neuropeptide-y and Huntington-Disease

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

There is currently no effective treatment either for neurological illnesses (ischemia and neurodegenerative diseases) or psychiatric disorders (depression), in which the Glu/GABA balance is disturbed and accompanied by significant excitotoxicity. Therefore, the search for new and effective therapeutic strategies is imperative for these disorders. Studies conducted over the last several years indicate that the neuropeptide Y (NPY)-ergic system may be a potential therapeutic target for neuroprotective or antidepressant compounds. This review focuses on the neuroprotective roles of Y2 and Y5 receptors (YRs) in neurological disorders such as ischemia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and in psychiatric disorders such as depression. It summarizes current knowledge on the possible mechanisms underlying the neuroprotective or antidepressant-like actions of Y2R and Y5R ligands. The review also discusses ligands acting at Y2R and Y5R and their limitations as in vivo pharmacological tools. The results from the preclinical studies discussed here may be useful in developing effective therapeutic strategies to treat neurological diseases on the one hand and psychiatric disorders on the other, and may pave the way for the development of novel Y2R and Y5R ligands as candidate drugs for the treatment of these diseases.

Topics: Alzheimer Disease; Animals; Depression; Drug Discovery; Humans; Huntington Disease; Ischemia; Mice; Neuropeptide Y; Neuroprotection; Receptors, Neuropeptide Y; Synapses

Topics: Alzheimer Disease; Basal Ganglia; Brain; Brain Chemistry; Cerebral Cortex; Choline O-Acetyltransferase; Enkephalin, Methionine; FMRFamide; gamma-Aminobutyric Acid; Glutamate Decarboxylase; Humans; Huntington Disease; Nerve Tissue Proteins; Neurofibrils; Neuropeptide Y; Neurotensin; Oligopeptides; Peptides; Substance P; Tyrosine 3-Monooxygenase; Vasoactive Intestinal Peptide

Topics: Adenylyl Cyclase Inhibitors; Alzheimer Disease; Amygdala; Animals; Basal Ganglia; Behavior, Animal; Brain Stem; Cell Membrane Permeability; Central Nervous System; Cerebral Cortex; Chemical Phenomena; Chemistry; Hippocampus; Humans; Huntington Disease; Hypothalamus; Insulin; Insulin Secretion; Molecular Weight; NADPH Dehydrogenase; Nerve Tissue Proteins; Nervous System Diseases; Neuropeptide Y; Receptors, Cell Surface; Receptors, Somatostatin; Septal Nuclei; Somatostatin; Spinal Cord; Substantia Innominata

The discovery of neuropeptides in mammalian nervous tissue has proceeded at an astonishing pace in recent years, encouraged by novel detection techniques which allow peptides to be extracted and sequenced before their biological activity has been determined (Mutt 1983; Sudcliffe et al. 1983). Most of these methods, poached from molecular biology, are nowadays reversing former trends which evolved either as a systematic search for factors known to control pituitary hormone release (vasopressin and oxytocin), for instance, or as an endeavour to find endogenous ligands for newly discovered receptors (the endorphins) (see Krieger 1983 for review). Neuropeptide tyrosine (NPY) has emerged as an important member of this new generation of peptides, not least because it is the most abundant and widely distributed in the mammalian brain. However, despite the considerable attention this peptide has attracted, we are far from understanding its functional significance. The following account traces the history of NPY and appraises some of the literature in an attempt to raise some speculation concerning its function; several reviews on this peptide already exist (Emson and de Quidt 1984; Solomon 1985; Allen and Bloom 1986; Gray and Morley 1986), Particular attention is paid to studies which have recently suggested that NPY might be involved with the pathogenesis of two neurodegenerative disorders, Huntington's chorea and Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Brain; Cats; Humans; Huntington Disease; Neuropeptide Y; Rabbits; Rats

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

Huntington's disease (HD) is an inherited and fatal polyglutamine neurodegenerative disorder caused by an expansion of the CAG triplet repeat coding region within the HD gene. Progressive dysfunction and loss of striatal GABAergic medium spiny neurons (MSNs) may account for some of the characteristic symptoms in HD patients. Interestingly, in HD, MSNs expressing neuropeptide Y (NPY) are spared and their numbers is even up-regulated in HD patients. Consistent with this, we report here on increased immuno-linked NPY (IL-NPY) levels in human cerebrospinal fluid (hCSF) from HD patients (Control n = 10; early HD n = 9; mid HD n = 11). As this antibody-based detection of NPY may provide false positive differences as a result of the antibody-based detections of only fragments of NPY, the initial finding was validated by investigating the proteolytic stability of NPY in hCSF using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and selective inhibitors. A comparison between resulting NPY-fragments and detailed epitope analysis verified significant differences in IL-NPY1-36/3-36 and NPY1-30 levels between HD patients and control subjects with no significant differences between early vs mid HD cases. Ex vivo degradomics analysis demonstrated that NPY is initially degraded to NPY1-30 by cathepsin D in both HD patients and control subjects. Yet, NPY1-30 is then further differentially hydrolyzed by thimet oligopeptidase (TOP) in HD patients and by neprilysin (NEP) in control subjects. Furthermore, altered hCSF TOP-inhibitor Dynorphin A1-13 (Dyn-A1-13 ) and TOP-substrate Dyn-A1-8 levels indicate an impaired Dyn-A-TOP network in HD patients. Thus, we conclude that elevated IL-NPY-levels in conjunction with TOP-/NEP-activity/protein as well as Dyn-A1-13 -peptide levels may serve as a potential biomarker in human CSF of HD. Huntington's disease (HD) patients' cerebrospinal fluid (CSF) exhibits higher neuropeptide Y (NPY) levels. Further degradomics studies show that CSF-NPY is initially degraded to NPY1-30 by Cathepsin D. The NPY1-30 fragment is then differentially degraded in HD vs control involving Neprilysin (NEP), Thimet Oligopeptidase (TOP), and TOP-Dynorphin-A network. Together, these findings may help in search for HD biomarkers.

