Peritoneal exudate cells from long-lived rats exhibit increased IL-10/IL-1 beta expression ratio and preserved NO/urea ratio following LPS-stimulation in vitro

In humans, usual aging, differently from successful aging, is associated with deregulation of proinflammatory/anti-inflammatory cytokine balance. The corresponding data from rat studies are limited. Therefore, we examined (i) cytokine messenger RNA (mRNA) profile of fresh peritoneal cells from 6-(adult), 24-(old), and 31-month-old (long-lived) AO rats and (ii) proinflammatory (IL-1 beta and IL-6) and antiinflammatory (IL-10) cytokine, NO, and urea production in their LPS-stimulated cultures. Comparing with adult rats, cells from old ones expressed lower amount of TNF-alpha and IL-6 mRNAs, but greater amount of IL-1 beta mRNA. On the other hand, cells fromlong-lived rats exhibited a dramatic increase in IL-10 mRNA expression followed by diminished TNF-alpha and IL-6 mRNA expression, and comparable expression of IL-1 beta mRNA relative to adult rats. Consequently, IL-10/IL-1 beta mRNA ratio was greater in cells from long-lived rats than in adult and old rats. In LPS-stimulated peritoneal cell cultures (contained = 95 % macrophages) from old rats, concentration of common proinflammatory cytokines was higher than in those from adult rats. Comparing with adult and old rats, in LPS-stimulated macrophage cultures from long-lived rats, TNF-alpha and IL-6 concentrations were lower; IL-1 beta concentration was comparable or greater (in respect to adult rats), whereas that of IL-10 was strikingly higher. Consistently, in macrophage cultures from long-lived rats, NO (iNOS activity marker)/urea (arginase activity marker) ratio was less and not different from that in old and adult rats, respectively. The study suggests that macrophages from longlived rats, differently from those of old ones, have substantial ability to limit proinflammatory mediator production, which may contribute to their longevity

Neuropeptide Y and its receptor subtypes specifically modulate rat peritoneal macrophage functions in vitro: counter regulation through Y1 and Y2/5 receptors

It is well documented that neuropeptide Y (NPY) exerts a wide range of biological functions through at least five NPY Y receptor subtypes (Y1-Y5), but its immunological effects only recently came into focus. Using NPY family pepticles and NPY-related receptor-specific peptides as well as Y1 and Y2 receptor antagonists, we have tested which NPY Y receptors are involved in NPY-induced modulation of rat peritoneal macrophage function in vitro. NPY and PYY increased oxidative burst in phorbol myristate acetate (PMA)-stimulated macrophages involving activation of protein kinase C (PKC), and decreased it in zymosan-stimulated cells resembling inhibition of signaling pathways subsequent to binding of zymosan particles for the iC3b fragment receptor on macrophages. The combined treatment with NPY and NPY Y receptor antagonists revealed that NPY-induced potentiation of oxidative burst in PMA-stimulated cells is mediated through Y1 and Y2 receptors, while NPY-induced suppression in zymosan-stimulated cells is mediated through Y2 receptors only. NPY-related peptides differently modulated macrophage function, confirming involvement of NPY Y2 receptor in both potentiation and suppression of oxidative burst in these cells. Additionally, it was shown that NPY Y5 receptor mediated suppression of oxidative burst in PMA- and zymosan-stimulated macrophages. Taken together, the present data reveal an NPY Y1 and Y2/Y5 receptor interaction in NPY-induced modulation of macrophage functions related to inflammation. (C) 2004 Elsevier B.V. All rights reserved

Regional and subtype selective changes of neurotransmitter receptor density in a rat transgenic for the Huntington's disease mutation

Huntington's disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disorder caused by a CAG/polyglutamine repeat expansion in the gene encoding the huntingtin protein. We have recently generated a rat model transgenic for HD, which displays a slowly progressive phenotype resembling the human adult-onset type of disease. In this study we systematically assessed the distribution and density of 17 transmitter receptors in the brains of 2-year-old rats using quantitative multi-tracer autoradiography and high-resolution positron emission tomography. Heterozygous animals expressed increased densities of M(2) acetylcholine (increase of 148 +/- 16% of controls; p > 0.001; n = 7), nicotine (increase of 149 +/- 16% of controls; p > 0.01; n = 6), and alpha(2) noradrenergic receptors (increase of 141 +/- 15% of controls; p > 0.001; n = 6), respectively. Densities of these receptors were decreased in homozygous animals. Decreases of receptor density in both hetero- and homozygous animals were found for M1 acetylcholine, 5-HT 2A serotonin, A 2A adenosine, D1 and D2 dopamine, and GABA(A) receptors, respectively. Other investigated receptor systems showed small changes or were not affected. The present data suggest that the moderate increase of CAG/polyglutamine repeat expansions in the present rat model of Huntington's disease is characterized by subtype-selective and region-specific changes of neuroreceptor densities. In particular, there is evidence for a contribution of predominantly presynaptically localized cholinergic and noradrenergic receptors in the response to Huntington's disease pathology

Corrigendum: Regional and subtype selective changes of neurotransmitter receptor density in a rat transgenic for the Huntington's disease mutation

