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1.
Abstract: Recent studies indicate the lumped constant (LC), which defines the relative rates of brain utilization of glucose and 2-deoxyglucose (2-DG), doubles to values > 1.0 under conditions of hypoglycemia. Since changes in the LC should be predictable given the kinetic parameters of blood-brain barrier (BBB) transport and brain phosphorylation of glucose and 2-DG, the present studies were designed to measure the necessary kinetic parameters. The carotid injection technique was used to determine cerebral blood flow and the Km , Vmax, and K D of glucose and 2-DG transport through the BBB in seven brain regions in rats anesthetized with 50 mg/kg i.p. pentobarbital. Regional glucose transport through the BBB was characterized by an average Km = 6.3 m m , average Vmax = 0.53 μmol min−1g−1, and average K D= 0.022 ml min−1g−1. The nonsaturable route of transport of glucose represented on the average 40% of the total glucose influx into brain regions at an arterial glucose concentration of 10 m m . In addition, the rate constants of phosphorylation of glucose and 2-DG were measured for each region. Substitutions of the measured kinetic parameters for sugar transport and phosphorylation into equations defining the LC confirm the observation that the LC would be expected to vary under extreme conditions such as hypoglycemia and to exceed values of 1.0 under these conditions.  相似文献   

2.
The aim of the present study was to determine the effect of social crowding stress and significance of nitric oxide (NO) and prostaglandins (PG) generated by constitutive and inducible nitric oxide synthase (NOS) and cyclooxygenase (COX) in the stimulation of hypothalamic-pituitary-adrenal (HPA) axis by cholinergic muscarinic receptor agonist carbachol. Inhibitors of neuronal NOS (nNOS) L-NNA, general NOS L-NAME and inducible NOS (iNOS) aminoguanidine, as well as inhibitors of COX-1, piroxicam, and COX-2, compound NS-398 were administered 15 min prior to carbachol to control or crowded rats (24 rats in cage for 7, during 3 and 7 days). In stressed rats L-NAME, L-NNA and aminoguanidine significantly intensified the carbachol-induced ACTH and corticosterone secretion, like in control rats. Piroxicam, markedly decreased the carbachol-induced ACTH and corticosterone response under either basal or stress conditions. Compound NS-398 did not markedly alter the carbachol-induced HPA response in control and stressed rats. Crowding stress (3 days) significantly impaired the i.c.v. prostaglandin E(2)-induced ACTH response. Corticotropin releasing hormone (CRH) receptor antagonists, alpha-helical CRH [9-14], given i.c.v. did not alter the PGE(2)-evoked corticosterone response in either control or stressed rats, indicating that hypothalamic CRH is not involved in the PGE(2)-induced central stimulation of HPA axis. In control rats L-NAME considerably enhanced, while L-arginine, a physiological NOS substrate, abolished the PGE(2)-induced ACTH and corticosterone response. In stressed rats this NOS blocker significantly increased and L-Arg reduced the stimulatory effect of PGE(2) on ACTH and corticosterone secretion. The carbachol-induced corticosterone response was significantly increased by pretreatment with nNOS inhibitor L-NNA and was considerably reduced by indomethacin, a general COX inhibitor. Pretreatment with both antagonists left the carbachol-induced corticosterone level unchanged, suggesting an independent and reciprocal effect of NO and PG in the cholinergic stimulation of pituitary-adrenocortical response. These results indicate that in the stimulatory action of muscarinic agonist, carbachol, NO is an inhibitory transmitter under basal and crowding stress conditions. This psychosocial stress does not functionally affect the NOS/NO systems. Prostaglandins are involved in the cholinergic muscarinic-induced stimulation of HPA response to a significant extent in non-stressed rats. PGE(2) may be involved in the carbachol-elicited HPA response under basal and stress conditions. Prostaglandins released in response to muscarinic stimulation did not evoke the hypothalamic CRH mediation. NO significantly impairs and PG stimulates the carbachol-induced HPA response in rats under basal and social stress conditions.  相似文献   