Topics: Adult; Aged; Animals; Biomarkers; Female; HEK293 Cells; Humans; Huntington Disease; Male; Mice; Middle Aged; Neuropeptide Y; Peptide Fragments; Proteolysis; Rats

Huntington disease (HD) is caused by the expansion of a CAG repeat within exon 1 of the HTT gene. Although the variation in age at onset (AO) is partly explained by the lengths of the expanded repeats, the unexplained variation is highly heritable, emphasizing the role of the so-called genetic background on disease expression. Neuropeptide Y (NPY) has been implicated in the modulation of neuroprotection, neurogenesis, and neuroinflammation. Therefore, the aim of the present study was to analyze different single nucleotide polymorphisms (SNPs) in order to test the possibility that genetic variation in NPY or three of its receptor genes (NPY1R, NPY2R, and NPY5R) may explain some of the variation in AO of HD motor manifestations, in a comprehensive cohort of 487 German HD patients. We found modest association of the AO with two NPY promoter variations and a highly significant association with a NPY2R promoter SNP (rs2234759; p = 0.0004). Investigating the functional impact of rs2234759 by luciferase assays revealed that the high-expression NPY2R genotypes were associated with later AO in HD. Additionally, treatment of PC12 cells expressing mutant huntingtin (htt) exon 1 with NPY and the NPY2R agonist NPY(3-36) has a protective effect against mutant htt-induced cell death. Thus, NPY might act through Y2 receptors to slow down the course of HD, and hence, this peptide could be of interest as a possible therapeutic agent.

Topics: Age of Onset; Animals; Cell Line, Tumor; Cell Survival; Cohort Studies; Exons; Gene Frequency; Genotype; Germany; Humans; Huntingtin Protein; Huntington Disease; Mutation; Nerve Tissue Proteins; Neuropeptide Y; PC12 Cells; Peptide Fragments; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Rats; Receptors, Neuropeptide Y

Psychiatric symptoms such as depression and anxiety are important clinical features of Huntington's disease (HD). However, the underlying neurobiological substrate for the psychiatric features is not fully understood. In order to explore the biological origin of depression and anxiety in HD, we used a mouse model that expresses the human full-length mutant huntingtin, the BACHD mouse. We found that the BACHD mice displayed depressive- and anxiety-like features as early as at 2 months of age as assessed using the Porsolt forced swim test (FST), the sucrose preference test and the elevated plus maze (EPM). BACHD mice subjected to chronic treatment with the anti-depressant sertraline were not different to vehicle-treated BACHD mice in the FST and EPM. The behavioral manifestations occurred in the absence of reduced hippocampal cell proliferation/neurogenesis or upregulation of the hypothalamic-pituitary-adrenal axis. However, alterations in anxiety- and depression-regulating genes were present in the hypothalamus of BACHD mice including reduced mRNA expression of neuropeptide Y, tachykinin receptor 3 and vesicular monoamine transporter type 2 as well as increased expression of cocaine and amphetamine regulated transcript. Interestingly, the orexin neuronal population in the hypothalamus was increased and showed cellular atrophy in old BACHD mice. Furthermore, inactivation of mutant huntingtin in a subset of the hypothalamic neurons prevented the development of the depressive features. Taken together, our data demonstrate that the BACHD mouse recapitulates clinical HD with early psychiatric aspects and point to the role of hypothalamic dysfunction in the development of depression and anxiety in the disease.

Topics: Animals; Anxiety; Behavior, Animal; Depression; Disease Models, Animal; Female; Humans; Huntingtin Protein; Huntington Disease; Hypothalamus; Male; Mice; Mice, Transgenic; Nerve Tissue Proteins; Neuropeptide Y; Receptors, Tachykinin; Sertraline; Vesicular Monoamine Transport Proteins

In Huntington disease (HD), hypothalamic neuropeptidergic systems are not equally affected at the peptide and mRNA levels. Because prohormone convertases (PCs) are critically involved in the conversion of propeptides into their active forms, we postulated that a decrease in PC expression may underlie these discrepancies. Therefore, we assessed the expression of PC1/3 and PC2 in the hypothalamic infundibular, suprachiasmatic, and paraventricular nuclei in postmortem tissues of HD patients and controls (n = 9, each) using immunocytochemistry and quantitative reverse transcription polymerase chain reaction. We also assessed PC1/3 and PC2 mRNA expression in the inferior frontal gyrus and colocalization of both PCs with corticotropin-releasing hormone and α-melanocyte-stimulating hormone. In HD patients, PC1/3 and PC2 expression was decreased in the hypothalamic infundibular (both p = 0.046) and paraventricular nuclei (p = 0.031 and p = 0.019). In the suprachiasmatic nucleus, PC1/3 and PC2 expressions were not different between HD and control cases; PC1/3 and PC2 mRNA levels in the inferior frontal gyrus were also not different. None of the PCs was colocalized with corticotropin-releasing hormone, whereas α-melanocyte-stimulating hormone showed colocalization with PC1/3 and PC2. These data suggest that defects in the processing of hypothalamic neuropeptides in HD may partially arise from decreased PC1/3 and PC2 expressions. These changes might contribute to selective neuropathology underlying various clinical manifestations and may provide novel therapeutic targets in HD patients.

