ABSTRACT
Although 6-hydroxydopamine-induced (6-OHDA-induced) rats are a well-known Parkinson's disease model, the effects of dopamine D2 agonists in mice with 6-OHDA-induced lesions are not completely understood. We produced mice with 6-OHDA-induced lesions and measured their total locomotion counts following administration of several dopamine D2 agonists (pramipexole, ropinirole, cabergoline, rotigotine, apomorphine, talipexole, and quinelorane). Cabergoline showed the longest duration of drug action, which was in agreement with its long-lived anti-Parkinson effects in rats and humans. In contrast, pramipexole and ropinirole had notably short durations of drug action. We demonstrated that mice with 6-OHDA-induced lesions accompanied with significant lesions in the striatum may be reasonable models to predict the action duration of anti-Parkinson drug candidates in humans.
Subject(s)
Antiparkinson Agents/pharmacokinetics , Corpus Striatum/pathology , Dopamine Agonists/pharmacokinetics , Motor Activity/drug effects , Parkinsonian Disorders/chemically induced , Receptors, Dopamine D2/agonists , Animals , Apomorphine/pharmacokinetics , Azepines/pharmacokinetics , Benzothiazoles/pharmacokinetics , Cabergoline , Corpus Striatum/drug effects , Disease Models, Animal , Ergolines/pharmacokinetics , Indoles/pharmacokinetics , Injections, Intraventricular , Male , Mice , Oxidopamine/pharmacology , Parkinsonian Disorders/pathology , Parkinsonian Disorders/psychology , Pramipexole , Quinolines/pharmacokinetics , Tetrahydronaphthalenes/pharmacokinetics , Thiophenes/pharmacokineticsABSTRACT
BACKGROUND AND AIM OF THE STUDY: The symptoms of Parkinson's disease are alleviated by dopamine D2 agonists, which are classified as ergot dopamine D2 agonists and non-ergot D2 agonists. Among the former, pergolide has been associated with valvular heart disease, since it has both potent D2 receptor and serotonin 5-HT(2B) receptor agonistic properties. Among the latter, pramipexole has few incidences of heart valve disease onset, since it has an absence of 5-HT(2B) receptor agonism. METHOD: A [3H]thymidine incorporation assay was performed to monitor function, and microarray global analysis to monitor gene expression, on porcine heart valve interstitial cells (VICs) treated with pergolide or pramipexole. RESULTS: The 5-HT(2B) receptor was abundantly expressed in porcine VICs. The 5-HT(2B) receptor agonist pergolide induced an increase in [3H]thymidine incorporation, accompanied by a decrease in 5-HT(2B) receptor mRNA expression. [3H]thymidine incorporation was blocked by lisuride, a 5-HT(2B) receptor antagonist, and also by LY-294002, a specific inhibitor of PI3K and Akt. Moreover, type 2 iodothyronine deiodinase (Dio2) expression in porcine VICs treated with pergolide was shown, by a global analysis of mRNA, to be markedly increased compared to that induced by pramipexole. Such changes in VICs may correlate with the mechanism of heart valve disease pathogenesis. CONCLUSION: There were substantial differences (increased [3H]thymidine incorporation, and Dio2 expression) between pergolide and pramipexole, which might correlate with the mechanism of heart valve disease onset.
