neuropeptide-y and Fever

Prevailing changes in the feeding status or the nutritional status, in general, can modify the expression of many orexigenic and anorexigenic peptides, which influence hypothalamic functions. These peptides usually adjust body temperature according to anabolic (increased appetite with suppressed metabolic rate and body temperature) or catabolic (anorexia with enhanced metabolism and temperature) patterns. It was plausible to presume that such peptides contribute to regulated changes of body temperature (either fever or hypothermia) in systemic inflammation, particularly since anorexia is a common feature in inflammatory processes. No consistent, common, or uniform way of action was, however, demonstrated, which could have described the effects of various peptides. With the exception of cholecystokinin (CCK), all investigated peptides were devoid of real thermoregulatory actions: they influenced the metabolic rate (and consequently body temperature), but not the mechanisms of heat loss. Central CCK is indeed catabolic and may participate in febrigenesis. Leptin may activate various cytokines, catabolic peptides and may inhibit anabolic peptides, but it probably has no direct febrigenic effect and it is not indispensable in fever. Melanocortins and corticotropin-releasing factor provide catabolic adaptive mechanisms to food intake (diet induced thermogenesis) and environmental stress, respectively, but they act rather as endogenous antipyretic substances during systemic inflammation, possibly contributing to the mechanisms of limitation of fever. Bacterial lipopolysaccharides enhance the expression of most of these catabolic peptides. In contrast, neuropeptide Y (NPY) expression may not be changed, only its release is decreased at specific nuclei, a defective NPY effect may also contribute to the febrile rise in body temperature. The data provide no clear-cut explanation for the mechanism of hypothermia seen in systemic inflammation. According to speculations, a presumed, overflow,-type release of NPY from the hypothalamic nuclei, as well as a suppression of the activity of catabolic peptides, could possibly cause hypothermia. There are no cues, however, referring to the identity of factors that could trigger such changes during systemic inflammation in order to induce hypothermia.

Topics: alpha-MSH; Animals; Body Temperature; Cholecystokinin; Corticotropin-Releasing Hormone; Eating; Endotoxins; Fever; Humans; Hypothermia; Inflammation; Leptin; Mice; Neuropeptide Y; Peptides; Rats

Environmental enrichment (EE) refers to the provision of a complex and stimulating housing condition which improves well-being, behaviour and brain function of laboratory animals. The mechanisms behind these beneficial effects of EE are only partially understood. In the current report, we describe a link between EE and neuropeptide Y (NPY), based on findings from NPY knockout (KO) mice exposed to EE. Relative to EE-housed wildtype (WT) animals, NPY KO mice displayed altered behaviour as well as molecular and morphological changes in amygdala and hippocampus. Exposure of WT mice to EE reduced anxiety and decreased central glucocorticoid receptor expression, effects which were absent in NPY KO mice. In addition, NPY deletion altered the preference of EE items, and EE-housed NPY KO mice responded to stress with exaggerated hyperthermia, displayed impaired spatial memory, had higher hippocampal brain-derived neurotrophic factor mRNA levels and altered hippocampal synaptic plasticity, effects which were not seen in WT mice. Accordingly, these findings suggest that NPY contributes to the anxiolytic effect of EE and that NPY deletion reverses the beneficial effects of EE into a negative experience. The NPY system could thus be a target for "enviromimetics", therapeutics which reproduce the beneficial effects of enhanced environmental stimulation.

Topics: Animals; Anxiety; Behavior, Animal; Brain-Derived Neurotrophic Factor; Fever; Housing, Animal; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuronal Plasticity; Neuropeptide Y; Receptors, Glucocorticoid; RNA, Messenger; Spatial Memory

Resilience to mental and physical stress is a key determinant for the survival and functioning of mammals. Although the importance of stress resilience has been recognized, the underlying neural mediators have not yet been identified. Neuropeptide Y (NPY) is a peptide known for its anti-anxiety-like effects mediated via the amygdala. The results of our current study demonstrate, for the first time that repeated administration of NPY directly into the basolateral nucleus of the amygdala (BLA) produces selective stress-resilient behavioral responses to an acute restraint challenge as measured in the social interaction test, but has no effect on hypothalamic-adrenal-pituitary axis activity or stress-induced hyperthermia. More importantly, the resilient behaviors observed in the NPY-treated animals were present for up to 8 weeks. Antagonizing the activity of calcineurin, a protein phosphatase involved in neuronal remodeling and present in NPY receptor containing neurons within the BLA, blocked the development of long-term, but not the acute increases in social interaction responses induced by NPY administration. This suggests that the NPY-induced long-term behavioral resilience to restraint stress may occur via mechanisms involving neuronal plasticity. These studies suggest one putative physiologic mechanism underlying stress resilience and could identify novel targets for development of therapies that can augment the ability to cope with stress.