Topics: Aged; alpha-MSH; Female; Gene Expression Regulation; Humans; Huntingtin Protein; Huntington Disease; Hypothalamus; Male; Middle Aged; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Proprotein Convertase 1; Proprotein Convertase 2; RNA, Messenger; Statistics, Nonparametric; Trinucleotide Repeats

Data from transgenic mouse models of Huntington's disease (HD) suggest that dysfunction of the hypothalamic infundibular nucleus (INF) (in rodents, the arcuate nucleus) may contribute to unintended weight loss and insatiable appetite among HD patients. Using post-mortem paraffin-embedded tissue, we assessed the total number of INF neurones by thionin staining and four major regulatory neuropeptides in the INF of HD patients by immunocytochemistry and in situ hybridisation. In HD patients, the total number of neurones in the INF was unchanged compared to control subjects (P = 0.92), whereas it contained over 30% less neuropeptide Y-immunoreactive (IR) neurones (P = 0.016), as well as reduced peptide levels, in fibres to the paraventricular and ventromedial nucleus (P = 0.003, P = 0.005, respectively). Conversely, neuropeptide Y mRNA expression levels were increased three-fold (P = 0.047). No changes were observed in the number of neurones immunoreactive for α-melanocyte-stimulating hormone, agouti-related peptide, and cocaine- and amphetamine-regulated transcript (P ≥ 0.17). Our findings suggest changes in the pathology of the INF neuropeptide Y-expressing neurones in HD patients without changes in other (an)orexigenic neuropeptides and without neuronal cell loss. These findings indicate that unintended weight loss in patients suffering from this disease may be partly a result of neuropeptidergic alterations in the hypothalamic infundibular nucleus.

Topics: Adult; Aged; alpha-MSH; Arcuate Nucleus of Hypothalamus; Autopsy; Case-Control Studies; Female; Humans; Huntington Disease; Immunohistochemistry; Male; Middle Aged; Neurons; Neuropeptide Y; Neuropeptides

Cannabinoid receptor 1 (CB(1) receptor) controls several neuronal functions, including neurotransmitter release, synaptic plasticity, gene expression and neuronal viability. Downregulation of CB(1) expression in the basal ganglia of patients with Huntington's disease (HD) and animal models represents one of the earliest molecular events induced by mutant huntingtin (mHtt). This early disruption of neuronal CB(1) signaling is thought to contribute to HD symptoms and neurodegeneration. Here we determined whether CB(1) downregulation measured in patients with HD and mouse models was ubiquitous or restricted to specific striatal neuronal subpopulations. Using unbiased semi-quantitative immunohistochemistry, we confirmed previous studies showing that CB(1) expression is downregulated in medium spiny neurons of the indirect pathway, and found that CB(1) is also downregulated in neuropeptide Y (NPY)/neuronal nitric oxide synthase (nNOS)-expressing interneurons while remaining unchanged in parvalbumin- and calretinin-expressing interneurons. CB(1) downregulation in striatal NPY/nNOS-expressing interneurons occurs in R6/2 mice, Hdh(Q150/Q150) mice and the caudate nucleus of patients with HD. In R6/2 mice, CB(1) downregulation in NPY/nNOS-expressing interneurons correlates with diffuse expression of mHtt in the soma. This downregulation also occludes the ability of cannabinoid agonists to activate the pro-survival signaling molecule cAMP response element-binding protein in NPY/nNOS-expressing interneurons. Loss of CB(1) signaling in NPY/nNOS-expressing interneurons could contribute to the impairment of basal ganglia functions linked to HD.

Topics: Adult; Aged; Animals; Basal Ganglia; Calbindin 2; Cannabinoid Receptor Agonists; Case-Control Studies; Cyclic AMP; Disease Models, Animal; Down-Regulation; Female; Gene Expression; Humans; Huntingtin Protein; Huntington Disease; Interneurons; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Nerve Tissue Proteins; Neuropeptide Y; Nitric Oxide Synthase; Nuclear Proteins; Parvalbumins; Receptor, Cannabinoid, CB1; S100 Calcium Binding Protein G; Serotonin Plasma Membrane Transport Proteins

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by progressive neuronal dysfunction and cell loss, especially striatal GABAergic neurons, generating motor, cognitive and affective problems. Although the disease-causing gene is known, the exact mechanism by which it induces its pathological effect remains unknown, and no cure is currently available for this disease. Interestingly, striatal neurons that express neuropeptide Y (NPY) are preferentially spared in HD and the number of such cells is increased in the striatum of HD patients. Furthermore, neurogenesis in the subventricular zone (SVZ) also appears to be up-regulated in HD patients, and previously we also demonstrated in wild-type mice that intracerebroventricular (ICV) NPY promotes SVZ neurogenesis with migration of the newborn cells towards the striatum where they differentiate into GABAergic neurons. Therefore, we sought to determine whether NPY could be of therapeutic benefit in a transgenic mouse model of HD (R6/2) through an action on SVZ neurogenesis. We found that a single ICV injection of NPY in R6/2 mice increased survival time through reduced weight loss as well as having a beneficial effect on motor function as evidenced by improving rotarod performance and reducing paw-clasping. We also demonstrated that the degree of cerebral and striatal atrophy was reduced following such a single NPY injection and that whilst the peptide also increased the number of BrdU-positive cells in the SVZ (but not in the dentate gyrus) of R6/2 mice, this was not sufficient to account for the changes in anatomy and function that we found.. These results suggest that NPY may be of some therapeutic interest in patients with HD, although further work is needed to ascertain exactly how it mediates its beneficial effects.

