Long-term Administration Of Dexamethasone Research Articles

Impact of Perioperative Dexamethasone Administration on Infection and Implant Osseointegration in a Preclinical Model of Orthopedic Device-Related Infection.

Glucocorticoids may be given prior to major orthopedic surgery to decrease postoperative nausea, vomiting, and pain. Additionally, many orthopedic patients may be on chronic glucocorticoid therapy. The aim of our study was to investigate whether glucocorticoid administration influences Orthopedic-Device-Related Infection (ODRI) in a rat model. Screws colonized with Staphylococcus epidermidis were implanted in the tibia of skeletally mature female Wistar rats. The treated groups received either a single shot of dexamethasone in a short-term risk study, or a daily dose of dexamethasone in a longer-term interference study. In both phases, bone changes in the vicinity of the implant were monitored with microCT. There were no statistically significant differences in bacteriological outcome with or without dexamethasone. In the interference study, new bone formation was statistically higher in the dexamethasone-treated group (p = 0.0005) as revealed by CT and histopathological analysis, although with relatively low direct osseointegration of the implant. In conclusion, dexamethasone does not increase the risk of developing periprosthetic osteolysis or infection in a pre-clinical model of ODRI. Long-term administration of dexamethasone seemed to offer a benefit in terms of new bone formation around the implant, but with low osseointegration.

Exercise Prevents Glucocorticoid-Induced Myocardial 4-Hydroxynonenal Production.

Long-term administration of glucocorticoids (GCs) increases myocardial oxidative stress. 4-Hydroxynonenal (4-HNE) protein adducts, a marker of oxidative damage, have been associated with several cardiovascular diseases, including atherosclerosis, cardiac hypertrophy, cardiomyopathy, and ischemia-reperfusion injury. Exercise training has been shown to have a protective effect on the heart by lowering the level of oxidative stress in cardiomyocytes. Therefore, we aimed to investigate the effect of long-term dexamethasone treatment and exercise training on myocardial 4-HNE levels. Twenty-four female Wistar albino rats were assigned to sedentary control-saline treated (C, n = 8), sedentary-dexamethasone treated (D, n = 8), and exercise training-dexamethasone treated (DE, n = 8) groups. Daily dexamethasone was injected for 28days at a 1mgkg-1 dose, while C animals were injected with the same volume of saline subcutaneously. DE animals underwent an exercise training protocol of 60min/day, 5days a week, at 25m/min-1 (0% grade) for 28days. Left ventricular 4-HNE, Hsp72 levels, and pHsp25/Hsp25 ratio were determined by Western blot. The administration of dexamethasone led to a significant elevation in 4-HNE levels in the myocardium of adult rats (p < 0.05; D vs. C). The concurrent implementation of exercise training impeded this increase (p > 0.05; DE vs. C). Exercise training induced a threefold increase in myocardial Hsp72 expression (p < 0.001; DE vs. C and D) and attenuated the dexamethasone-induced increase in Hsp25 phosphorylation (p < 0.05; C vs. D) (p < 0.001; DE vs. D). Our results indicate that long-term administration of dexamethasone is associated with an increase in cardiac 4-HNE levels, which is hindered by the addition of exercise training.

Study of hepatoprotective effect of bearberry leaves extract under insulin resistance in rats

The aim of our study was to evaluate the antidiabetic and hepatoprotective efficacy of dry extract from bearberry leaves enriched with arginine in dexamethasone induced IR. Materials and methods. IR was induced in rats by low dose intraperitoneally injections of dexamethasone. Dexamethasone-induced IR in rats was treated by bearberry leaves extract enriched with arginine. Thus, animals were randomized into several groups including intact animals and animals, which administered reference compounds and medications. The activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamine transferase (GGT) were determined in blood serum and liver homogenate, in addition, in blood serum we measured lactate dehydrogenase (LDH) activity and lactate level and glycogen content liver tissue. Also, for the purpose of our experiment, in liver tissue were determined: thiobarbituric acid reactive substances (TBARS), diene conjugates (DC), and reduced glutathione (GSH) content; and superoxide dismutase (SOD), glutathione peroxidase (Gpx), and catalase (CAT) activities. All indices were determined using generally accepted unified methods or commercially available kits. Results. Long-term dexamethasone administration led to an increase in AST, ALT and GGT overall activity in the liver homogenate and serum; this could be the result of increased permeability of hepatocyte plasma membranes, as well as their enhanced synthesis in the liver. Studied extract ameliorate these indices of liver injury. Evaluation of indices that reflected oxidative stress and the antioxidant system status in liver confirmed oxidative stress development in IR rats` liver. Administration of arginine enriched bearberry leaves extract decrease TBARS and DC content in liver tissue, at the same time, improve SOD, Gpx, and CAT activities and increase GSH content. Conclusions. Bearberry leaves dry extract enriched with arginine inhibit oxidative stress development, improve membrane integrity, and normalize some indices of carbohydrate metabolism, particularly glycogen content in liver and lactate level in blood.