3.
The role of endogenous catecholamines in the regulation of brain prostaglandin (PG) synthesis was studied in the rat. Male rats were injected in the brain lateral ventricle or in the ventral noradrenergic bundle with either the catecholaminergic neurotoxin 6-hydroxydopamine or vehicle. Other groups of rats were injected intraperitoneally with the tyrosine hydroxylase inhibitor, alpha-methyl-p-tyrosine, or with the inhibitor of dopamine-beta-hydroxylase, FLA-63. All these drugs produced a significant depletion of norepinephrine (NE) content in the cortex and hypothalamus. The rats that had lower levels of NE exhibited reduced capacity to synthesize PGE2 but not thromboxane B2 and 6-keto-PGE1 alpha in the cortex and hypothalamus. However, induced production of PG, stimulated by the bacterial endotoxin lipopolysaccharide (LPS), remained unchanged, namely, a similar (2- to 2.5-fold) increase of PG synthesis was noted in control and in NE-depleted rats. We suggest that the regulation of PG synthesis under basal condition requires intact adrenergic input, whereas LPS-induced production of PG is independent of the adrenergic innervation.  相似文献   

4.
IL-6 expression in skeletal muscle is stimulated by contractions. We sought to examine whether hyperinsulinaemia increases IL-6 mRNA in skeletal muscle and whether any increase is modified in insulin resistant muscle. We hypothesized that intramuscular IL-6 mRNA would be increased in response to insulin, but such an affect would be unaffected by insulin resistance because the primary insulin sensitive signalling protein responsible for activating IL-6 functions normally in insulin resistant muscle. Transgenic rats over-expressing the gluconeogenic regulatory enzyme phosphoenolpyruvate carboxykinase (PEPCK) were studied. White gastrocnemius muscle samples were obtained under hyperinsulinaemic, euglycaemic clamp (4 mU kg(-1)min(-1) insulin, plasma glucose concentration 4-6 mmol L(-1)) and basal conditions in both PEPCK (basal n=4; insulin n=5) and wild-type (CON) (basal n=5; insulin n=4) rats, which were previously injected with a bolus of 2-[1-14C]deoxyglucose (2-DG) into the carotid artery. Muscle samples were assayed for 2-DG uptake and IL-6 mRNA. No differences in 2-DG uptake or IL-6 mRNA were observed when comparing groups under basal conditions. Under clamp conditions, 2-DG uptake was lower (P<0.05) in PEPCK compared with CON. Insulin stimulation in CON did not change IL-6 mRNA compared with basal levels. In contrast, there was an approximately 8-fold increase (P<0.05) in IL-6 mRNA in insulin-stimulated PEPCK compared with CON basal levels. Insulin stimulation increases IL-6 gene expression in insulin resistant, but not healthy, skeletal muscle, suggesting that IL-6 expression in skeletal muscle is sensitive to changes in insulin in circumstances of insulin resistance. It is likely that the differences observed when comparing healthy with insulin resistant muscle are due to the differential activation of insulin sensitive signalling proteins responsible for activating IL-6.  相似文献   

5.
Dietary restriction and physical exercise can enhance stress resistance and reduce the risk of cardiovascular disease. We investigated the effects of dietary supplementation with 2-deoxy-d-glucose (2-DG), a glucose analog that limits glucose availability at the cellular level, on cardiovascular and neuroendocrine responses to stress in rats. Young adult male Sprague-Dawley rats were implanted with telemetry probes to monitor blood pressure (BP), heart rate, body temperature, and body movements. These variables were measured at designated times during a 6-mo period in rats fed control and 2-DG-supplemented (0.4% 2-DG, fed ad libitum on a schedule of 2 days on the diet and 1 day off the diet) diets during unperturbed conditions and during and after immobilization stress or cold-water swim stress. Rats fed the 2-DG diet exhibited significant reductions in resting BP, attenuated BP responses during stress, and accelerated recovery to baseline after stress. Plasma concentrations of ACTH and corticosterone were elevated under nonstress conditions in rats fed the 2-DG diet and exhibited differential responses to single (enhanced response) and multiple (reduced response) stress sessions compared with rats fed control rat chow ad libitum. The 2-DG diet improved glucose metabolism, as indicated by decreased concentrations of blood glucose and insulin under nonstress conditions, but glucose and insulin responses to stress were maintained. We conclude that improvements in some cardiovascular risk factors and stress adaptation in rats maintained on a 2-DG-supplemented diet are associated with reduced neuroendocrine responses to the stressors.  相似文献   