Topics: Amygdala; Animals; Fever; Hypothalamo-Hypophyseal System; Male; Neuropeptide Y; Pituitary-Adrenal System; Rats; Rats, Wistar; Social Behavior; Stress, Psychological; Time

Febrile seizures (FSs) typically occur at the onset of fever and do not recur within the same febrile episode despite enduring or increased hyperthermia. Recurrent seizures during the same febrile episode are considered "complex," with potentially altered prognosis. A characterized immature rat model of FS was used to test the hypotheses that (1) a first FS influences the threshold temperature for subsequent ones, and (2) the underlying mechanisms involve the release and actions of the endogenous inhibitory hippocampal neuropeptide Y (NPY). Experimental FSs were induced two or three times, at 3- to 4-h intervals, and threshold temperatures measured. To determine the potential effects of seizure-induced endogenous NPY on thresholds for subsequent seizures, an antagonist of the major hippocampal NPY receptor (type 2) was infused prior to induction of the second seizure. As an indicator of NPY release, NPY expression was determined 4 and 24 h later. Threshold core and brain temperatures for hyperthermic seizures were consistent with those observed during human fever. Threshold temperatures for a second and third seizure were significantly and progressively higher than those required for the first. This "protective" effect involved induction of endogenous NPY because it was abolished by the NPY antagonist. In addition, NPY mRNA expression was increased in dentate gyrus, CA3 and CA1, after an experimental FS, consistent with peptide release. Collectively these data indicate that the absence of repetitive seizures during a febrile episode involves the inhibitory actions of endogenous NPY, suggesting that the signaling cascade triggered by this peptide might provide targets for therapeutic intervention.

Topics: Age Factors; Animals; Body Temperature; Disease Models, Animal; Fever; Hippocampus; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Recurrence; Seizures, Febrile

The mediation of orexin-A-induced hypothermia was investigated. Different doses of orexin-A (140-560 pmol) were administered intracerebroventricularly (i.c.v.) to adult male rats, and the colon temperature was used as an index of the thermoregulatory action. Orexin-A decreased both the basal colon temperature and the lipopolysaccharide-induced fever and exhibited a bell-shaped dose-response curve. I.c.v. pretreatment with neuropeptide Y (NPY) antiserum 24 h before orexin administration significantly decreased the hypothermic effect of orexin-A. These data strengthen the hypothesis that this appetite-regulating peptide might also play a role in thermoregulation, and its hypothermic effect seems to be mediated at least partially by NPY.

Topics: Animals; Body Temperature; Body Temperature Regulation; Carrier Proteins; Colon; Dose-Response Relationship, Drug; Fever; Hypothermia; Injections, Intraventricular; Intracellular Signaling Peptides and Proteins; Lipopolysaccharides; Male; Neuropeptide Y; Neuropeptides; Orexins; Rats; Rats, Wistar

Young and old Long-Evans rats respond with fevers of equal magnitude and duration to the brain administration of interleukin-1beta (IL-1beta). Here, we characterized brain regional mRNA expression of cytokine and neuropeptide components in response to the brain administration of IL-1beta. We used specific and highly sensitive RNase protection assays to determine mRNA changes for IL-1beta, IL-1 receptor type I (IL-1RI), IL-1R accessory proteins I and II (IL-1R AcP I and II), IL-1 receptor antagonist (IL-1Ra), transforming growth factor-beta1 (TGF-beta1), glycoprotein 130 (gp 130), leptin receptor (OB-R), neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) in the cerebellum, parieto-frontal cortex, hippocampus, hypothalamus, and midbrain of male young (3-5 months) and old (24-26 months) Long-Evans rats. In both young and old rats, IL-1beta induced a significant up-regulation of cerebellar IL-1Ra, IL-1RI, and TGF-beta1 mRNAs; hippocampal TGF-beta1 mRNA; hypothalamic IL-1beta, IL-1Ra, TGF-beta1, and gp 130 mRNAs; and midbrain IL-1beta and TGF-beta1 mRNAs. There were no age-related differences in any cytokine mRNA levels under basal or IL-1beta-stimulated conditions. Levels of hypothalamic POMC mRNA were different between age groups under basal and stimulated conditions. IL-1R AcP I and leptin receptor did not change in any brain region from either young or old rats, suggesting specificity of transcriptional changes. The data show that old Long-Evans rats are not defective in their capacity to develop an appropriate cytokine response to the brain administration of IL-1beta. The implications of these findings for neuroimmunological-neuroinflammatory and neurotoxic/neurodegenerative processes are discussed.

