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1.
J Pharmacol Sci ; 135(3): 126-130, 2017 Nov.
Article in English | MEDLINE | ID: mdl-29113790

ABSTRACT

Saxagliptin, a potent and selective DPP-4 inhibitor, exhibits a slow dissociation from DPP-4. We investigated the sustained effects of saxagliptin on renal DPP-4 activity in a washout study using renal tubular (HK-2) cells, and in a pharmacodynamic study using normal rats. In HK-2 cells, the inhibitory potency of saxagliptin on DPP-4 activity persisted after washout, while that of sitagliptin was clearly reduced. In normal rats, a single treatment of saxagliptin or sitagliptin inhibited the plasma DPP-4 activity to similar levels. The inhibitory action of saxagliptin on the renal DPP-4 activity was retained, even when its inhibitory effect on the plasma DPP-4 activity disappeared. However, the inhibitory action of sitagliptin on the renal DPP-4 activity was abolished in correlation with the inhibition of the plasma DPP-4 activity. In situ staining showed that saxagliptin suppressed the DPP-4 activity in both glomerular and tubular cells and its inhibitory effects were significantly higher than those of sitagliptin. Saxagliptin exerted a sustained inhibitory effect on the renal DPP-4 activity in vitro and in vivo. The long binding action of saxagliptin in renal tubular cells might involve the sustained inhibition of renal DPP-4.


Subject(s)
Adamantane/analogs & derivatives , Dipeptides/pharmacology , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Kidney Glomerulus/enzymology , Kidney Tubules/enzymology , Adamantane/metabolism , Adamantane/pharmacology , Animals , Cells, Cultured , Dipeptides/metabolism , Dipeptidyl Peptidase 4/blood , Dipeptidyl-Peptidase IV Inhibitors/metabolism , Humans , Male , Protein Binding , Rats, Sprague-Dawley , Sitagliptin Phosphate/pharmacology
2.
J Pharmacol Sci ; 132(1): 65-70, 2016 Sep.
Article in English | MEDLINE | ID: mdl-27666017

ABSTRACT

Saxagliptin, a potent and selective DPP-4 inhibitor, is characterized by its slow dissociation from DPP-4 and its long half-life and is expected to have a potent tissue membrane-bound DPP-4-inhibitory effect in various tissues. In the present study, we examined the effects of saxagliptin on in situ cardiac DPP-4 activity. We also examined the effects of saxagliptin on isoproterenol-induced the changes in the early stage such as, myocardial remodeling and cardiac diastolic dysfunction. Male SD rats treated with isoproterenol (1 mg/kg/day via osmotic pump) received vehicle or saxagliptin (17.5 mg/kg via drinking water) for 2 weeks. In situ cardiac DPP-4 activity was measured by a colorimetric assay. Cardiac gene expressions were examined and an echocardiographic analysis was performed. Saxagliptin treatment significantly inhibited in situ cardiac DPP-4 activity and suppressed isoproterenol-induced myocardial remodeling and the expression of related genes without altering the blood glucose levels. Saxagliptin also significantly ameliorated cardiac diastolic dysfunction in isoproterenol-treated rats. In conclusion, the inhibition of DPP-4 activity in cardiac tissue by saxagliptin was associated with suppression of myocardial remodeling and cardiac diastolic dysfunction independently of its glucose-lowering action in isoproterenol-treated rats. Cardiac DPP-4 activity may contribute to myocardial remodeling in the development of heart failure.


Subject(s)
Adamantane/analogs & derivatives , Dipeptides/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Heart/drug effects , Ventricular Remodeling/drug effects , Adamantane/pharmacology , Animals , Diastole , Dipeptidyl Peptidase 4/blood , Echocardiography , Heart/diagnostic imaging , Heart/physiopathology , Isoproterenol , Male , Myocardium/metabolism , Myocardium/pathology , Rats, Sprague-Dawley
3.
Eur J Pharmacol ; 783: 56-63, 2016 Jul 15.
Article in English | MEDLINE | ID: mdl-27063445

ABSTRACT

Although previous studies have shown an important role of renal dipeptidyl peptidase-4 (DPP-4) inhibition in ameliorating kidney injury in hypertensive rats, the renal distribution of DPP-4 and mechanisms of renoprotective action of DPP-4 inhibition remain unclear. In this study, we examined the effects of the DPP-4 inhibitor saxagliptin on DPP-4 activity in renal cells (using in situ DPP-4 staining) and on renal gene expression related to inflammation and fibrosis in the renal injury in hypertensive Dahl salt-sensitive (Dahl-S) rats. Male rats fed a high-salt (8% NaCl) diet received vehicle (water) or saxagliptin (12.7mg/kg/day) for 4 weeks. Blood pressure (BP), serum glucose and 24-h urinary albumin and sodium excretions were measured, and renal histopathology was performed. High salt-diet increased BP and urinary albumin excretion, consequently resulting in glomerular sclerosis and tubulointerstitial fibrosis. Although saxagliptin did not affect BP and blood glucose levels, it significantly ameliorated urinary albumin excretion. In situ staining showed DPP-4 activity in glomerular and tubular cells. Saxagliptin significantly suppressed DPP-4 activity in renal tissue extracts and in glomerular and tubular cells. Saxagliptin also significantly attenuated the increase in inflammation and fibrosis-related gene expressions in the kidney. Our results demonstrate that saxagliptin inhibited the development of renal injury independent of its glucose-lowering effect. Glomerular and tubular DPP-4 inhibition by saxagliptin was associated with improvements in albuminuria and the suppression of inflammation and fibrosis-related genes. Thus, local glomerular and tubular DPP-4 inhibition by saxagliptin may play an important role in its renoprotective effects in Dahl-S rats.