6.
To understand the mechanisms whereby recurrent hypoglycemia increases the risk of subsequent hypoglycemia, it was necessary to differentiate the effects of recurrent hyperinsulinemia from those of hyperinsulinemic hypoglycemia. We examined basal and hypoglycemic endocrine function in normal rats, streptozotocin-diabetic controls, and diabetic rats exposed to 4 days of 2 episodes/day of hyperinsulinemic hypoglycemia (DH) or hyperinsulinemic hyperglycemia (DI). DH and DI rats differentiated the effects of hyperinsulinemia from those of hypoglycemia. In diabetic controls, basal plasma ACTH tended to be increased, and plasma corticosterone, plasma somatostatin, and pancreatic prosomatostatin and proglucagon mRNA were increased (P < 0.05) vs. normal rats. These parameters were normalized in DH and DI rats. In diabetic controls, glucagon, epinephrine, norepinephrine, corticosterone, and peak glucose production responses to hypoglycemia were reduced (P < 0.05) vs. normal rats. In DI rats, epinephrine responses were normalized. Conversely, DH rats displayed marked further impairment of epinephrine and glucose production responses and increased peripheral insulin sensitivity (P < 0.05 vs. diabetic controls). Both insulin regimens partially normalized glucagon and fully normalized norepinephrine and corticosterone responses. In summary, recurrent hyperinsulinemia in diabetic rats normalized most pituitary-adrenal, sympathoadrenal, and pancreatic parameters. However, concurrent hypoglycemia further impaired epinephrine and glucose production responses and increased insulin sensitivity. We conclude that 1) recurrent hypoglycemia may increase the risk of subsequent hypoglycemia by increasing insulin sensitivity, and 2) epinephrine counterregulation is particularly sensitive to impairment by recurrent hypoglycemia.  相似文献   

7.
We describe prostaglandin (PG) biosynthesis by microsomal-enriched fractions of fat body prepared from larvae of the tenebrionid beetle, Zophobas atratus. PG biosynthesis was sensitive to incubation time, temperature, pH, substrate and protein concentration. Optimal PG biosynthesis conditions of those we examined included 2 mg of microsomal-enriched protein, incubated at 22 degrees C for 2 min at pH 6. These preparations yielded four major PGs: PGA(2), PGE(2), PGD(2) and PGF(2 alpha). PGA(2) and PGF(2 alpha) were the predominant eicosanoids produced under these conditions. Two non-steroidal anti-inflammatory drugs, indomethacin and naproxen, effectively inhibited PG biosynthesis in low concentrations. In vitro PG biosynthetic reaction conditions, using vertebrate or invertebrate enzyme sources, usually include a cocktail of reaction co-factors. The Z. atratus preparation similarly performs better in the presence of co-factors. Arch.  相似文献   

8.
The aim of the present study was to compare the effect of social stress on the corticotropin releasing hormone (CRH) and arginine vasopressin (AVP)-induced pituitary-adrenocortical activity. Also the significance of prostaglandins (PG) generated by constitutive and inducible cyclooxygenase (COX-1 and COX-2) in the stimulation of hypothalamic-pituitary-adrenal (HPA) axis by AVP under basal and crowding stress conditions was investigated. The control rats were housed 7 in a standard cage and stressed rats were crowded 24 in a cage of the same size during 7 days. The activity of HPA axis was determined by measuring plasma ACTH and serum corticosterone levels 1 h after i.p. AVP administration. Indomethacin (2.0 mg/kg i.p.), a non-selective COX inhibitor, piroxicam (0.2, 2.0, and 5.0 mg/kg), a more potent COX-1 than COX-2 inhibitor, and compound NS-398 (0.2 and 2.0 mg/kg) a selective COX-2 inhibitor, were administered i.p. 15 min prior to AVP (5.0 microg/kg i.p.) to control or crowded rats. The obtained results indicate that social stress for 7 days considerably inhibits the stimulatory action of AVP on ACTH secretion, while it intensifies the CRH-induced ACTH secretion. Indomethacin, piroxicam and NS-398 significantly diminished the AVP-elicited ACTH and corticosterone secretion in non-stressed rats. None of these COX antagonist induced any significant inhibition of the AVP-induced ACTH and corticosterone secretion in stressed rats. Therefore, PG generated by COX-1 or COX-2 do not participate to a significant extent in the HPA stimulation by AVP during crowding stress. These results suggest that social crowding stress desensitizes the PG stimulatory mechanism which considerably mediates the AVP-induced HPA stimulation under basal conditions. The results contrast with a lack of any involvement of PG in the CRH-induced stimulation of HPA response under basal or crowding stress conditions.  相似文献   