Subject(s)
Benzothiazoles/toxicity , Dopamine Agonists/toxicity , Mitral Valve/drug effects , Pergolide/toxicity , Receptors, Dopamine D2/agonists , Animals , Cell Proliferation/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Gene Expression Profiling/methods , Gene Expression Regulation/drug effects , Mitral Valve/metabolism , Mitral Valve/pathology , Oligonucleotide Array Sequence Analysis , Pramipexole , Protein Kinase Inhibitors/pharmacology , RNA, Messenger/metabolism , Real-Time Polymerase Chain Reaction , Receptor, Serotonin, 5-HT2B/drug effects , Receptor, Serotonin, 5-HT2B/genetics , Receptor, Serotonin, 5-HT2B/metabolism , Receptors, Dopamine D2/metabolism , Reproducibility of Results , Serotonin 5-HT2 Receptor Agonists/toxicity , Serotonin 5-HT2 Receptor Antagonists/pharmacology , Signal Transduction/drug effectsABSTRACT
INTRODUCTION: The effect of beta3-adrenergic receptor agonists on beta cells in the islets of Langerhans is not yet clear. This study examined the beta3-adrenergic receptor agonist on beta cells in the islets of Langerhans. METHODS: Obese diabetic C57BL/KsJ-db/db mice were treated with KTO-7924, a newly-developed beta3-adrenergic receptor agonist for 28-day. We analyzed plasma parameters, insulin resistance, and insulin-positive areas among beta-cells in the islets of Langerhans. RESULTS AND CONCLUSION: After a 28-day oral administration period, plasma levels of hemoglobin (Hb) A1c, glucose, triglyceride (TG), and free fatty acid (FFA) were all significantly reduced in KTO-7924 treatment groups compared with controls. Plasma adiponectin levels decreased with age in the control group, but were significantly higher in a treatment group throughout the study period. Furthermore, sequential administration of KTO-7924 led to an improvement in insulin resistance in the OGTT (Oral glucose tolerance test (OGTT)), and an increase in the percentage of insulin-positive areas among beta-cells in the islets of Langerhans compared with controls. This is the first study to show islet histology after treatment of a beta3-adrenergic receptor agonist, and reveals that KTO-7924 reduces hyperglycemia, and protects beta-cells in the islets of Langerhans of db/db mice.
Subject(s)
Adrenergic Agonists/pharmacology , Hyperglycemia/blood , Hyperglycemia/drug therapy , Insulin-Secreting Cells/drug effects , Adiponectin/blood , Adiponectin/genetics , Animals , Blood Glucose/metabolism , Fatty Acids, Nonesterified/blood , Glucose Tolerance Test , Glycated Hemoglobin/metabolism , Hyperglycemia/pathology , Insulin/blood , Male , Mice , Mice, Inbred C57BL , Mice, Obese , RNA/chemistry , RNA/genetics , Reverse Transcriptase Polymerase Chain Reaction , Triglycerides/bloodABSTRACT
Obese (fa/fa) Zucker rat is a spontaneous genetic obesity model and, by comparison with lean Zucker rat, exhibits hyperphagia, hyperinsulinemia, and hyperlipidemia. The aim of this study was to examine the physiological difference concerning adiponectin between obese (fa/fa) Zucker rats and control lean Zucker rats. We therefore measured plasma adiponectin level and analyzed adiponectin and adiponectin receptor 1 mRNA expression in retroperitoneal white adipose tissue (RT WAT), brown adipose tissue (BAT), liver, and soleus muscle. We also examined the tissue mRNA expression of peroxisome proliferator-activated receptor alpha (PPAR alpha), PPAR delta, and PPAR gamma, which regulate adiponectin expression sensitivity to a PPAR gamma agonist shown by brown adipocytes from obese (fa/fa) Zucker rats and lean Zucker rats, by measuring adiponectin release from these cells. Plasma adiponectin levels of obese (fa/fa) Zucker rats were significantly higher than those of lean Zucker rats. Adiponectin mRNA expression levels in RT WAT were lower in obese (fa/fa) Zucker rats than in lean Zucker rats, but those in BAT were higher. Adiponectin receptor 1 expression levels in RT WAT, BAT, and liver of obese (fa/fa) Zucker rats were lower than in lean Zucker rats. The expression level of PPAR alpha, PPAR delta, and PPAR gamma in BAT was lower in obese (fa/fa) Zucker rats than in lean Zucker rats. Moreover, the PPAR gamma agonist increased adiponectin release only from the brown adipocytes isolated from lean Zucker rats. It is the conclusive difference between obese (fa/fa) Zucker rats and lean Zucker rats that plasma adiponectin levels of obese (fa/fa) Zucker rats are significantly higher than those of lean Zucker rats. Moreover, we clarified that mRNA expression level of adiponectin receptor 1 in RT WAT, BAT, and liver of obese (fa/fa) Zucker rats is low despite high plasma adiponectin level, and low expression of PPARs in BAT leads to less sensibility of adiponectin release from brown adipocytes to a PPAR gamma agonist in obese (fa/fa) Zucker rats.