Subject(s)
Adamantane/analogs & derivatives , Cytoprotection/drug effects , Dipeptides/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Hypertension/drug therapy , Kidney/drug effects , Adamantane/pharmacology , Adamantane/therapeutic use , Animals , Blood Glucose/metabolism , Blood Pressure/drug effects , Creatinine/blood , Dipeptides/therapeutic use , Dipeptidyl Peptidase 4/blood , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Fibrosis , Gene Expression Regulation/drug effects , Hypertension/metabolism , Hypertension/pathology , Hypertension/physiopathology , Kidney/metabolism , Kidney/pathology , Kidney Glomerulus/drug effects , Kidney Glomerulus/metabolism , Kidney Glomerulus/pathology , Kidney Tubules/drug effects , Kidney Tubules/metabolism , Kidney Tubules/pathology , Male , Myocardium/pathology , Organ Size/drug effects , Rats , Rats, Inbred Dahl , Sodium/urine
4.
Eur J Pharmacol ; 761: 109-15, 2015 Aug 15.
Article in English | MEDLINE | ID: mdl-25936515

ABSTRACT

Saxagliptin, a potent dipeptidyl peptidase-4 (DPP-4) inhibitor, is currently used to treat type 2 diabetes mellitus, and it has been reported to exhibit a slower rate of dissociation from DPP-4 compared with another DPP-4 inhibitor, sitagliptin. In this study, we compared the effects of saxagliptin and sitagliptin on hypertension-related renal injury and the plasma and renal DPP-4 activity levels in Dahl salt-sensitive hypertensive (Dahl-S) rats. The high-salt diet (8% NaCl) significantly increased the blood pressure and quantity of urinary albumin excretion and induced renal glomerular injury in the Dahl-S rats. Treatment with saxagliptin (14mg/kg/day via drinking water) for 4 weeks significantly suppressed the increase in urinary albumin excretion and tended to ameliorate glomerular injury without altering the blood glucose levels and systolic blood pressure. On the other hand, the administration of sitagliptin (140mg/kg/day via drinking water) did not affect urinary albumin excretion and glomerular injury in the Dahl-S rats. Meanwhile, the high-salt diet increased the renal DPP-4 activity but did not affect the plasma DPP-4 activity in the Dahl-S rats. Both saxagliptin and sitagliptin suppressed the plasma DPP-4 activity by 95% or more. Although the renal DPP-4 activity was also inhibited by both drugs, the inhibitory effect of saxagliptin was more potent than that of sitagliptin. These results indicate that saxagliptin has a potent renoprotective effect in the Dahl-S rats, independent of its glucose-lowering actions. The inhibition of the renal DPP-4 activity induced by saxagliptin may contribute to ameliorating renal injury in hypertension-related renal injury.


Subject(s)
Adamantane/analogs & derivatives , Dipeptides/pharmacology , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Hypertension/drug therapy , Kidney Diseases/prevention & control , Kidney Glomerulus/drug effects , Adamantane/pharmacology , Albuminuria/enzymology , Albuminuria/prevention & control , Animals , Blood Glucose/drug effects , Blood Glucose/metabolism , Blood Pressure/drug effects , Cytoprotection , Dipeptidyl Peptidase 4/blood , Disease Models, Animal , Dose-Response Relationship, Drug , Hypertension/enzymology , Hypertension/pathology , Hypertension/physiopathology , Kidney Diseases/enzymology , Kidney Diseases/pathology , Kidney Diseases/physiopathology , Kidney Glomerulus/enzymology , Kidney Glomerulus/pathology , Kidney Glomerulus/physiopathology , Male , Rats, Inbred Dahl , Sitagliptin Phosphate/pharmacology
5.
Glia ; 59(2): 208-18, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21125641

