures has been suggested. We have shown previously that NPY inhibits glutamate release evoked from hippocampal nerve terminals and has a neuroprotective effect in rat organotypic hippocampal cultures exposed to an excitotoxic insult. Moreover, changes in NPY levels have been observed in different pathological conditions such as brain ischemia and neurodegenerative diseases (Huntington's, Alzheimer's and Parkinson's diseases). Taken together, these studies suggest that NPY and NPY receptors may represent pharmacological targets in different pathophysiological conditions in the CNS.

Topics: Animals; Brain; Cell Survival; Epilepsy; Humans; Ischemia; Neurodegenerative Diseases; Neuropeptide Y; Neuroprotective Agents; Rats; Receptors, Neuropeptide Y; Tissue Distribution

The senescence-accelerated mouse prone 8 (SAMP8) strain is considered a neurodegeneration model showing age-related cognitive deficits with little physical impairment. Young SAMP8 mice, however, exhibit signs of disturbances in development such as marked hyperactivity and reduced anxiety well before the onset of cognitive impairment. As the key enzyme in local regulation of thyroid hormone (TH) signaling, type 2 deiodinase, was significantly reduced in the SAMP8 hippocampus relative to that of the normally aging SAM-resistant 1 (SAMR1), we used these two strains to compare the development of the hippocampal GABAergic system, which is known to be strongly affected by hypothyroidism. Among GABAergic components, neuronal K+ /Cl- co-transporter 2 was down-regulated in SAMP8 transiently at 2 weeks. Although distribution of total GABAergic neurons was similar in both strains, 22-30% reduction was observed in the neuropeptide Y (NPY)-positive subpopulation of GABAergic neurons in SAMP8. Electrophysiological studies on hippocampal slices obtained at 4 weeks revealed that epileptiform activity, induced by high-frequency stimulation, lasted four times longer in SAMP8 compared with SAMR1, indicating a dysregulation of excitability that may be linked to the behavioral abnormalities of young SAMP8 and to neurodegeneration later on in life. Local attenuation of TH signaling may thus impact the normal development of the GABAergic system.

Topics: Aging; Animals; Behavior, Animal; Cognition Disorders; Cyclic AMP Response Element-Binding Protein; Electrophysiological Phenomena; gamma-Aminobutyric Acid; Hippocampus; Iodide Peroxidase; K Cl- Cotransporters; Learning Disabilities; Male; Memory Disorders; Mice; Neurodegenerative Diseases; Neurons; Neuropeptide Y; Phosphorylation; Symporters; Thyroid Hormones

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 introduction of a reporter gene into bacterial artificial chromosome (BAC) constructs allows a rapid identification of the cell type expressing the gene of interest. Here we used BAC transgenic mice expressing a tau-sapphire green fluorescent protein (GFP) under the transcriptional control of the neuropeptide Y (NPY) genomic sequence to characterize morphological and electrophysiological properties of NPY-GFP interneurons of the mouse juvenile primary somatosensory cortex. Electrophysiological whole-cell recordings and biocytin injections were performed to allow the morphological reconstruction of the recorded neurons in three dimensions. Ninety-six recorded NPY-GFP interneurons were compared with 39 wild-type (WT) NPY interneurons, from which 23 and 19 were reconstructed, respectively. We observed that 91% of the reconstructed NPY-GFP interneurons had developed an atypical axonal swelling from which emerge numerous ramifications. These abnormalities were very heterogeneous in shape and size. They were immunoreactive for the microtubule-associated protein tau and the lysosomal-associated membrane protein 1 (LAMP1). Moreover, an electron microscopic analysis revealed the accumulation of numerous autophagic and lysosomal vacuoles in swollen axons. Morphological analyses of NPY-GFP interneurons also indicated that their somata were smaller, their entire dendritic tree was thickened and presented a restricted spatial distribution in comparison with WT NPY interneurons. Finally, the morphological defects observed in NPY-GFP interneurons appeared to be associated with alterations of their electrophysiological intrinsic properties. Altogether, these results demonstrate that NPY-GFP interneurons developed dystrophic axonal swellings and severe morphological and electrophysiological defects that could be due to the overexpression of tau-coupled reporter constructs.