Topics: Aging; Animals; Brain; Cytokines; Fever; Gene Expression Regulation, Developmental; Injections, Intraventricular; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Male; Nerve Degeneration; Nerve Tissue Proteins; Neuropeptide Y; Neuropeptides; Organ Specificity; Pro-Opiomelanocortin; Rats; Receptors, Cytokine; Receptors, Interleukin-1; RNA, Messenger; Sialoglycoproteins; Transcription, Genetic; Transforming Growth Factor beta

Neuropeptide Y (NPY) is a highly potent endogenous peptide which when injected into the medial hypothalamus causes spontaneous eating behaviour and an intense fall in body temperature (Tb). This study used antisense oligodeoxynucleotides (ODNs) to determine whether the Y1 subtype of NPY receptor could underlie these remarkable physiological responses. In the unrestrained rat, the ventromedial hypothalamus (VMH) which is highly reactive to NPY was injected with antisense for NPY (aNPY), Y1 receptors (aNPY-Y1) and mismatched controls (mNPY; mNPY-Y1). After cannulae were implanted bilaterally in the brain of 19 rats, 0.4 or 0.8 microgram per 0.8 microliter of the phosphorothioate synthesised ODNs were delivered to the VMH of the rats at 12 h intervals over 2 d. Only the lower dose of aNPY-Y1, but not aNPY, evoked an intense phasic rise in the Tb following each micro-injection. Simultaneously, 0.4 microgram per 0.8 microliter of aNPY-Y1, but not aNPY, suppressed feeding behaviour after a sequence of micro-injections and on the following day. Body weights and locomotor activity of the rats likewise declined concomitantly with the hyperthermia and hypophagia caused by the Y1 receptor antisense. Neither of the control ODNs for NPY or Y1 receptors injected similarly in the VMH of the rats exerted any effects on these measures. These results clearly provide convincing evidence that in the VMH the Y1 subtype of NPY receptor mediates, in part, the neuronal mechanisms responsible for spontaneous feeding and hypothermia produced by native NPY when applied directly to this structure. The concurrent decline in body weight and activity caused by aNPY-Y1 could be caused by the episodes of hyperthermia.

Topics: Animals; Base Sequence; Body Temperature; Body Weight; Feeding Behavior; Fever; Hypothermia; Male; Microinjections; Molecular Sequence Data; Motor Activity; Neuropeptide Y; Oligonucleotides, Antisense; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Thionucleotides; Time Factors; Transcription, Genetic; Ventromedial Hypothalamic Nucleus

We investigated the effect of recombinant human interleukin-1 beta (rhIL-1 beta)-induced anorexia and pyrexia on the hypothalamic neuropeptide Y (NPY)-ergic system, which stimulates feeding and reduces thermogenesis. In meal-fed rats, food intake decreased by 83%, 90 min after IL-1 beta treatment (1.3 micrograms/100 g ip; n - 8) vs. controls. NPY concentrations were significantly higher in the medial preoptic area (MPO), paraventricular (PVN), ventromedial (VMN), and dorsomedial (DMN) nuclei but unchanged in the arcuate nucleus (ARC) in both IL-1 beta-treated and pair-fed groups. Indomethacin (0.25 mg/100 g ip) reduced IL-1 beta-induced anorexia and tended to normalize NPY concentrations. In study 2, IL-1 beta increased core temperature by 1.1 degrees C above preinjection values (P < 0.001) and significantly raised NPY concentrations in the MPO, PVN, VMN, and DMN compared with controls, 60 min postinjection. Indomethacin prevented the pyrexia and normalized hypothalamic NPY levels. As NPY concentrations were not increased in the ARC (the hypothalamic site of synthesis), we suggest that the increased NPY levels may result from blocked release, which would be in accord with the known experimental effects of NPY.

Topics: Animals; Anorexia; Body Temperature; Eating; Fever; Humans; Hypothalamus; Interleukin-1; Male; Neuropeptide Y; Rats; Rats, Wistar; Recombinant Proteins