9.
We describe prostaglandin (PG) biosynthesis by microsomal-enriched fractions of fat body prepared from true armyworms, Pseudaletia unipuncta. PG biosynthesis was sensitive to experimental conditions, including incubation time, temperature, pH, substrate and protein concentration. Optimal PG biosynthesis conditions included 1 mg of microsomal-enriched protein, incubated at 28 degrees C for 7.5 min at pH 8. These preparations yielded four major PGs: PGA(2), PGE(2), PGD(2) and PGF(2alpha). PGA(2) and PGE(2) were the predominant eicosanoids produced under these conditions. Two non-steroidal anti-inflammatory drugs, indomethacin and naproxen, effectively inhibited PG biosynthesis. Unlike other invertebrate PG biosynthetic systems studied so far, the true armyworm system appeared to be independent of the usual exogenous co-factors required by mammalian and other invertebrate systems. These findings are discussed with respect to PG biosynthesis in other invertebrate and vertebrate systems.  相似文献   

10.
Recently, we established that hypothalamo-pituitary-adrenal (HPA) and counterregulatory responses to insulin-induced hypoglycemia were impaired in uncontrolled streptozotocin (STZ)-diabetic (65 mg/kg) rats and insulin treatment restored most of these responses. In the current study, we used phloridzin to determine whether the restoration of blood glucose alone was sufficient to normalize HPA function in diabetes. Normal, diabetic, insulin-treated, and phloridzin-treated diabetic rats were either killed after 8 days or subjected to a hypoglycemic (40 mg/dl) glucose clamp. Basal: Elevated basal ACTH and corticosterone in STZ rats were normalized with insulin but not phloridzin. Increases in hypothalamic corticotrophin-releasing hormone (CRH) and inhibitory hippocampal mineralocorticoid receptor (MR) mRNA with STZ diabetes were not restored with either insulin or phloridzin treatments. Hypoglycemia: In response to hypoglycemia, rises in plasma ACTH and corticosterone were significantly lower in diabetic rats compared with controls. Insulin and phloridzin restored both ACTH and corticosterone responses in diabetic animals. Hypothalamic CRH mRNA and pituitary pro-opiomelanocortin mRNA expression increased following 2 h of hypoglycemia in normal, insulin-treated, and phloridzin-treated diabetic rats but not in untreated diabetic rats. Arginine vasopressin mRNA was unaltered by hypoglycemia in all groups. Interestingly, hypoglycemia decreased hippocampal MR mRNA in control, insulin-, and phloridzin-treated diabetic rats but not uncontrolled diabetic rats, whereas glucocorticoid receptor mRNA was not altered by hypoglycemia. In conclusion, despite elevated basal HPA activity, HPA responses to hypoglycemia were markedly reduced in uncontrolled diabetes. We speculate that defects in the CRH response may be related to a defective MR response. It is intriguing that phloridzin did not restore basal HPA activity but it restored the HPA response to hypoglycemia, suggesting that defects in basal HPA function in diabetes are due to insulin deficiency, but impaired responsiveness to hypoglycemia appears to stem from chronic hyperglycemia.  相似文献   