Prunetin Protects Against Dexamethasone-Induced Pancreatic Β-Cell Apoptosis via Modulation of p53 Signaling Pathway

Long-term administration of dexamethasone results in insulin resistance and pancreatic β-cell apoptosis. Prunetin (an O-methylated isoflavone, a type of flavonoid) is demonstrated to protect diabetes, but the molecular mechanism of this protection is still unclear. This study thus aims to investigate how prunetin protects against dexamethasone-induced pancreatic β-cell apoptosis. Rat insulinoma (INS-1) cells were cultured in medium with or without dexamethasone in the presence or absence of prunetin or pifithrin-α, a p53 inhibitor. Cell apoptosis was measured by Annexin V/propidium iodide staining. Dexamethasone significantly induced INS-1 apoptosis but dexamethasone plus prunetin significantly reduced INS-1 apoptosis. Dexamethasone-treated INS-1 upregulated p53 protein expression; the induction of p53 was also reduced in the presence of RU486, a glucocorticoid receptor (GR) inhibitor. This suggested that dexamethasone induced P53 via GR. Dexamethasone-treated INS-1 significantly increased p53, Bax, and Rb protein expressions, whereas treatments of dexamethasone plus prunetin or pifithrin-α significantly decreased these protein expressions. In addition, dexamethasone significantly decreased B-cell lymphoma 2 (Bcl2), while dexamethasone plus prunetin or pifithrin-α significantly increased Bcl2. Dexamethasone significantly increased caspase-3 activity while co-treatment of dexamethasone plus prunetin or pifithrin-α significantly decreased caspase-3 activity to the control level. Taken together, our results revealed that prunetin protected against dexamethasone-induced pancreatic β-cells apoptosis via modulation of the p53 signaling pathway.

Оценка эффективности β2-адреноагониста формотерола в компенсации электрофизиологических проявлений стероидной миопатии в модельных экспериментах на животных