Topics: Animals; Antimetabolites; Behavior, Animal; Body Weight; Bromodeoxyuridine; Cell Count; Cell Proliferation; Disease Progression; Female; Hippocampus; Humans; Huntington Disease; Immunohistochemistry; Injections, Intraventricular; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neostriatum; Neuropeptide Y; Postural Balance; Stereotaxic Techniques; Survival Analysis

Previous studies in the rodent brain have characterised the cell types present in the subependymal layer, however the general organisation and cellular morphology of the adult human subependymal layer has not been demonstrated previously. In this study, we have demonstrated that the normal human brain subependymal layer contains three morphologically distinct types of cells, A, B and C type cells. The type A cells resembling migrating neuroblasts were located in the superficial part of the subependymal layer, type B cells resembling glial cells were evenly distributed throughout the subependymal layer and caudate nucleus, and type C cells that resembled progenitor cells were located in the deeper regions of the subependymal layer close to the caudate nucleus. We also examined the subependymal layer in the Huntington's disease brain to determine whether neurodegenerative pathology of the caudate nucleus (adjacent to the subependymal layer) altered the cellular composition of the subependymal layer. In the Huntington's disease subependymal layer there was a significant increase in the thickness of the subependymal layer compared with the normal subependymal layer (p < 0.01) and there was a 2.8-fold increase in the number of cells present in the Huntington's disease subependymal layer compared with the normal subependymal layer but the density of cells remained unchanged. As the grade of Huntington's disease increased, so did the overall number of cells in the subependymal layer. An increase in the number of type B cells was responsible for most of the increase demonstrated, however there was also an increase in the numbers of type A and C cells. To further characterise the human normal and Huntington's disease subependymal layer we used immunohistochemistry and antibodies against a range of projection neuron markers, interneuron markers, glial cell markers and GABAA receptor subunits. The results demonstrated the presence of increased numbers of neuropeptide Y positive cells in the Huntington's disease subependymal layer compared with the normal subependymal layer, suggesting that neuropeptide Y neurons may play a role in progenitor cell proliferation. Also there was an increased level of the developmentally active GABAA receptor subunit gamma 2 that indicates that the adult subependymal layer still retains the ability to proliferate. Taken together our results give a detailed description of the adult human subependymal layer and also demonstrate the plasti

Topics: Adult; Aged; Aged, 80 and over; Caudate Nucleus; Female; Humans; Huntington Disease; Image Processing, Computer-Assisted; Immunohistochemistry; Male; Middle Aged; Neuroglia; Neuronal Plasticity; Neurons; Neuropeptide Y; Stem Cells

One experimental strategy that may offer hope in the neurodegenerative disorder Huntington's disease (HD) has been neural transplantation. In HD, most of the pathological changes occur in the corpus striatum. Fetal human striatal implants will most likely be the first transplant strategy attempted in clinical trials to replace lost neurons and/or prevent the degeneration of neurons destined to die. The temporal expression of neurotransmitters in the developing human corpus striatum is a key factor in determining the optimum age of transplantable tissue. To this end, an immunocytochemical analysis of various neurotransmitters was performed on second trimester human brains. Antibodies against acetylcholine, gamma-aminobutyric acid, enkephalin, neuropeptide-Y and substance P were used in ten human fetal brains ranging from 13 to 21 weeks gestation. The presence and pattern of distribution for these neurotransmitters varied in the different parts of the corpus striatum (globus pallidus, putamen, caudate nucleus). These results are compared to the already existing data for the adult human corpus striatum.

Topics: Acetylcholine; Age Factors; Brain Tissue Transplantation; Corpus Striatum; Enkephalins; Female; Fetal Tissue Transplantation; Fetus; gamma-Aminobutyric Acid; Humans; Huntington Disease; Neurons; Neuropeptide Y; Neurotransmitter Agents; Pregnancy; Pregnancy Trimester, Second; Substance P

Patients with Huntington's disease (HD) develop pathological changes in cerebral cortex as well as in striatum. We studied levels of neuropeptide immunoreactivity in 13 areas of postmortem cerebral cortex dissected from 24 cases of HD and 12 controls. Concentrations of immunoreactive cholecystokinin (CCK-LI) were consistently elevated 57 to 153% in HD cortex. Levels of vasoactive intestinal polypeptide (VIP-LI) and neuropeptide Y (NPY-LI) were significantly increased in 10 and 8 of the 13 cortical regions, respectively. Concentrations of somatostatin (SRIF-LI) were increased in only 3 areas, while substance P (SP-LI) was, for the most part, unchanged. Detailed analyses of the CCK-LI and VIP-LI data showed there to be no relationship between the increased cortical peptide levels and the degree of striatal atrophy. We studied the same cortical peptides in rats with long-standing striatal lesions and found no significant changes of CCK-LI, NPY-LI, VIP-LI, or SRIF-LI in any of the 8 cortical regions that were examined. These results indicate that there are widespread and differential changes in cortical neuropeptide systems in HD and that these changes occur independently of the striatal pathology that characterizes the illness.