ABSTRACT

Neuropathic pain produced by damage to or dysfunction of the nervous system is a common and severely disabling state that affects millions of people worldwide. Recent evidence indicates that activated microglia are key cellular intermediaries in the pathogenesis of neuropathic pain and that ATP serves as the mediator. However, the in vivo mechanism underlying the retention of activated microglia in the injured region has not yet been completely elucidated. Prostaglandin E(2) (PGE(2)) is the principal proinflammatory prostanoid and plays versatile roles by acting via four PGE receptor subtypes, EP1-EP4. In the present study, we investigated the role of PGE(2) in spinal microglial activation in relation to neuropathic pain by using genetic and pharmacological methods. Mice deficient in microsomal prostaglandin E synthase-1 impaired the activation of microglia and the NMDA-nitric oxide (NO) cascade in spinal neurons in the dorsal horn and did not exhibit mechanical allodynia after peripheral nerve injury. The intrathecal injection of indomethacin, a nonsteroidal anti-inflammatory drug, ONO-8713, a selective EP1 antagonist, or 7-nitroindole, a neuronal NO synthase inhibitor, attenuated mechanical allodynia and the increase in activated microglia observed in the established neuropathic-pain state. We further demonstrated that ATP-induced microglial migration was blocked in vitro by PGE(2) via EP2 and by S-nitrosoglutathione, an NO donor. Taken together, the present study suggests that PGE(2) participated in the maintenance of neuropathic pain in vivo not only by activating spinal neurons, but also by retaining microglia in the central terminals of primary afferent fibers via EP2 subtype and via EP1-mediated NO production.


Subject(s)
Cell Movement/physiology , Dinoprostone/metabolism , Microglia/physiology , Neuralgia/metabolism , Neuralgia/pathology , Spinal Cord/pathology , Adenosine Triphosphate/pharmacology , Animals , Cell Movement/genetics , Cerebral Cortex/cytology , Cinnamates/pharmacology , Cinnamates/therapeutic use , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Gene Expression Regulation, Enzymologic/drug effects , Gene Expression Regulation, Enzymologic/genetics , Hyperalgesia/drug therapy , Hyperalgesia/etiology , Indazoles/pharmacology , Indazoles/therapeutic use , Intramolecular Oxidoreductases/deficiency , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Knockout , Microglia/drug effects , Neuralgia/complications , Neuralgia/drug therapy , Neurons/metabolism , Nitric Oxide/metabolism , Nitric Oxide Donors/pharmacology , Nitric Oxide Synthase Type I/metabolism , Prostaglandin-E Synthases , S-Nitrosoglutathione/pharmacology , Spinal Cord/drug effects , Spinal Nerves/injuries
6.
Eur J Neurosci ; 32(5): 798-810, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20722721

ABSTRACT

Ca(2+) /calmodulin-dependent protein kinase II (CaMKII) is a key mediator of long-term potentiation (LTP), which can be triggered by N-methyl-d-aspartate (NMDA) receptor-mediated Ca(2+) influx. We previously demonstrated that Fyn kinase-mediated phosphorylation of NR2B subunits of NMDA receptors at Tyr1472 in the dorsal horn was involved in a neuropathic pain state even 1 week after nerve injury. Here we show that Y1472F-KI mice with a knock-in mutation of the Tyr1472 site to phenylalanine did not exhibit neuropathic pain induced by L5 spinal nerve transection, whereas they did retain normal nociceptive responses and induction of inflammatory pain. Phosphorylation of NR2B at Tyr1472 was only impaired in the spinal cord of Y1472F-KI mice among the major phosphorylation sites. There was no difference in the Ca(2+) response to glutamate and sensitivity to NMDA receptor antagonists between naive wild-type and Y1472F-KI mice, and the Ca(2+) response to glutamate was attenuated in the Y1472F-KI mice after nerve injury. Autophosphorylation of CaMKII at Thr286 was markedly impaired in Y1472F-KI mice after nerve injury, but there was no difference in phosphorylation of CaMKII at Thr305 or protein kinase Cγ at Thr674, and activation of neuronal nitric oxide synthase and microglia in the superficial layer of spinal cord between wild-type and Y1472F-KI mice after the operation. These results demonstrate that the attenuation of neuropathic pain is caused by the impaired NMDA receptor-mediated CaMKII signaling in Y1472F-KI mice, and suggest that autophosphorylation of CaMKII at Thr286 plays a central part not only in LTP, but also in persistent neuropathic pain.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Neuralgia/physiopathology , Pain/physiopathology , Receptors, N-Methyl-D-Aspartate/physiology , Animals , Calcium/metabolism , Disease Models, Animal , Gene Knock-In Techniques , Glutamic Acid/pharmacology , Inflammation/genetics , Inflammation/physiopathology , Mice , Mice, Inbred C57BL , Models, Neurological , Neuralgia/genetics , Nitric Oxide Synthase Type I/biosynthesis , Phosphorylation/genetics , Protein Kinase C/metabolism , Receptors, N-Methyl-D-Aspartate/genetics , Receptors, N-Methyl-D-Aspartate/metabolism , Signal Transduction/genetics , Signal Transduction/physiology , Spinal Cord/drug effects , Spinal Cord/metabolism , Spinal Nerves/injuries , Spinal Nerves/physiopathology
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