Цель исследования - изучение с помощью стимуляционной электромиографии в экспериментах на крысах эффективности β2-адреноагониста формотерола в компенсации электрофизиологических нарушений передней большеберцовой мышцы (m. tibialis anterior), вызванных длительным введением дексаметазона. Методика. Исследования выполнены на 40 половозрелых крысах-самках в возрасте 4-5 мес массой 180-200 г. Животные были разделены на 4 группы: контрольную (К - группа, без каких-либо воздействий, n=10) и 3 экспериментальных по 10 животных в каждой. Крысы 1-й группы на протяжении 30 сут получали дексаметазон, 2-й группы - дексаметазон в комплексе с формотеролом, 3-я - получала только формотерол. Дексаметазон вводили внутрибрюшинно (0,25 мг/кг) 1 раз в 2 сут. Формотерол (1,5 мкг/кг) вводили ежедневно под кожу. Через 30 сут на наркотизированных животных (тиопентал натрия 100мг/кг внутрибрюшинно) проводили острый опыт. Изучали электрофизиологические параметры передней большеберцовой мышцы с помощью экспериментальной двухканальной установки, оба канала были связаны с регистрирующим устройством - запоминающим цифровым осциллографом Tektronix (TDS2004C). Результаты. Установлено, что формотерол в комплексе с дексаметазоном, предотвращал уменьшение количества активируемых двигательных единиц мышцы и удлинение латентного периода М-ответов. А также обусловливал существенное повышение амплитуды М-ответов (на 115% в сравнении с контролем). Вместе с тем, формотерол в комплексе с дексаметазоном не предотвращал появление полифазных М-ответов, но компенсировал снижение их амплитуды. Введение дексаметазона с формотеролом уменьшало частоту случаев сниженной надежности синаптической передачи (до 30% против 70% в группе крыс, получавших дексаметазон изолированно). Вместе с тем, в случае комплексного введения дексаметазона с формотеролом наблюдалось удлинение латентного периода М-ответов после выполнения утомляющей работы. Заключение. Полученные данные указывают на высокую эффективность β2-адреноагониста формотерола в предотвращении электрофизиологических нарушений в мышце, вызванных длительным введением дексаметазона. Вместе с тем формотерол в комплексе с дексаметазоном, хотя и снижал частоту случаев низкой надежности синаптической передачи в группе (до 30% против 70% в группе, получавших дексаметазон изолированно), в полной мере не предотвращал данного эффекта стероидной миопатии. Aim. To study efficacy of β2-adrenergic agonist formoterol (F) in compensation of electrophysiological disorders in mixed-type skeletal muscles (m. tibial anterior) induced by long-term dexamethasone (D) treatment. Methods. Experiments were performed on sexually mature female rats (180-210 g) divided into four groups: 1) control, group C (intact rats, n=10); 2) first experimental group, 30D (30-day dexamethasone treatment, n=10); 3) second experimental group, 30D+F (30-day dexamethasone plus formoterol treatment, n=10); and third experimental group, 30F (30-day formoterol treatment, n=10). Dexamethasone (KRKA, Slovenia) was administered every two days, i.p., at a dose of 0.25 mg/kg, which was equivalent to the clinical therapeutic dose. Formoterol (Foradil, Novartis, Switzerland) was administered daily at a dose of 1.5 µ/kg, s.c. On day 30, rats were anesthetized with sodium thiopental (100 mg/kg), and stimulation electromyography was performed in an acute experiment. The anterior tibial muscle was stimulated with suprathreshold electrical current via the fibular nerve, and electrophysiological parameters of the muscle were recorded. Results. Formoterol in combination with dexamethasone prevented the decrease in the number of activated muscle motor units and the prolongation of M-response latency, which were typical for the 30D group. Also, formoterol not only corrected the decreased M-response amplitude but even significantly increased it in the 30D+F group by 115% compared to the control (p&lt;0.05). At the same time, formoterol in combination with dexamethasone did not prevent the emergence of polyphasic M-responses (as observed in 50% of animals in the 30D+F group and 40% of animals in the 30D group) but compensated for the decrease in their amplitude. Administration of F+D reduced the incidence of less reliable synaptic transmission (up to 30% in the 30D+F group vs. 70% in the 30D group) but did not completely prevent it. Formoterol administered together with dexamethasone did not prevent marked facilitation of synaptic transmission in 50% of rats at the optimal neuromuscular stimulation rate (30 imp/s). However, this combination increased the amplitude of the first M-response in a series, which indicated the absence of blocked synapses in the 30D+F group. Formoterol in combination with dexamethasone prevented the typical for D-group disorder of M-response, which was more pronounced than in control, and the decrease in the number of activated muscle motor units after performing a fatigable work. At the same time, the D+F treatment increased the M-response latency after performing the fatigable work, which was typical for the 30D group but was not characteristic of the control. This fact confirmed a lower reliability of synaptic transmission both in 30D and 30D+F groups. Conclusion. The study demonstrated a high efficacy of the β2-adrenergic agonist formoterol for preventing electrophysiological disorders in the muscle induced by long-term administration of dexamethasone, which indicated myopathic alterations. At the same time, formoterol in combination with dexamethasone, although reduced the incidence of low-reliability synaptic transmission (up to 30% vs. 70% in the group receiving dexamethasone alone), did not completely prevent this manifestation of steroid myopathy.

Fluconazole, a Fungal Cytochrome P450 Enzyme Inhibitor: The Potential Role in Augmenting Hepatotoxicity and Hyperinsulinemia Induced by Dexamethasone in Rats