Topics: Animals; Cerebral Cortex; Corpus Striatum; Humans; Huntington Disease; Male; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Vasoactive Intestinal Peptide

To investigate whether differences in vulnerability to free radicals might underlie differences among striatal neurons in their vulnerability to neurodegenerative processes such as occur in ischemia and Huntington's disease, we have analyzed the localization of superoxide free radical scavengers in different striatal neuron types in normal rhesus monkey. Single- and double-label immunohistochemical experiments were carried out using antibodies against the enzymes copper, zinc superoxide dismutase (SOD1), or manganese superoxide dismutase (SOD2), and against markers of various striatal cell types. Our results indicate that the striatal cholinergic and parvalbumin interneurons are enriched in SOD1 and/or SOD2, whereas striatal projection neurons and neuropeptide Y/somatostatin (NPY+/SS+) interneurons express only low levels of both SOD1 and SOD2. We also found that projection neurons of the matrix compartment express significantly higher levels of SOD than those in the striosome compartment. Since projection neurons have been reported to be more vulnerable than interneurons and striosome neurons more vulnerable than matrix neurons to neurodegenerative processes, our results are consistent with the notion that superoxide free radicals are at least partly involved in producing the differential neuron loss observed in the striatum following global brain ischemia or in Huntington's disease.

Topics: Animals; Antibodies; Brain Ischemia; Corpus Striatum; Female; Free Radical Scavengers; Humans; Huntington Disease; Immunohistochemistry; Interneurons; Isoenzymes; Macaca mulatta; Male; Nerve Degeneration; Neurons; Neuropeptide Y; Reperfusion Injury; Somatostatin; Superoxide Dismutase

The cellular abundance of neuronal nitric oxide synthase and somatostatin messenger RNAs was compared in the caudate nucleus, putamen and sensorimotor cortex of Huntington's disease and control cases. Neuronal nitric oxide synthase messenger RNA was significantly decreased in the caudate nucleus and putamen, but not in the sensorimotor cortex in Huntington's disease; the decrease in neuronal nitric oxide synthase messenger RNA became more pronounced with the severity of the disease. Somatostatin gene expression was significantly decreased in the dorsal putamen in Huntington's disease, but was essentially unchanged in all other regions examined. The density of neurons expressing detectable levels of neuronal nitric oxide synthase messenger RNA was reduced in the striata of Huntington's disease cases with advanced pathology; the density of neurons expressing detectable levels of somatostatin messenger RNA was similar in control and Huntington's disease cases. Neuropeptide Y-, somatostatin- and NADPH-diaphorase-positive neurons were consistently present throughout the striatum across all the grades of the disease. Neuronal nitric oxide synthase and NADPH-diaphorase activity (a histochemical marker for nitric oxide synthase-containing neurons) co-localize with somatostatin and neuropeptide Y in interneurons in the human striatum and cerebral cortex. Although the neurodegeneration associated with Huntington's disease is most evident in the striatum (particularly the dorsal regions), neuronal nitric oxide synthase/neuropeptide Y/somatostatin interneurons are relatively spared. Nitric oxide released by neuronal nitric oxide synthase-containing neurons may mediate glutamate-induced excitotoxic cell death, a mechanism proposed to be instrumental in causing the neurodegeneration seen in Huntington's disease. The results described here suggest that although the population of interneurons containing somatostatin, neuropeptide Y and neuronal nitric oxide synthase do survive in the striatum in Huntington's disease they are damaged during the course of the disease. The results also show that the reduction in neuronal nitric oxide synthase and somatostatin messenger RNAs is most pronounced in the more severely affected dorsal regions of the striatum. Furthermore, the loss of neuronal nitric oxide messenger RNA becomes more pronounced with the severity of the disease; thus implying a down-regulation in neuronal nitric oxide synthase messenger RNA synthesis, and potentiall

Topics: Aged; Aged, 80 and over; Antibody Specificity; Biomarkers; Cell Count; Cell Death; Female; Gene Expression; Histocytochemistry; Humans; Huntington Disease; Immunohistochemistry; In Situ Hybridization; Male; Middle Aged; Motor Cortex; NADPH Dehydrogenase; Neostriatum; Neurons; Neuropeptide Y; Nitric Oxide Synthase; RNA, Messenger; Somatosensory Cortex; Somatostatin