11.
The effect of the hexose analogue 2-deoxy-D-glucose (2-DG) on the functional activity of various populations of cytolytic T lymphocytes (CTL) has been compared. Under aerobic conditions, CTL harvested at the peak of the response (day 4) in primary or secondary mixed leukocyte cultures (MLC) were much more readily inhibited by 2-DG that CTL obtained from MLC at later times (day 11 to 18) or from the peritoneal cavity of alloimmune mice. Quantitatively, 0.4 mM 2-DG was sufficpient to inhibit cytolysis by 50% in day 4 CTL populatons, whereas 25 mM had little or no effect on day 11 to 18 CTL. Evidence was obtained that inhibition of cytolysis by 2-DG under these conditions was accompanied by a parallel inhibition of effector:target cell binding. In contradistinction to these findings, the cytolytic activity of both day 4 and day 11 MLC cells was readily inhibited by 2-DG under conditions where cell respiration was blocked by sodium azide. Furthermore, uptake of radiolabeled 2-DG was observed under aerobic conditions in both day 4 and day 11 MLC cells. These results strongly suggest that inhibition of cytolysis by 2-DG under aerobic conditions is mediated via a direct effect on CTL which is independent of the consequences of energy depletion. An indirect method by which CTL may be inhibited by 2-DG is suggested.  相似文献   

12.
This study was undertaken to evaluate the effects of streptozotocin (STZ)-induced hyperglycemia and insulin-induced hypoglycemia in cortical and hippocampal mitochondria bioenergetics and oxidative status. For that purpose we used, citrate (vehicle)-treated Wistar rats, STZ-treated rats [i.p., 50 mg/kg body weight] and STZ-treated rats injected with insulin [s.c., dose adjusted to blood glucose levels] 1 h prior to sacrifice to induce an acute episode of hypoglycemia. Several parameters were analyzed: respiratory chain, phosphorylation system, thiobarbituric acid reactive substances (TBARS) levels, hydrogen peroxide (H2O2) production rate, and non-enzymatic and enzymatic antioxidant defenses. Cortical mitochondria from insulin-induced hypoglycemic rats present a significant decrease in the ADP/O index, a significant increase in the repolarization lag phase and a decrease in GSH/GSSG ratio when compared with STZ and control mitochondria. Both STZ-induced diabetes and insulin-induced hypoglycemia promote a significant increase in TBARS levels and a decrease in glutathione disulfide reductase activity. Diabetic cortical mitochondria present a significant decrease in glutathione peroxidase (GPx) activity compared to control mitochondria. In turn, insulin-induced hypoglycemia induced a significant increase in GPx and manganese superoxide dismutase (MnSOD) activities. In hippocampal mitochondria, insulin-induced hypoglycemia increases the respiratory control ratio whereas both situations, hyper- and hypoglycemia, potentiate H2O2 production and decrease the activity of MnSOD. These results suggest that the poor glycemic control that occurs in type 1 diabetic patients undergoing insulin therapy may have detrimental effects in brain areas involved in learning and memory.  相似文献   

13.
Although the role of prostaglandins (PG) in the mechanism of dilatation of the ductus arteriosus (DA) has received considerable attention, no data on their possible interaction with the pressure-induced myogenic reaction are available. There is also a lack of information on PG production by the foetal blood vessels of the guinea-pig, in which the DA closes rapidly. Use of the RIA method showed relatively low PG production by isolated foetal guinea pig blood vessels, as represented by the main products, PGI1 and PGE2. When computed in pmol per mg wet weight, the production of 6-keto-PGF1 alpha (an equivalent of PGI2) was statistically significantly higher in the foetal DA (4.06 +/- 1.13) than in the foetal aorta (2.04 +/- 0.33). The isolated DA reacts to a sudden increase in perfusion pressure by marked constriction, which in some cases leads to functional closure of the DA. In 10(-7) to 10(-5) mol.l-1 concentration, PGE2 reversibly inhibits pressure-induced myogenic constriction, while under the same conditions the contractility of the DA in response to oxygen is unaffected. In concentrations of 10(-6)-10(-5) mol.l-1, indomethacin, a blocker of PG biosynthesis, also induces pressure constriction and it raises the basal flow resistance of isolated DA preparations. The results indicate that PGs play a modulator role in the pressure myogenic response of the DA of guinea-pig and rabbit foetuses.  相似文献   