Insulin resistance (IR) is a widespread health problem characterized by failure of cell responses to insulin. IR increases the risk of fungal infections. Long-term administration of dexamethasone is a therapeutic need accompanied IR and fungal infections. Fluconazole is the first-line antifungal therapy that inhibit fungal cytochrome P450 (CYP450) enzyme. It has a hepatotoxic effect and moderate inhibitory effect on multiple CYP450 enzymes that could affect the pharmacokinetics of drugs used to treat insulin resistance such as metformin. This study aims to evaluate the effect of administration of fluconazole on liver function, CYP450 concentration and level of insulin resistance induced by dexamethasone and high fat diet. Insulin resistance in rats was induced by dexamethasone (0.1mg/kg/day s.c) (DEX) for 2 weeks, after eight weeks of high fat diet (HFD) until the end of the experiment. Oral administration of fluconazole (20, 40 mg/kg) (FLU20, 40) was started concomitantly with DEX for 2 weeks. Metformin (400mg/kg) (MET) was used as a reference treatment for IR and administered orally for 2 weeks with DEX and FLU (20, 40). Concomitant administration of FLU either 20mg/kg or 40 mg/kg with DEX showed significant increase in IR, AST and ALT compared by that caused by DEX alone or with MET. FLU showed a significant decrease in serum CYP450 that elevated by DEX. Massive fibrosis was noticed in histological assessments of liver tissues of HFD+DEX+FLU (20, 40) groups. In conclusion administration of FLU in case of IR induced by HFD+DEX resulted in deterioration of liver functions and decrease in the therapeutic efficacy of MET.

Long-term dexamethasone treatment diminishes store-operated Ca2+ entry in salivary acinar cells

Corticosteroids are used in the treatment of many diseases; however, they also induce various side effects. Dexamethasone is one of the most potent corticosteroids, and it has been reported to induce the side effect of impaired salivary gland function. This study aimed to evaluate the effects of dexamethasone on mouse submandibular gland function to gain insight into the mechanism of dexamethasone-induced salivary hypofunction. The muscarinic agonist carbachol (CCh) induced salivary secretion and was not affected by short-term dexamethasone treatment but was decreased following long-term dexamethasone administration. The expression levels of the membrane proteins Na+-K+-2Cl− cotransporter, transmembrane member 16A, and aquaporin 5 were comparable between the control and long-term dexamethasone treatment groups. The CCh-induced increase in calcium concentration was significantly lower in the presence of extracellular Ca2+ in the long-term dexamethasone treatment group compared to that in the control group. Furthermore, CCh-induced salivation in the absence of extracellular Ca2+ and Ca2+ ionophore A23187-induced salivation was comparable between the control and long-term dexamethasone treatment groups. Moreover, salivation induced by the Ca2+-ATPase inhibitor thapsigargin was diminished in the long-term dexamethasone treatment group. In summary, these results demonstrate that short-term dexamethasone treatment did not impair salivary gland function, whereas long-term dexamethasone treatment diminished store-operated Ca2+ entry, resulting in hyposalivation in mouse submandibular glands.

Dexamethasone causes dose-dependent decrease in insulin sensitivity in Wistar albino rats