An excitotoxic process mediated by the NMDA type glutamate receptor may be involved in striatal neuron death in Huntington's disease (HD). To explore this possibility, we have injected an NMDA-receptor-specific excitotoxin, quinolinic acid (QA), into the striatum in adult rats and 2-4 months postlesion explored the relative patterns of survival for the various different types of striatal projection neurons and interneurons and for the striatal efferent fibers in the different striatal projection areas. The perikarya of specific types of striatal neurons were identified by neurotransmitter immunohistochemical labeling or by retrograde labeling from striatal target areas, while the striatal efferent fiber plexuses were identified by neurotransmitter immunohistochemical labeling. The pattern of survival for the perikarya of each neuron type as a function of distance from the center of the injection site was determined, and the relative survival of each type was compared. For the fibers in target areas, computer-assisted image analysis was used to determine the degree of fiber loss for each projection target. In the study of perikaryal vulnerability, we found that the somatostatin-neuropeptide Y (SS/NPY) interneurons were the most vulnerable to QA and the cholinergic neurons were invulnerable to QA. The perikarya of all projection neuron types (striatopallidal, striatonigral, and striato-entopeduncular) were less vulnerable than the SS/NPY interneurons and more vulnerable than the cholinergic interneurons. Among projection neuron perikarya, there was evidence of differential vulnerability, with striatonigral neurons appearing to be the most vulnerable. Examination of immunolabeled striatal fibers in the striatal target areas indicated that striato-entopeduncular fibers better survived intrastriatal QA than did striatopallidal or striatonigral fibers. The apparent order of vulnerability observed in this study among projection neurons and/or their efferent fiber plexuses and the invulnerability observed in this study of cholinergic interneurons is similar to that observed in HD. The vulnerability of the SS/NPY interneurons to QA is, however, in stark contrast to their invulnerability in HD. The results thus suggest that although the excitotoxin hypothesis of striatal neuron death in HD has merit, QA injections into adult rat striatum do not strictly mimic the outcome in HD. This suggests that either adult rats are not a completely suitable subject for mimicking

Topics: Animals; Antibodies; Cell Survival; Choline O-Acetyltransferase; Corpus Striatum; Efferent Pathways; Enkephalin, Leucine; Enkephalin, Methionine; Globus Pallidus; Huntington Disease; Immunohistochemistry; Interneurons; Male; Microinjections; Nerve Fibers; Neurons; Neuropeptide Y; Neurotoxins; Quinolinic Acid; Rats; Rats, Sprague-Dawley; Somatostatin

Topics: Animals; Biomarkers; Brain Tissue Transplantation; Cyclosporine; Disease Models, Animal; Fetal Tissue Transplantation; Histocytochemistry; Humans; Huntington Disease; Motor Activity; NADPH Dehydrogenase; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Rotation; Somatostatin

We previously found a relative sparing of somatostatin and neuropeptide Y neurons 1 week after producing striatal lesions with NMDA receptor agonists. These results are similar to postmortem findings in Huntington's disease (HD), though in this illness there are two- to threefold increases in striatal somatostatin and neuropeptide Y concentrations, which may be due to striatal atrophy. In the present study, we examined the effects of striatal excitotoxin lesions at 6 months and 1 yr, because these lesions exhibit striatal shrinkage and atrophy similar to that occurring in HD striatum. At 6 months and 1 yr, lesions with the NMDA receptor agonist quinolinic acid (QA) resulted in significant increases (up to twofold) in concentrations of somatostatin and neuropeptide Y immunoreactivity, while concentrations of GABA, substance P immunoreactivity, and ChAT activity were significantly reduced. In contrast, somatostatin and neuropeptide Y concentrations did not increase 6 months after kainic acid (KA) or alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) lesions. At both 6 months and 1 yr, QA lesions showed striking sparing of NADPH-diaphorase neurons as compared with both AMPA and KA lesions, neither of which showed preferential sparing of these neurons. Long-term QA lesions also resulted in significant increases in concentrations of both 5-HT and 5-hydroxyindoleacetic acid (HIAA), similar to findings in HD. Chronic QA lesions therefore closely resemble the neurochemical features of HD, because they result in increases in somatostatin and neuropeptide Y and in 5-HT and HIAA. These findings strengthen the possibility that an NMDA receptor-mediated excitotoxic process could play a role in the pathogenesis of HD.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Atrophy; Biogenic Amines; Cerebral Cortex; Choline O-Acetyltransferase; Corpus Striatum; Disease Models, Animal; gamma-Aminobutyric Acid; Glutamates; Huntington Disease; Ibotenic Acid; Kainic Acid; Male; Mesencephalon; NADPH Dehydrogenase; Neurons; Neuropeptide Y; Quinolinic Acid; Quinolinic Acids; Rats; Rats, Inbred Strains; Reference Values; Somatostatin; Substance P

Neuropeptide immunohistochemistry was used to test several hypotheses of the anatomical bases of chorea and rigidity-akinesia. To test the hypothesis that elevated concentration of striatal somatostatin causes chorea, we visually compared the density of striatal neurons containing somatostatin and neuropeptide Y in brains affected by choreic or rigid-akinetic Huntington's disease (HD). The density of these neurons was elevated in both rigid-akinetic and choreic HD specimens with an apparently normal total number of these neurons, indicating that elevated somatostatin concentration, by itself, does not lead to chorea. We tested the hypothesis that rigid-akinetic HD results from deficient dopaminergic nigrostriatal neurotransmission by examining tyrosine hydroxylase-immunoreactive (TH-IR) neurons in the substantia nigra. In rigid-akinetic HD brains, there was no obvious reduction of nigral TH-IR neurons, indicating that rigid-akinetic HD is probably not due to loss of nigral dopaminergic neurons. Finally, we also examined the status of striatal projection neurons and found near total loss of all striatal neurons projecting to the lateral globus pallidus, medial globus pallidus, and substantia nigra in brains affected by rigid-akinetic HD in contrast to the preservation of neurons projecting to the medial globus pallidus in choreic HD. These results are consistent with the hypothesis that chorea results from preferential loss of striatal neurons projecting to the lateral globus pallidus and that rigid-akinetic HD is a consequence of the additional loss of striatal neurons projecting to the medial segment of the pallidum.

