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The expression of matrix metalloproteinase of the first type was studied in frontal sections of the adult rat brain one month after a single intracerebroventricular injection of P-amyloid peptide (25-35), which is known to be a well-known model of the development of Alzheimer's disease. Brain sections were stained immunocytochemically to detect MMP-1 expression, and histologically to reveal the state of hippocampal neurons. Administration of P-amyloid peptide induced a significant degeneration of cells in the dorsal hippocampus. This was demonstrated by a significant decrease in the total number of cells and by the appearance of acidophilic neurons of altered (often triangular) shape. Altered cells were most often found in the hippocampal field CA3, and in a smaller quantity in the CA1 field. MMP-1-like immunoreactivity was found in the same hippocampal areas, the staining being restricted to the cells of altered shape (staining of somata and primary neurites). The data suggest possible involvement of the type 1 metalloproteinase in the development of Alzheimer's disease.
Leptin and glucagon-like peptide-1 (GLP-1) were proved to act in concert to control the activity of feeding centres. Since leptin receptor was identified in the gut endocrine L cells and neurons producing GLP-1, we have checked whether GLP-1 mediates the effects of leptin on feeding and drinking behaviour. To this aim, an intraperitoneal or intracerebroventricular injection of exendin (9 - 39), a GLP-1 antagonist, (50 or 10 µg per rat, respectively) followed by leptin (100 or 5 µg per rat, respectively) was made and 24-hour food intake and body weight changes were measured. Previous injection of exendin (9 - 39) completely abolished the suppressory effect of peripheral leptin on food intake and body weight gain. Moreover, exendin (9 - 39) significantly attenuated the effect of intracerebroventricular leptin on food but not water consumption. It is concluded that intact GLP-1 signalling is necessary to mediate the effect of leptin on food intake in the rat. Conversely, leptin seems to affect the thirst center function independently of GLP-1. Also, these findings produce further evidence for close interactions between long- and short-term factors regulating the activity of feeding centres.
Nitric oxide (NO) has been shown to be an important mediator of febrile response to lipopolisaccharide (LPS). To clarify the role of different isoforms of NO synthase (NOS) in febrile response to immune challenge, effects of selective iNOS and nNOS inhibitors on fever to LPS were examined in freely moving biotelemetered rats. Vinyl-L-NIO (N5 - (1-Imino-3-butenyl) - ornithine (vL-NIO), a neuronal nitric oxide synthase (nNOS) inhibitor, and aminoguanidine hydrochloride, an inducible nitric oxide synthase (iNOS) inhibitor, were injected intracerebroventricularly at a dose of 10 µg/rat just before intraperitoneal injection of LPS at a dose of 50 µg/kg. Both inhibitors injected at a selected doses had no effect on normal day-time body temperature (Tb) and normal night-time Tb. vinyl-L-NIO and aminoguanidine injected intracerebroventricularly at a dose of 10 µg/animal suppressed the LPS-induced fever in rats. The fever index calculated for rats pretreated with v-LNIO or with aminoguanidine and injected with LPS was reduced by 43% and 72%, respectively, compared to that calculated for water-pretreated and LPS-injected rats. Whereas vL-NIO partly attenuated both phases of febrile rise in Tb, administration of aminoguanidine into the brain completely prevented fever induced by LPS. These data indicate that activation of iNOS inside the brain is not only responsible for triggering but also for maintaining of LPS-induced fever in rats. It is, therefore, reasonable to hypothesize that, activation of iNOS inside the brain is more important in fever development than activation of nNOS.
The purpose of this study was to investigate the role of neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS) in the brain during development of fever in response to localized tissue inflammation caused by injection of turpentine in freely moving biotelemetered rats. To determine the role of both NOSs in turpentine-induced fever, we injected vinyl-L-NIO (N5 – (1-Imino-3-butenyl) – ornithine (vL-NIO), a selective nNOS inhibitor, and aminoguanidine hydrochloride, a selective iNOS inhibitor, intracerebroventricularly (i.c.v.) 5 h after turpentine injection. Rats responded with fever to intramuscular injection of 20 µl of turpentine that commenced about 5 - 6 h after injection and reached peak value between 9 - 11 h post-turpentine. The inhibition of nNOS as well as iNOS in the brain did not affect fever induced by turpentine. Fevers in control rats (treated i.c.v. with pyrogen-free water) and iNOS or nNOS inhibitor-i.c.v. treated rats injected with turpentine were essentially the same. Furthermore, on the basis of these data, we concluded that iNOS and nNOS inside the brain do not participate in generation of fever to turpentine in rats.
Opioids administered by intracerebroventricular injections produce analgesic responses in rats. The present study was undertaken to investigate the effects of a highly selective m-opioid receptor ligand morphiceptin on trigemino-hypoglossal reflex in rats. The analgesic effect of morphiceptin was compared with another opioid peptide, Met-enkephalin. With the experimental settings used in this study, we have demonstrated that both morphiceptin and Met-enkephalin show significant dose-dependent analgesic effects after i.c.v. administration in rats as assayed by trigemino-hypoglossal reflex test. The antinociceptive response to Met-enkephalin was short lasting and was observed 10 to 15 min after i.c.v. perfusion. Morphiceptin had a relatively longer duration of antinociceptive action, the effect was observed 20- 50 min after i.c.v. perfusion. Neither morphiceptin nor Met-enkephalin produced antinociception after peripheral injections. The results of the present study indicate that both tested peptides act at µ-opioid receptors situated in the central nervous system. They also suggest that µ-opioid receptors present in the central nervous system are an important element of the trigemino-hypoglossal reflex arc. For that reason selective m-opioid receptor ligands, like morphiceptin, inhibit the reflex more significantly.
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Centrally applied ghrelin affects feeding dynamics in male rats

67%
Ghrelin is 28-amino acid peptide, which is produced mainly in the stomach. Since plasma ghrelin are strictly dependent on food intake, this hormone has significant effects on appetite and energy balance. The aim of this investigation was to examine the effects of centrally applied ghrelin on feeding dynamism by measuring the approaches to food container and the amount of food and water intake within 2 hours immediately after ghrelin or PBS injections. Body weight was obtained daily, while ending retroperitoneal (RP) and epididymal (EPI) white adipose tissue (WAT) contents as well as blood levels of leptin and insulin were measured. Five injections of rat ghrelin or PBS (n = 8 per group) were administered once per day (1 µg = 0.15 nmol of ghrelin in 5 µL of PBS), into lateral cerebral ventricle (ICV) of free feeding adult male rats. Results showed that in the first and the second 30-min intervals number of approaches to food container were significantly increased already after the 2nd ICV ghrelin application (p < 0.05), by 50% and 67% respectively, in comparison with control rats. Centrally applied ghrelin increased body weight after the 2nd injection till the end of treatment (p < 0.05), which was followed by increased food and water intake (p < 0.05). At the end of treatment, RP and EPI WAT contents were increased (by 221%, p < 0.01 and 82%, p < 0.05, respectively). Serum insulin levels were elevated (by 41%, p < 0.05) while serum leptin levels were decreased (by 75%, p < 0.05). These data and the available literature strongly support the opinion that repetitive subnanomolar doses of central ghrelin administration play essential role in food initiation and feeding dynamics in freely feeding adult male rats.
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