Event Abstract Back to Event Dexamethasone causes dose-dependent decrease in insulin sensitivity in Wistar albino rats Rajasekhar Chinta1*, Kokila B Nagaraju2, Raghu Jetti3 and NagendraNayak IM4 1 Manipal Academy of Higher Education, Department of Pharmacology, Melaka Manipal Medical College, India 2 KVG Medical College & Hospital, Department of Pharmacology, India 3 King Khalid University, Department of Basic Medical Sciences, College of Applied Medical Sciences, Saudi Arabia 4 Mount Zion Medical College Hospital, Department of Pharmacology, India Background Long term administration of dexamethasone induces adverse effects such as muscle catabolism, hyperplasia, increased adiposity, and insulin resistance (IR). In view of these data, many authors tried to induce IR with different individual dose ranges with varied induction period. In this study, dexamethasone was used to find the dose to induce maximum insulin resistance in rodents. Methods A sum of 42 healthy male Wistar albino rats were categorized into six groups of dexamethasone treatment and one control group (n=6/group). In a six-day study period, all treatment groups received respective graded doses of dexamethasone starting from low- (0.5mg/kg and 1mg/kg), intermediate- (2mg/kg and 4mg/kg) and high-dose (8mg/kg and 16mg/kg). Results Graded doses of dexamethasone treatment for six days produced hyperglycemia and hyperinsulinemia in a dose-dependent manner and the maximum effect was noted with high doses of dexamethasone compared to intermediate and low (p<0.05). The profound reduction in insulin sensitivity was caused by high-doses of dexamethasone treatment evidenced by sustained elevation of homeostatic model assessment of insulin resistance (HOMA-IR) which was strongly associated with declined homeostatic model assessment of insulin sensitivity (HOMA-IS), The peripheral sensitivity indices, Gutt and Matsuda, were markedly elevated in high dexamethasone groups compared to intermediate- and low-dose groups (p<0.05). Serum lipids and creatinine (p<0.05), whereas high density lipoprotein cholesterol (HDL-CH) was markedly reduced and resulted in the subsequent rise in atherogenic index (AGI) (p<0.05). Moderate to severe glycosuria and ketonuria were noted in intermediate- and high-dose treatment groups only. However, there is no significant difference in metabolic effects between 8mg/kg and 16mg/kg treatments (p>0.05). Conclusion Administration of 8mg/kg dexamethasone for six days would be sufficient for the induction of maximum insulin resistance in Wistar albino rats. Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Image 1 Image 2 Keywords: HOMA, Insulin Resistance, Hyperglycemia, hyperinsulinemia, Metabolic effects Conference: International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18) “Seizing Opportunities and Addressing Challenges of Precision Medicine”, Putrajaya, Malaysia, 3 Dec - 5 Feb, 2019. Presentation Type: Poster Presentation Topic: Metabolic diseases Citation: Chinta R, B Nagaraju K, Jetti R and IM N (2019). Dexamethasone causes dose-dependent decrease in insulin sensitivity in Wistar albino rats. Front. Pharmacol. Conference Abstract: International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18) “Seizing Opportunities and Addressing Challenges of Precision Medicine”. doi: 10.3389/conf.fphar.2019.63.00014 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 30 Sep 2018; Published Online: 17 Jan 2019. * Correspondence: Dr. Rajasekhar Chinta, Manipal Academy of Higher Education, Department of Pharmacology, Melaka Manipal Medical College, Manipal, India, diya.chinta@manipal.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Rajasekhar Chinta Kokila B Nagaraju Raghu Jetti NagendraNayak IM Google Rajasekhar Chinta Kokila B Nagaraju Raghu Jetti NagendraNayak IM Google Scholar Rajasekhar Chinta Kokila B Nagaraju Raghu Jetti NagendraNayak IM PubMed Rajasekhar Chinta Kokila B Nagaraju Raghu Jetti NagendraNayak IM Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Long-term dexamethasone treatment alters the histomorphology of acinar cells in rat parotid and submandibular glands.

Glucocorticoids (GCs) induce insulin resistance (IR), a condition known to alter oral homeostasis. This study investigated the effects of long-term dexamethasone administration on morphofunctional aspects of salivary glands. Male Wistar rats received daily injections of dexamethasone [0.1 mg/kg body weight (b.w.), intraperitoneally] for 10 days (DEX), whereas control rats received saline. Subsequently, glycaemia, insulinaemia, insulin secretion and salivary flow were analysed. The parotid and submandibular glands were collected for histomorphometric evaluation and Western blot experiments. The DEX rats were found to be normoglycaemic, hyperinsulinaemic, insulin resistant and glucose intolerant (P < 0.05). DEX rat islets secreted more insulin in response to glucose (P < 0.05). DEX rats had significant reductions in the masses of the parotid (29%) and submandibular (16%) glands (P < 0.05) that was associated with reduced salivary flux rate. The hypotrophy in both glands observed in the DEX group was associated with marked reduction in the volume of the acinar cells in these glands of 50% and 26% respectively (P < 0.05). The total number of acinar cells was increased in the submandibular glands of the DEX rats (P < 0.05) but not in the parotid glands. The levels of proteins related to insulin and survival signalling in both glands did not differ between the groups. In conclusion, the long-term administration of dexamethasone caused IR, which was associated with significant reductions in both mass and flux rate of the salivary glands. The parotid and submandibular glands exhibited reduced acinar cell volume; however, the submandibular glands displayed acinar hyperplasia, indicating a gland-specific response to GCs. Our data emphasize that GC-based therapies and insulin-resistant states have a negative impact on salivary gland homeostasis.