Subject(s)
Body Weight , Intercellular Signaling Peptides and Proteins/blood , Intercellular Signaling Peptides and Proteins/genetics , Obesity/metabolism , Obesity/physiopathology , Adipocytes/physiology , Adiponectin , Adipose Tissue, Brown/cytology , Adipose Tissue, Brown/physiology , Animals , Liver/physiology , Male , Muscle, Skeletal/physiology , PPAR alpha/genetics , PPAR delta/genetics , PPAR gamma/genetics , RNA, Messenger/analysis , Rats , Rats, Zucker , Receptors, Adiponectin , Receptors, Cell Surface/geneticsABSTRACT
We aimed to examine the effects of KTO-7924 (beta3-adrenoceptor agonist) on lipid metabolism and mRNA expressions in retroperitoneal white adipose tissue (RP WAT) in obese (fa/fa) Zucker rats using DNA microarray. Oral KTO-7924 for 28 days significantly decreased RP WAT weight, plasma triglyceride, free fatty acid, and insulin, and improved insulin resistance in oral glucose tolerance tests. In RP WAT of KTO-7924-treated rats, DNA microarray analysis revealed specifically enhanced mRNA expressions of uncoupling protein 1 (UCP1) and cytochrome c oxidase subunit VIII-H (COX8H), which are reportedly highly expressed in brown adipose tissue (BAT). Since these mRNA expression levels in RP WAT were significantly lower in obese (fa/fa) Zucker rats than in lean Zucker rats, these genes may be important in lipid metabolism. Our results imply that in obese (fa/fa) Zucker rats, continuous stimulation of beta3-adrenoceptors by KTO-7924 causes BAT-like adipocytes to appear in RP WAT, and improves lipid metabolism.
Subject(s)
Adipose Tissue/metabolism , Adrenergic Agonists/pharmacology , Adrenergic beta-3 Receptor Agonists , Obesity/metabolism , Oligonucleotide Array Sequence Analysis , Adipose Tissue, Brown/metabolism , Animals , Gene Expression Profiling , Insulin Resistance , Lipid Metabolism/drug effects , Male , Rats , Rats, ZuckerABSTRACT
Our aim was to determine the effect of a beta3-adrenoceptor agonist on plasma adiponectin levels and on the level of expression of mRNA for adiponectin, adiponectin receptor 1, and adiponectin receptor 2 in db/db mice. Two weeks' oral administration of CL-316,243 led to decreased plasma levels of hemoglobin A1c, glucose, insulin, triglyceride and free fatty acid, and to an increased plasma adiponectin levels. It also improved insulin resistance in the oral glucose tolerance test. Adiponectin mRNA expression was significantly higher in the CL-316,243-treatment group than in the control group in epididymal white adipose tissue but not in brown adipose tissue, soleus muscle or liver. Adiponectin receptor 2 mRNA expression was significantly lower only in the liver of the CL-316,243-treatment group (versus the control group). These results suggest that the increased plasma adiponectin levels seen in db/db mice treated with this beta3-adrenoceptor agonist induce a down-regulation of adiponectin receptor 2 mRNA expression specifically in the liver.