Topics: Adult; Child; Chorea; Corpus Striatum; Female; Globus Pallidus; Humans; Huntington Disease; Immunohistochemistry; Muscle Rigidity; Neural Pathways; Neuropeptide Y; Somatostatin; Substantia Nigra

We examined the distribution of neuropeptide Y immunoreactive local circuit neurons and nonphosphorylated neurofilament (SMI 32) immunoreactive pyramidal projection neurons in superior frontal cortex of patients with Huntington's disease and age-matched control subjects to determine the histological counterpart of increased neuropeptide Y and decrease glutamate concentrations previously found in the cortex of patients with Huntington's disease. We found no difference between the relative density of neuropeptide Y neurons in Huntington's disease and control brains in regions where the relative density of SMI 32 immunoreactive was significantly reduced. Animal studies show that cortical local circuit neurons are resistant to N-methyl-D-aspartate-type excitotoxins such as quinolinic acid. Relative sparing of neuropeptide Y neurons in cerebral cortex with Huntington's disease may, therefore, be a result of excessive N-methyl-D-aspartate receptor activation.

Topics: Aged; Antibodies, Monoclonal; Cerebral Cortex; Cytoskeleton; Humans; Huntington Disease; Immunohistochemistry; Intermediate Filaments; Middle Aged; Neuropeptide Y

Several neuropathologic studies have suggested that there may be pathologic involvement of the cerebellum in Huntington's disease (HD). To investigate this further, we measured concentrations of neurotransmitter amino acids and the neuropeptides, somatostatin, neuropeptide Y and substance P, in HD cerebellar cortex and dentate nucleus. Twenty-seven pathologically confirmed cases of HD were compared with 20 controls. There were no significant changes in concentrations were significantly increased by 21% in HD cerebellar cortex. In the dentate nucleus, there were small significant increases of neuropeptide Y-like immunoreactivity and substance P-like immunoreactivity. The meaning of the neurotransmitter changes found is unclear: however, the lack of change in GABA and glutamate concentrations argues against a substantial loss of intrinsic cerebellar neurons.

Topics: Aged; Aspartic Acid; Cerebellum; Female; Humans; Huntington Disease; Male; Middle Aged; Neuropeptide Y; Neuropeptides; Somatostatin; Substance P

Quinolinic acid (QA) is an endogenous excitotoxin present in mammalian brain that reproduces many of the histologic and neurochemical features of Huntington's disease (HD). In the present study we have examined the ability of a variety of systemically administered compounds to modify striatal QA neurotoxicity. Lesions were assessed by measurements of the intrinsic striatal neurotransmitters substance P, somatostatin, neuropeptide Y, and GABA. Histologic examination was performed with Nissl stains. The antioxidants ascorbic acid, beta-carotene, and alpha-tocopherol administered s.c. for 3 d prior to striatal QA lesions had no significant effect. Other drugs were administered i.p. 1/2 hr prior to QA striatal lesions. The following were ineffective in blocking QA excitotoxicity: allopurinol, 50 and 100 mg/kg; ketamine, 75 mg/kg; nimodipine, 2.4, and 10 mg/kg; baclofen, 10 mg/kg; 2-amino-5-phosphonovalerate, 50 mg/kg; and 2-amino-7-phosphonoheptanoate, 50 mg/kg. Oral taurine administration for 4 weeks resulted in significantly increased levels of brain taurine but had no significant effect in blocking QA neurotoxicity. Systemic administration of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 resulted in a dose-responsive protection against QA toxicity, with complete block at a dose of 4 mg/kg. If the pathogenesis of HD involves QA or another excitotoxin acting at the NMDA receptor, it is possible that MK-801 could retard the degenerative process.

Topics: 2-Amino-5-phosphonovalerate; Allopurinol; Amino Acids; Animals; Antioxidants; Baclofen; Corpus Striatum; Dibenzocycloheptenes; Disease Models, Animal; Dizocilpine Maleate; Huntington Disease; Ketamine; Male; Neuropeptide Y; Nimodipine; Peptides; Pyridines; Quinolinic Acid; Quinolinic Acids; Rats; Rats, Inbred Strains; Substance P; Taurine; Valine

Somatostatin and neuropeptide Y concentrations have previously been reported to be increased in the basal ganglia in Huntington's disease (HD). In the present study we have extended these findings by examining both somatostatin-like immunoreactivity (SLI) and neuropeptide Y-like immunoreactivity (NPYLI) in cases of HD, which were graded according to the severity of pathological degeneration in the striatum. In addition, we surveyed a large number of subcortical nuclei and cortical regions for alterations. Both SLI and NPYLI were significantly increased about threefold in the caudate, putamen, and the nucleus accumbens. Increases in mild and severe grades were similar, which is consistent with a relative but not absolute sparing of striatal aspiny neurons in which somatostatin and neuropeptide Y are colocalized. Significant increases of NPYLI were also found in the external pallidum, subthalamic nucleus, substantia nigra compacta, claustrum, anterior and dorsomedial thalamus, bed nucleus of the stria terminalis, and locus ceruleus. SLI was significantly increased in the external pallidum, red nucleus, and locus ceruleus. Measurements of both neuropeptides were made in 24 regions of the cerebral cortex. Significant increases in both NPYLI and SLI were found in the frontal cortex (Brodmann areas 6, 8, 9, 10, 11, and 45) and temporal cortex (Brodmann area 21), whereas NPYLI was also increased in Brodmann areas 12, 20-22, 25, and 42. Alterations in the cerebral cortex were as pronounced in cases with mild striatal pathological changes as in those with severe striatal pathological changes. These alterations may occur early in HD and could reflect a selective sparing of somatostatin-neuropeptide Y cortical neurons combined with cortical atrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Brain; Brain Chemistry; Female; Humans; Huntington Disease; Male; Middle Aged; Neuropeptide Y; Organ Specificity; Radioimmunoassay; Somatostatin