Morphofunctional Alterations in Endocrine Pancreas of Short- and Long-term Dexamethasone-treated Rats

Long-term dexamethasone therapy may induce peripheral insulin resistance (IR), which in turn elicits increased beta-cell function and proliferation. However, whether such adaptive compensations occur during short-term treatment with dexamethasone is unclear. Here, we compared morphofunctional parameters in endocrine pancreas after short- and long-term dexamethasone administration. Groups of rats received daily i. p. injection of 1 mg/kg b. w. dexamethasone for 1 (DEX-1), 3 (DEX-3), or 5 consecutive days (DEX-5), whilst control rats were saline-treated (CTL). Despite the absence of apparent IR in DEX-1 rats, this group exhibited increased circulating insulin levels and glucose-stimulated insulin secretion (GSIS), compared to the CTL group (p<0.05). Evident IR as well as marked hyperinsulinemia and GSIS, as judged by the static and dynamic insulin secretion values, were observed in DEX-3 and DEX-5 rats (p<0.05). GSIS in islets cultured with 1 μM dexamethasone was lower compared to the control (p<0.05). Marked increases in beta-cell proliferation were observed in DEX-3 and DEX-5 rats, compared to CTL and DEX-1 rats (p<0.05). The alterations observed in DEX-3 rats were more pronounced in DEX-5 rats, which also exhibited a higher content of islet Cdk4 and Cd2 proteins, compared to the CTL group (p<0.05). We conclude that short-term dexamethasone treatment (DEX-1) induces an increase in beta-cell function that does not require the presence of discernible IR. As the treatment continues, the IR develops rapidly, and increased insulin secretion as well as beta-cell hyperplasia is demanded for the appropriate maintenance of glucose homeostasis.

SPINAL µ‐OPIOID RECEPTOR EXPRESSION AND HYPERALGESIA WITH DEXAMETHASONE IN CHRONIC ADJUVANT‐INDUCED ARTHRITIS IN RATS

1. It is known that inflammation influences peripheral and central mu-opioid receptor expression. Previous studies have indicated that glucocorticoids may influence the density of mu-opioid receptors. In the present study, we investigated the fluctuations of spinal mu-opioid receptor expression and hyperalgesia induced by complete Freund's adjuvant (CFA) under long-term administration of dexamethasone. 2. Adjuvant arthritis (AA) was induced by subcutaneous injection of CFA in the right hindpaw of male Wistar rats. Spinal mu-opioid receptor expression was detected by semiquantitative reverse transcription-polymerase chain reaction on Days 6 and 21 following AA induction. Dexamethasone (0.1 mg/kg) was administered intraperitoneally for 21 days. Variations in thermal hyperalgesia were checked by radiant heat on the same days as mu-opioid receptor expression was determined. 3. The results indicated a significant increase in spinal mu-opioid receptor expression on Days 6 and 21 after AA induction compared with the control group. Spinal mu-opioid receptor expression decreased significantly only on Day 21 in the AA + dexamethasone group compared with the AA alone group. Thermal hyperalgesia on Day 6 after AA induction showed a significant increase compared with the control group. Hyperalgesia decreased significantly on Day 21 after AA compared with Day 6. The AA + dexamethasone group showed a significant decrease in hyperalgesia on Day 6 compared with the AA group, but hyperalgesia increased significantly on Day 21 in the AA + dexamethasone group compared with the AA group. 4. The effects of long-term dexamethasone on both spinal mu-opioid receptor expression and hyperalgesia during persistent AA inflammation are time dependent. In addition, the effect of long-term dexamethasone administration on hyperalgesia during persistent arthritis inflammation needs to be investigated further.

Effects of dexamethasone, vitamin A and vitamin D3 on DSP-PP mRNA expression in rat tooth organ culture

Vitamin A, 1,25-dihydroxyvitamin D3 and dexamethasone are well-characterized hydrophobic molecules whose biological actions are mediated via different members of the nuclear hormone receptor family. We report here their actions on tooth formation at the molecular level. We have tested the effects of these compounds on osteopontin (OPN), dentin sialoprotein (DSP-PP), and collagen type I expression in pre-mineralization and mineralization stage rat tooth organ cultures which mirror in vivo developmental patterns. These proteins are all believed to participate in the mineralization of dentin. 1,25-Dihydroxyvitamin D3 up-regulated OPN, but had no effect on DSP-PP mRNA expression. Vitamin A up-regulated DSP-PP expression as did dexamethasone. Dexamethasone also up-regulated collagen type I expression. Our results suggest that 1,25-dihydroxyvitamin D3 does not modulate dentin mineralization by directly affecting DSP-PP expression. Vitamin A likely contributes to dentin mineralization by up-regulating DSP-PP expression. Finally, the up-regulation of DSP-PP expression in tooth germ cultures treated with dexamethasone suggests that its application to patient's dental pulp might promote increased extracellular matrix synthesis and mineralization in the pulp and may explain the narrowing of the dental pulp cavity in patients undergoing long-term dexamethasone administration.