14.
The aim of the present study was to determine the effect of social stress and significance of prostaglandins (PG) generated by constitutive and inducible cyclooxygenase (COX-1 and COX-2) in the stimulation of hypothalamic-pituitary-adrenal (HPA) axis by corticotropin releasing hormone (CRH) under basal and social crowding stress conditions. The stressed rats were crowded in groups of 24 to a cage for 3 or 7 days, whereas the control animals were haused in groups of 7 to a cage of the same size. The activity of HPA axis was determined by measuring plasma ACTH and serum corticosterone levels 1 h after i.p. CRH administration. Inhibitors of COX-1, piroxicam (0.2, 2.0, and 5.0 mg/kg), and COX-2, compound NS-398 (0.2 and 2.0 mg/kg), were administered i.p. 15 min prior to CRH (0.1 microg/kg i.p.) to control or crowded rats. The obtained results indicate that social stress for 3 and 7 days markedly intensifies the stimulatory action of CRH on ACTH secretion. Neither piroxicam nor NS-398 induce any significant effect on the CRH-elicited ACTH and corticosterone secretion in non-stressed or crowded rats. Therefore, PG generated by COX-1 or COX-2 do not participate to a significant extent in the stimulation of HPA axis by CRH under either basal conditions or during crowding stress. These results also indicate that the stimulatory action of CRH on ACTH secretion is not only completely resistant to desensitization but is sensitized during social crowding stress. The results contrast with a significant involvement of PG in the vasopressin-induced stimulation of HPA response during crowding stress.  相似文献   

15.
Isolated pancreatic islets of the rat were either prelabeled with [3H]arachidonic acid, or were incubated over the short term with the concomitant addition of radiolabeled arachidonic acid and a stimulatory concentration of glucose (17mM) for prostaglandin (PG) analysis. In prelabeled islets, radiolabel in 6-keto-PGF1 alpha, PGE2, and 15-keto-13,14-dihydro-PGF2 alpha increased in response to a 5 min glucose (17mM) challenge. In islets not prelabeled with arachidonic acid, label incorporation in 6-keto-PGF1 alpha increased, whereas label in PGE2 decreased during a 5 min glucose stimulation; after 30-45 min of glucose stimulation labeled PGE levels increased compared to control (2.8mM glucose) levels. Enhanced labelling of PGF2 alpha was not detected in glucose-stimulated islets prelabeled or not. Isotope dilution with endogenous arachidonic acid probably occurs early in the stimulus response in islets not prelabeled. D-Galactose (17mM) or 2-deoxyglucose (17mM) did not alter PG production. Indomethacin inhibited islet PG turnover and potentiated glucose-stimulated insulin release. Islets also converted the endoperoxide [3H]PGH2 to 6-keto-PGF1 alpha, PGF2 alpha, PGE2 and PGD2, in a time-dependent manner and in proportions similar to arachidonic acid-derived PGs. In dispersed islet cells, the calcium ionophore ionomycin, but not glucose, enhanced the production of labeled PGs from arachidonic acid. Insulin release paralleled PG production in dispersed cells, however, indomethacin did not inhibit ionomycin-stimulated insulin release, suggesting that PG synthesis was not required for secretion. In confirmation of islet PGI2 turnover indicated by 6-keto-PGF1 alpha production, islet cell PGI2-like products inhibited platelet aggregation induced by ADP. These results suggest that biosynthesis of specific PGs early in the glucose secretion response may play a modulatory role in islet hormone secretion, and that different pools of cellular arachidonic acid may contribute to PG biosynthesis in the microenvironment of the islet.  相似文献   

16.
Prostaglandin (PG) production was evaluated in the three cell types (endothelial, smooth muscle, and fibroblast) comprising the bovine pulmonary artery. Prostacyclin (PGI2) was the predominant prostaglandin (PG) produced by endothelial, smooth muscle, and fibroblast cells as they exist in culture or in freshly excised tissue fragments. In addition to PGI2, measurable amounts of PGE2, PGF2a, and thromboxane A2 (TXA2) were also produced by these cells. Endothelial cells were the most active producers of PGs. However, the type of PG produced was characteristic of the particular cell type, while the level of production was dependent on external factors. Prostaglandin production by cultured cells, both under basal conditions and in response to stimulatory agents, was quite similar to that of the respective freshly excised tissue fragments containing a given cell type. These cells in culture could be stimulated to produce PGI2 by both angiotensin and bradykinin at very low (physiological) concentrations, a further indication of the retention of the physiological responsiveness of these cells in culture. Endothelial cells and fibroblasts were activated by bradykinin at concentrations as low as 10(-12) M but did not respond to angiotensin. Smooth muscle cells in primary and first passage cultures were activated by both bradykinin and angiotensin at 10(-12) M concentrations. Serial subcultivations of smooth muscle cells resulted in a progressive loss in their responsiveness to bradykinin stimulation. The state of cell growth proved to be an important determinant of PG production. Actively growing cells in culture synthesized less PG when compared to cells which had entered into a "quiescent" nongrowth state.  相似文献   