Topics: Animals; Axons; Dendrites; Fluorescent Antibody Technique; In Vitro Techniques; Interneurons; Luminescent Proteins; Lysine; Lysosomal Membrane Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Immunoelectron; Neurodegenerative Diseases; Neuropeptide Y; Patch-Clamp Techniques; Reverse Transcriptase Polymerase Chain Reaction; Somatosensory Cortex; tau Proteins

The functional role of the calcium-binding proteins parvalbumin, calretinin, and calbindin D-28k for epileptogenesis and long-term seizure-related alterations of the hippocampal formation was assessed in single- and double-knockout mice, using a kainate model of mesial temporal lobe epilepsy. The effects of a unilateral intrahippocampal injection of kainic acid were assessed at one day, 30 days, and four months post-injection, using various markers of GABAergic interneurons (GABA-transporter type 1, GABA(A)-receptor alpha1 subunit, calretinin, calbindin D-28k, somatostatin, and neuropeptide Y). Parvalbumin-deficient, parvalbumin/calbindin-deficient, and parvalbumin/calretinin-deficient mice exhibited no difference in cytoarchitecture of the hippocampal formation and in the number, distribution, or morphology of interneurons compared to wild-type mice. Likewise, mutant mice were not more vulnerable to acute kainate-induced excitotoxicity or to long-term effects of recurrent focal seizures, and exhibited the same pattern of neurochemical alterations (e.g., bilateral induction of neuropeptide Y in granule cells) and morphogenic changes (enlargement and dispersion of dentate gyrus granule cells) as wild-type animals. Quantification of interneurons revealed no significant difference in neuronal vulnerability among the genotypes.These results indicate that the calcium-binding proteins investigated here are not essential for determining the neurochemical phenotype of interneurons. Furthermore, they are not protective against kainate-induced excitotoxicity in this model, and do not appear to modulate the overall level of excitability of the hippocampus. Finally, seizure-induced changes in gene expression in granule cells, which normally express high levels of calcium-binding proteins, apparently were not affected by the gene deletions analysed.

Topics: Animals; Calbindin 2; Calbindins; Calcium-Binding Proteins; Carrier Proteins; Cell Survival; Disease Models, Animal; Epilepsy, Temporal Lobe; Excitatory Amino Acid Agonists; GABA Plasma Membrane Transport Proteins; Gene Expression Regulation; Hippocampus; Immunohistochemistry; Interneurons; Kainic Acid; Membrane Proteins; Membrane Transport Proteins; Mice; Mice, Knockout; Neurodegenerative Diseases; Neuropeptide Y; Organic Anion Transporters; Parvalbumins; Receptors, GABA-A; S100 Calcium Binding Protein G; Seizures; Somatostatin

Tumor necrosis factor-alpha (TNF-alpha) is a cytokine involved in a variety of neurobiological activities including changing behavior and regulation of both neurotrophin and neuropeptide levels. In this study we used two lines of transgenic mice overexpressing brain TNF-alpha characterized by neurological deficits (line Tg6074) or phenotypically normal (line TgK3). We analyzed whether or not impairments in learning and memory processes due to TNF-alpha overexpression were associated with changes in endogenous brain NGF, NPY and beta-amyloid. The results indicate that full TNF-alpha transgene expression disrupted the learning capabilities of transgenic mice (both Tg6074 and TgK3). NGF decreased in the hippocampus of both transgenic mice whereas hippocampal NPY slightly potentiated in Tg6074. The decrease in NGF is correlated with deficits in spatial learning and memory whereas inflammation in the brain of Tg6074 could be responsible of the hippocampal increase in NPY. As a whole, these results show that transgenic mice overexpressing TNF-alpha in the brain represent a useful model for studying neuronal degeneration and brain inflammatory processes.