Dexamethasone-induced changes in glucose transporter 4 in rat heart muscle, skeletal muscle and adipocytes.

To clarify the effect of glucocorticoid on glucose transporters (GLUT) in adipocytes and muscle, we examined the changes of GLUT4 in rat heart muscle, skeletal muscle and adipocytes during long-term administration of dexamethasone and the translocation of GLUT4. The levels of GLUT4 in the plasma membrane and the low-density microsome fraction were measured by Western blotting using anti-GLUT4 peptide antibody. The levels of GLUT4 in the heart and skeletal muscles of rat were unchanged by treatment of dexamethasone. In the adipocytes the level of GLUT4 in plasma membrane was changed, but it was decreased in the low-density microsome fraction. Although adipocytes are less involved in blood sugar regulation than skeletal muscle, this finding suggests that glucose metabolism in Cushing's syndrome is affected partly by a decrease of GLUT4 in the adipocytes.

Evidence against a role for inducible nitric oxide synthase in the hyperdynamic circulation of portal-hypertensive rats

Background/Aims Excessive nitric oxide biosynthesis caused by expression of inducible NO synthase has been implicated in the hyperdynamic circulation of portal hypertension. The aim of the study was to investigate whether inducible NO synthase is expressed in portal hypertension and accounts for the hyperdynamic circulation. Methods In study 1, NO synthase activities were measured by the conversion of l-arginine to citrulline in tissues from portal-hypertensive, cirrhotic, and sham-operated rats and from normal rats pretreated with endotoxin and after long-term administration of dexamethasone, which inhibits the expression of inducible NO synthase. In study 2, systemic and splanchnic hemodynamics (radiolabeled microspheres) and gastric blood flow (hydrogen gas clearance and reflectance spectrophotometry) were measured in portal-hypertensive rats after long-term administration of dexamethasone (0.25 mg·kg −1·day −1) or vehicle. Results In study 1, constitutive and inducible NO synthase activities in portal-hypertensive or cirrhotic rats were similar to those observed in sham-operated rats. The significant increase in the inducible activity observed after endotoxin injection was prevented when rats received long-term treatment with dexamethasone. In study 2, cardiac index, portal-pressure, portal venous inflow, and gastric blood flow were similar in dexamethasone or vehicle-treated portal-hypertensive rats. Conclusions These results do not support a role for an increased expression of the inducible NO synthase in the hyperdynamic circulation of portal hypertension.

Role of antiglucocorticoid RU 486 on dexamethasone-induced hypertension in rats

This study was conducted to investigate whether hypertension induced by long-term in vivo administration of dexamethasone in rats could be prevented by the newly synthesized potent antiglucocorticoid drug RU 486. Subcutaneous implantation of 5 mg of dexamethasone pellets in Sprague-Dawley rats resulted in a rapid increase in the blood pressure that remained elevated during the 3 wk of experimental observation. RU 486 (50 mg) administered alone surprisingly showed slight elevation of blood pressure over untreated control animals. However, the blood pressure leveled off to control levels over the next 2 wk. Interestingly, a 50-mg RU 486 pellet implanted along with 5 mg of dexamethasone effectively prevented the dexamethasone-induced increase in blood pressure. RU 486 administered together with dexamethasone prevented dexamethasone-induced diuresis and urinary Na+ excretion. However, RU 486 was unable to reverse the weight loss or involution of thymus observed by long-term treatment with dexamethasone alone. No abnormalities were found in either kidneys or hearts in any of the treated groups under microscopic examination. These results suggest that RU 486 successfully prevented the hypertension produced by the long-term administration of dexamethasone in male Sprague-Dawley rats.

Dexamethasone and estradiol treatment in pregnant rhesus macaques: Effects on gestational length, maternal plasma hormones, and fetal growth