We have previously found that a biochemically distinct subset of neurons, containing nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), is selectively resistant to the degenerative process that affects the striatum in Huntington's disease (HD). We report the morphologic and histochemical characteristics of these striatal neurons and their distribution with respect to the histochemical compartments as defined by acetylcholinesterase (AChE) activity. Sections of striatum were stained histochemically for NADPH-d and AChE and immunocytochemically for somatostatin and neuropeptide Y-like immunoreactivity. The diaphorase end-product was contained within medium-sized neurons which corresponded morphologically to a category of aspiny interneurons. Combined techniques showed that NADPH-d, somatostatin, and neuropeptide Y coexisted within the same neurons in controls and patients with HD. The density of these neurons was greater in the ventral putamen and the nucleus accumbens than in the remainder of the striatum. The distinctive AChE pattern of high and low enzyme activity was altered in HD. The AChE-rich matrix zone was markedly reduced in size, while the total area of zones of low enzyme activity was not different from that found in control striatum. The relation between these AChE chemical compartments and the distribution of preserved diaphorase neurons remained intact; NADPH-d neurons were predominantly observed in the matrix zone.

Topics: Acetylcholinesterase; Aged; Corpus Striatum; Histocytochemistry; Humans; Huntington Disease; NADPH Dehydrogenase; Neurons; Neuropeptide Y

The location of the neuropeptides methionine-enkephalin (ME), neurotensin (NT), neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP) within the amygdaloid complex of healthy human individuals, schizophrenics and patients suffering from Huntington's chorea was studied qualitatively by means of immunohistochemistry. VIP-like immunoreactivity (IR) was present predominantly in a dense cluster of fibers and terminals in the central amygdaloid nucleus. ME-IR was observed in fibers, terminals and cell bodies in the same subnucleus, exhibiting a characteristical distribution pattern. NT-positive cell bodies were situated within the center of the central amygdaloid nucleus, fibers and terminals being encountered mainly at the periphery. NPY-IR was found to be evenly distributed throughout the amygdala. Distribution and staining intensity of ME, NPY and NT in the amygdala showed no qualitatively recognizable difference between the normal and schizophrenic specimens, whereas VIP-IR appeared to be slightly increased in the central amygdaloid nucleus of schizophrenics. In the choreic cases, the considerably shrunken amygdala exhibited only very low staining intensity of the four investigated neuropeptides.

Topics: Adult; Aged; Amygdala; Enkephalin, Methionine; Female; Humans; Huntington Disease; Immunoenzyme Techniques; Male; Middle Aged; Neuropeptide Y; Neuropeptides; Neurotensin; Schizophrenia; Vasoactive Intestinal Peptide

The content of somatostatin-like immunoreactivity (SRIF-LI) and neuropeptide Y-like immunoreactivity (NPY-LI) has been measured in both control post-mortem human brains and in Huntington's disease brains. The content of both SRIF-LI and NPY-LI was found to be significantly increased in the basal ganglia of Huntington's disease brains compared with a control group. The nature of the SRIF-LI and NPY-LI in both control and Huntington's disease brains was investigated after separation on Sephadex G25 and G50 columns. Using a C-terminal-directed SRIF radioimmunoassay (RIA), 3 peaks of immunoreactivity were measured, whilst an N-terminal-directed SRIF RIA detected two peaks of immunoreactivity. In each case, the elution profile did not differ between control and Huntington's disease caudate nucleus. The content of immunoreactivity in each peak was found to be increased in Huntington's disease brains compared with controls. Only one peak of NPY-LI was detected in both control and Huntington's disease caudate after separation on Sephadex G25 and G50 columns. Immunohistochemical staining of the caudate and putamen of control and Huntington's disease brains revealed a population of neurones containing NPY-LI. The number of NPY-positive neurones was found to be increased in both the caudate and putamen of Huntington's disease brains compared to control caudate and putamen.

Topics: Basal Ganglia; Caudate Nucleus; Cell Count; Cell Survival; Chromatography, Gel; Histocytochemistry; Humans; Huntington Disease; Immunoenzyme Techniques; Nerve Tissue Proteins; Neuropeptide Y; Putamen; Somatostatin

A distinct subpopulation of striatal aspiny neurons, containing the enzyme nicotinamide adenine dinucleotide phosphate diaphorase, is preserved in the caudate nucleus in Huntington's disease. Biochemical assays confirmed a significant increase in the activity of this enzyme in both the caudate nucleus and putamen in postmortem brain tissue from patients with this disease. The resistance of these neurons suggests that the gene defect in Huntington's disease may be modifiable by the local biochemical environment. This finding may provide insight into the nature of the genetically programmed cell death that is a characteristic of the disease.

Topics: Adult; Aged; Caudate Nucleus; Corpus Striatum; Humans; Huntington Disease; Middle Aged; NADPH Dehydrogenase; Nerve Tissue Proteins; Neurons; Neuropeptide Y