Huntington's disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disorder caused by a CAG/polyglutamine repeat expansion in the gene encoding the huntingtin protein. We have recently generated a rat model transgenic for HD, which displays a slowly progressive phenotype resembling the human adult-onset type of disease. In this study we systematically assessed the distribution and density of 17 transmitter receptors in the brains of 2-year-old rats using quantitative multi-tracer autoradiography and high-resolution positron emission tomography. Heterozygous animals expressed increased densities of M(2) acetylcholine (increase of 148 +/- 16% of controls; p > 0.001; n = 7), nicotine (increase of 149 +/- 16% of controls; p > 0.01; n = 6), and alpha(2) noradrenergic receptors (increase of 141 +/- 15% of controls; p > 0.001; n = 6), respectively. Densities of these receptors were decreased in homozygous animals. Decreases of receptor density in both hetero- and homozygous animals were found for M1 acetylcholine, 5-HT 2A serotonin, A 2A adenosine, D1 and D2 dopamine, and GABA(A) receptors, respectively. Other investigated receptor systems showed small changes or were not affected. The present data suggest that the moderate increase of CAG/polyglutamine repeat expansions in the present rat model of Huntington's disease is characterized by subtype-selective and region-specific changes of neuroreceptor densities. In particular, there is evidence for a contribution of predominantly presynaptically localized cholinergic and noradrenergic receptors in the response to Huntington's disease pathology

Increased numbers of motor activity peaks during light cycle are associated with reductions in adrenergic alpha(2)-receptor levels in a transgenic Huntington's disease rat model

Huntington's disease (HID) is a neurodegenerative disorder caused by a CAG repeat expansion in the HD gene. Besides psychiatric, motor and cognitive symptoms, HD patients suffer from sleep disturbances. In order to screen a rat model transgenic for HD (tgHD rats) for sleep-wake cycle dysregulation, we monitored their circadian activity peaks in the present study. TgHD rats of both sexes showed hyperactivity during the dark cycle and more frequent light cycle activity peaks indicative for a disturbed sleep-wake cycle. Focusing on males at the age of 4 and 14 months, analyses of receptor levels in the hypothalamus and the basal forebrain revealed that 5-HT2A- and adrenergic alpha(2)-receptor densities in these regions were significantly altered in tgHD rats compared to their wild-type littermates. Adrenergic receptor densities correlated negatively with the light cycle hyperactivity peaks at later stages of the disease in male tgHD rats. Furthermore, reduced leptin levels, a feature associated with circadian misalignment, were present. Our study demonstrates that the male tgHD rat is a suitable model to investigate HD associated sleep alterations. Further studies are warranted to elucidate the role of adrenergic- and 5-HT2A- receptors as therapeutic targets for dysregulation of the circadian activity in HD. (C) 2009 Elsevier B.V. All rights reserved

Age-related effect of peptide YY (PYY) on paw edema in the rat: The function of Y1 receptors on inflammatory cells

It is well documented that neuropeptides participate in local inflammatory reaction and modulate functions of inflammatory cells. The aim of the study was to determine a link between in vivo and in vitro effects of NPY-related peptides on inflammatory response with respect to ageing. Peptide YY (PYY) intraplantarly applied decreases concanavalin A-induced paw edema in 3 and 8 months, but not in 24 months old male rats of Albino Oxford strain. The use of NPY-related receptor-specific peptides and Y1 receptor antagonist revealed that anti-inflammatory effect of PYY is mediated via NPY Y1 receptors. PYY in vitro decreases adherence of macrophages from 8 months, but not from 3 and 24 months old rats and this effect is also mediated via NPY Y1 receptor. Additionally, PYY (10(-6) M) decreases NBT reduction in macrophages from 3 and 8 months old rats, and suppresses NO production in cells from 24 months old rats, albeit regardless of absence of in vivo effect of PYY on inflammation in aged rats. It is concluded that aged rats are less responsive to anti-inflammatory action of PYY compared to adult and young rats, and that ageing is associated with altered NPY Y1 receptor functioning. (c) 2006 Elsevier Inc. All rights reserved

Effect of neuropeptide Y on inflammatory paw edema in the rat: involvement of peripheral NPYY1 and Y5 receptors and interaction with dipeptidyl-peptidase IV (CD26)

Several lines of evidence suggest that neuropeptide Y (NPY) may exert regulatory effects in local inflammatory responses. Here, we show that intraplantarly (i.pl.) applied NPY, peptide YY (PYY), and an NPY Y5 receptor-selective agonist dose-dependently potentiate concanavalin A (Con A)-induced paw edema in the rat. The NPY Y1 receptor antagonist BIBO 3304 abolishes the pro-inflammatory action of both NPY and PYY while the dipeptidyl-peptidase IV (CD26) inhibitor Ile-thiazolidide exerted synergistic and potentiating effects in vivo. Taken together, the present data reveal an NPY Y1/Y5 receptor interplay and an involvement of CD26 in the NPY-induced potentiation of paw edema in the rat. (C) 2002 Elsevier Science B.V. All rights reserved

Neuropeptide Y receptor-specifically modulates human neutrophil function

Despite a continuously growing body of evidence highlighting the role of NPY in the immune system, surprisingly little is known about its ability to alter human leukocyte function. We therefore set out to examine NPY receptor expression and functional effects of NPY in freshly isolated human neutrophils. Our results not only demonstrate for the first time the presence of specific NPY receptors on human neutrophils, but also unveil of how these receptors differentially modulate critical functions of neutrophils such as phagocytosis of bacteria as well as the release of reactive oxygen species. (C) 2008 Elsevier B.V. All rights reserved