To determine the effects of suppressing fetal and maternal adrenal activity on parturition, we treated pregnant rhesus macaques with dexamethasone (0.25 to 4.0 mg, twice a day) from gestation day 130 until delivery (term = 167 days). Long-term dexamethasone treatment increased gestation length: 71% of fetuses were born postmaturely (after day 175 of gestation; χ2 = 52.6; P < 0.001). The dexamethasone decreased basal levels of maternal estradiol and cortisol, but not progesterone, and abolished the prepartum estrogen and prolactin surges; doses greater than 0.16 mg/kg per day resulted in fetal death but not premature delivery. That vaginal delivery was induced by estradiol benzoate in monkeys with prolonged pregnancy and dead fetuses, but not in those with live fetuses, suggests active fetal inhibition of prostaglandin synthesis. The dexamethasone retarded fetal growth (410 ± 16 gm versus 501 ± 5 gm for controls; P < 0.001) and decreased thymus, spleen, and adrenal weights (P < 0.01). A less significant decrease in brain weight was noted (P < 0.1), as were decreases in biparietal diameter, occipitofrontal diameter, and head circumference (P < 0.05). These results indicate that corticosteroids do not induce premature labor in primates. On the contrary, long-term dexamethasone administration is associated with prolonged pregnancy and suppression of estrogen biosynthesis.

Adrenalectomy, dexamethasone or stress alters opioid peptides levels in rat anterior pituitary but not intermediate lobe or brain

After boiling and extraction with 4M Guanidine HCl to inactive endogenous peptidases, the anterior and neurointermediate lobes of the rat pituitary were analysed by gel filtration and a beta-endorphin radioimmunoassay which detects proopiocortin, beta-lipotropin and beta-endorphin with equimolar sensitivity. In the anterior lobe, immunoreactive (ir) beta-endorphin was eluted in three peaks: 10% of the total immunoreactivity had an apparent M r of proopiocortin, 57% had the M r of beta-lipotropin and 27% had the M r of beta-endorphin. In the neurointermediate lobe, all beta-endorphin immunoreactivity is eluted in one peak with an apparent M r of synthetic beta-endorphin. Total (ir) Beta-endorphin levels in the anterior lobe were increased by adrenalectomy and decreased after long term administration of dexamethasone (0.2 mg/kg for 16 days) or by stress (1 hour of inescapable footshock). Levels in the neurointermediate lobe were unchanged after these treatments. Neither adrenalectomy or long term administration of dexamethasone at 0.2 mg/kg/day for 16 days had any effects on the levels of (ir) Met 5-enkephalin and (ir) Leu 5-enkephalin in the striatum, hypothalamus and neurointermediate lobe. After larger doses of dexamethasone (1 mg/kg/each 12 hrs for 7 days) (ir) enkephalin levels were increased in the striatum (150% of controls) but not in hypothalamus or neurointermediate lobe. These data further support independent avenues of post-synthetic peptide processing in the brain and pituitary lobes.

Modification of the dopamine and noradrenaline content in rat carotid body by carbohydrate-active steroids

Short-term or long-term administration of dexamethasone (1 mg/kg, i.p.) increases the concentrations of both dopamine and noradrenaline in rat carotid body. This increase in catecholamine content elicited by dexamethasone also occurs after transection of th. carotid sinus nerve or removal of the superior cervical ganglion. Injections of cycloheximide curtail the dexamethasoneinduced increase in noradrenaline content but the increase in dopamine content remains unchanged. The rate of elimination of dihydroxyphenylacetic acid is decreased by more than 50% 12 h following the injection of dexamethasone, while the steady-state content of dopamine is increased. It is inferred that the increase in dopamine content is due to a reduction of dopamine metabolism. The long-term increase in noradrenaline content appears to be triggered by a mechanism that depends on new protein synthesis.

ステロイドミオバチーマウスの骨格筋形質膜分画におけるOuabain感受性(Na&lt;SUP&gt;+&lt;/SUP&gt;+K&lt;SUP&gt;+&lt;/SUP&gt;)-ATPase活性

In order to observe the membrane property in steroid myopathy, the ouabain-sensitive (Na++K+)-ATPase activities of skeletal muscle, kidney, and brain membrane fractions were studied with the mice administered dexamethasone intraperitoneally for 7.0 -8.5 weeks at a dosage of 5.5 mg/kg. The results obtained were as follows. 1) The body weight of mice treated with dexamethasome for 7.0-8.5 weeks decreased by approximately 5 g (ca. 20% of the control body wt.) against that of saline-treated mice. 2) The ouabain-sensitive (Na++K+)-ATPase activity of skeletal muscle sarcolemmal fraction from the steroid-treated mice was significantly higher than that from control by 30-50%. 3) With kidney and brain membrane fractions, no differences were observed between control and steroid-treated mice in the ouabain-sensitive (Na++K+)-ATPase activity. These results show that the membrane property of skeletal muscle is specifically influenced by the long-term administration of dexamethasone.