Topics: Amyloid beta-Peptides; Animals; Disease Models, Animal; Female; Gene Expression; Hippocampus; Immunohistochemistry; Male; Maze Learning; Memory; Mice; Mice, Transgenic; Nerve Growth Factor; Neurodegenerative Diseases; Neuropeptide Y; Radioimmunoassay; Swimming; Tumor Necrosis Factor-alpha

Ras is a universal eukaryotic intracellular protein integrating extracellular signals from multiple receptor types. To investigate its role in the adult central nervous system, constitutively activated V12-Ha-Ras was expressed selectively in neurons of transgenic mice via a synapsin promoter. Ras-transgene protein expression increased postnatally, reaching a four- to fivefold elevation at day 40 and persisting at this level, thereafter. Neuronal Ras was constitutively active and a corresponding activating phosphorylation of mitogen-activated kinase was observed, but there were no changes in the activity of phosphoinositide 3-kinase, the phosphorylation of its target kinase Akt/PKB, or expression of the anti-apoptotic proteins Bcl-2 or Bcl-X(L). Neuronal Ras activation did not alter the total number of neurons, but induced cell soma hypertrophy, which resulted in a 14.5% increase of total brain volume. Choline acetyltransferase and tyrosine hydroxylase activities were increased, as well as neuropeptide Y expression. Degeneration of motorneurons was completely prevented after facial nerve lesion in Ras-transgenic mice. Furthermore, neurotoxin-induced degeneration of dopaminergic substantia nigra neurons and their striatal projections was greatly attenuated. Thus, the Ras signaling pathway mimics neurotrophic effects and triggers neuroprotective mechanisms in adult mice. Neuronal Ras activation might become a tool to stabilize donor neurons for neural transplantation and to protect neuronal populations in neurodegenerative diseases.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 1-Methyl-4-phenylpyridinium; Animals; Axotomy; Brain; Cell Count; Cell Size; Cells, Cultured; Choline O-Acetyltransferase; Enzyme Activation; Hypertrophy; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinases; Motor Neurons; Mutation; Neurodegenerative Diseases; Neuropeptide Y; Neuroprotective Agents; Oxidopamine; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins p21(ras); RNA, Messenger; Signal Transduction; Substantia Nigra; Tyrosine 3-Monooxygenase

The effects of trimethyltin on the hippocampus were investigated in terms of changes in histology, depth electroencephalography, learning acquisition and memory retention, choline acetyltransferase and neuropeptides, and seizure-induced c-fos messenger RNA expression. The results were as follows. (1) Morphologically, trimethyltin produced a progressive loss of hippocampal CA3 and CA4 pyramidal cells, starting from four days after peroral treatment with trimethyltin hydroxide (9 mg/kg), as described previously. (2) Neurophysiologically, the increased seizure susceptibility to pentylenetetrazol treatment reached a maximum at four days post-trimethyltin and then declined after five days post-trimethyltin. The maximal seizure susceptibility at four days post-trimethyltin was confirmed by the immediate and long-lasting appearance of spike discharge in the hippocampus. However, this was not verified by the expression of c-fos messenger RNA in the hippocampus, which was comparable between trimethyltin-treated and control rats. (3) Behaviorally, the time-courses of aggression and learning impairment were similar to that of the seizure susceptibility. (4) Neurochemically, trimethyltin treatment caused changes of neurochemical markers, which were manifested by the elevation of neuropeptide Y content in the entorhinal cortex, and of choline acetyltransferase in the hippocampal CA3 subfield. Trimethyltin may offer potential as a tool for investigations on the relationship between neuronal death in the hippocampus and the development of seizure susceptibility and learning impairment. Alterations in glucocorticoids, glutamate and neuropeptides may all contribute to the manifestation of the trimethyltin syndrome.

Topics: Animals; Brain Chemistry; Choline O-Acetyltransferase; Corticotropin-Releasing Hormone; Disease Models, Animal; Electroencephalography; Hippocampus; Immunohistochemistry; In Situ Hybridization; Learning; Male; Maze Learning; Memory; Neurodegenerative Diseases; Neuropeptide Y; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Seizures; Somatostatin; Trimethyltin Compounds