Subject(s)
Adrenergic beta-Agonists/pharmacology , Diabetes Mellitus, Type 2/genetics , Dioxoles/pharmacology , Insulin Resistance , Liver/drug effects , Receptors, Cell Surface/genetics , Adiponectin , Adipose Tissue/drug effects , Adipose Tissue/growth & development , Adrenergic beta-3 Receptor Agonists , Animals , Blood Glucose/metabolism , Body Weight/drug effects , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Eating/drug effects , Fatty Acids/blood , Gene Expression/drug effects , Glucose Tolerance Test , Glycated Hemoglobin/metabolism , Insulin/blood , Intercellular Signaling Peptides and Proteins/genetics , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Obesity/blood , Obesity/drug therapy , Obesity/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Adiponectin , Reverse Transcriptase Polymerase Chain Reaction , Time FactorsABSTRACT
The effect of short-term bezafibrate (BF) administration over time on the expression of UCP mRNA in the tissues was examined in Otsuka Long Evans Tokushima Fatty (OLETF) rats. Eight-week-old rats were divided into a high-dose (100 mg/kg) BF group (n = 15), a low-dose (10 mg/kg) BF group (n = 15) and a control group (n = 15), and followed for 14 days. Feed intake by the high-dose BF group increased significantly between days 10 and 14 of administration. Triglyceride, free fatty acid, and T(4) levels decreased significantly in a dose-dependent manner in the high-dose BF group. Leptin and insulin levels significantly decreased on days 3 and 7. Throughout the study period, liver UCP2 mRNA increased in the high-dose BF group. On day 3 of BF administration, the levels of UCP2 mRNA expression in the skeletal muscles as well as UCP3 mRNA expression in the WAT were significantly increased in the high-dose BF group. PPAR-alpha mRNA significantly increased in the liver on day 3 of BF administration. We thus conclude that the PPAR-alpha-mediated effects of BF on the expression of liver UCP2 may be one of the factors that helped to decrease insulin levels.
Subject(s)
Bezafibrate/pharmacology , Hypolipidemic Agents/pharmacology , Obesity/genetics , Uncoupling Agents , Animals , Blood Glucose/analysis , Body Weight/drug effects , Carrier Proteins/drug effects , Carrier Proteins/genetics , Cholesterol/metabolism , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/genetics , Dose-Response Relationship, Drug , Eating/drug effects , Fatty Acids/metabolism , Gene Expression Regulation/drug effects , Insulin/metabolism , Ion Channels , Leptin/metabolism , Male , Membrane Proteins/drug effects , Membrane Proteins/genetics , Membrane Transport Proteins/drug effects , Membrane Transport Proteins/genetics , Mitochondrial Proteins/drug effects , Mitochondrial Proteins/genetics , Obesity/drug therapy , Obesity/etiology , PPAR alpha/drug effects , PPAR alpha/genetics , PPAR delta/drug effects , PPAR delta/genetics , RNA, Messenger/drug effects , Rats , Rats, Inbred Strains , Thyroid Hormones/metabolism , Uncoupling Protein 1 , Uncoupling Protein 2 , Uncoupling Protein 3 , Viscera/drug effectsABSTRACT
The effect of short-term bezafibrate (BF) administration over time on the expression of adiponectin mRNA in the tissues was examined in Otsuka Long Evans Tokushima Fatty (OLETF) rats. Eight-week-old rats were divided into the high-dose (100 mg/kg) BF group (n=15), the low-dose (10 mg/kg) BF group (n=15), or the control group (n=15) and followed up for 14 d. Tri-glyceride and free fatty acid levels significantly decreased in a dose-dependent manner in the high-dose BF group. The insulin levels increased with time, although they were significantly lower in the high-dose BF group on d 3 and 7 than the control group. Adiponectin levels significantly increased in the high-dose BF group. On d 14 of BF administration, the levels of VLDL and chy-lomicron were significantly lower in BF groups, and adiponectin mRNA expression in the white adipose tissue was significantly higher in the high-dose BF group. Findings from this study suggest that in type 2 diabetes with insulin resistance, hypertriglyceridemia is closely linked to adiponectin.