17.
Attenuation of fever occurs in pregnant animals. This study examined a hypothesis that brain production of PGE(2), the final mediator of fever, is suppressed in pregnant animals. Near-term pregnant rats and age-matched nonpregnant female rats were injected with lipopolysaccharide (100 microg/kg) intraperitoneally. Four hours later, colonic temperature was measured, their cerebrospinal fluid (CSF) was sampled for PGE(2) assay, and their brains were processed for immunohistochemistry of cyclooxygenase-2, an enzyme involved in PGE(2) biosynthesis. In the pregnant rats, lipopolysaccharide injection resulted in significantly smaller elevations in both colonic temperature and CSF-PGE(2) level than in nonpregnant rats. In the pregnant rats, lipopolysaccharide-induced cyclooxygenase-2 expression was blunted in terms of the number of positive cells. There was a significant correlation between PGE(2) level in CSF and the number of cyclooxygenase-2-positive endothelial cells. These results suggest that suppressed PGE(2) production in the brain is one cause for the attenuated fever response at near-term pregnancy and that this suppressed PGE(2) production is due to the suppressed induction of cyclooxygenase-2 in brain endothelial cells.  相似文献   

18.
19.
Aging is enhanced by hypoxia and oxidative stress. As the lens is located in the hypoglycemic environment under hypoxia, aging lens with diabetes might aggravate these stresses. This study was designed to examine whether low glucose under hypoxic conditions induces the unfolded protein response (UPR), and also if the UPR then generates the reactive oxygen species (ROS) in lens epithelial cells (LECs). The UPR was activated within 1 h by culturing the human LECs (HLECs) and rat LECs in <1.5 mM glucose under hypoxic conditions. These conditions also induced the Nrf2-dependent antioxidant-protective UPR, production of ROS, and apoptosis. The rat LECs located in the anterior center region were the least susceptible to the UPR, whereas the proliferating LECs in the germinative zone were the most susceptible. Because the cortical lens fiber cells are differentiated from the LECs after the onset of diabetes, we suggest that these newly formed cortical fibers have lower levels of Nrf2, and are then oxidized resulting in cortical cataracts. Thus, low glucose and oxygen conditions induce the UPR, generation of ROS, and expressed the Nrf2 and Nrf2-dependent antioxidant enzymes at normal levels. But these cells eventually lose reduced glutathione (GSH) and induce apoptosis. The results indicate a new link between hypoglycemia under hypoxia and impairment of HLEC functions.  相似文献   

20.
Glucocorticoid hormones are known to inhibit the production of prostaglandins in many cell types and tissues. The effect of these hormones on the biosynthesis of brain tissue is not yet clear. In the present study we investigated the effect of dexamethasone on the release of prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and 6-keto-PGF1 alpha from various brain areas of male rats. Slices from cortex, hippocampus, hypothalamus, and striatum taken from rats pretreated with dexamethasone 4 mg/kg body weight or vehicle, 18 h and 2 h prior to killing, were incubated in Krebs-Ringer-bicarbonate for 1 h. The accumulation of PGs in the medium was determined by radioimmunoassay. Pretreatment with dexamethasone significantly reduced the release of all PGs from the cortex by 40-50%. In the striatum and hippocampus only TXB2 was reduced by approximately 40%. In the hypothalamus the effect of dexamethasone was not significant. When slices of the same brain areas from intact rats were incubated for 1 h in the presence of 40 microM dexamethasone, only the release of PGE2 from the cortex was reduced (by 30%). These results suggest that glucocorticoids can inhibit PG synthesis in brain tissue, and that the cortex is the most sensitive area to the inhibitory effect of the hormone.  相似文献   

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