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1.
Behav Brain Res ; 261: 26-30, 2014 Mar 15.
Article in English | MEDLINE | ID: mdl-24304719

ABSTRACT

We previously demonstrated among several antipsychotics exhibiting potent dopamine D2 receptor antagonism that only lurasidone, (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1] heptanedicarboximide hydrochloride, improved performance in the object retrieval detour (ORD) task by marmosets. The mechanisms by which only lurasidone causes enhancements in cognitive function have not yet been established; however, most antipsychotics, except for lurasidone, have been shown to exhibit potent antagonistic activity against the dopamine D4 receptor. The objectives of this study were to evaluate the role of the dopamine D4 receptor on executive function with the selective agonist, Ro10-5824 and antagonist, L-745,870, and elucidate a possible mechanism for the procognitive effect of lurasidone. The effects of these drugs were evaluated in naïve marmosets using the ORD task. Changes in the success rate during the difficult trial in the task were used to assess the cognitive effect of the drugs. Ro10-5824 (0.3-3 mg/kg) increased the success rate in the difficult trial, potentiated the effect of lurasidone, and reversed the cognitive impairment induced by clozapine. Interestingly, the co-administration of L-745,870 with lurasidone decreased the success rate in the difficult trial, whereas the single administration of L-745,870 had no effect. These results suggest that activation of the dopamine D4 receptor may improve executive function, whereas concomitant blockade of dopamine D4 and D2 receptors may have the opposite effect. In addition to the other unique binding profiles of other monoamine receptors, the lack of affinity for the dopamine D4 receptor by lurasidone could also contribute, at least partly, to its cognitive-enhancing effect.


Subject(s)
Antipsychotic Agents/pharmacology , Cognition/drug effects , Isoindoles/pharmacology , Receptors, Dopamine D4/metabolism , Thiazoles/pharmacology , Animals , Callithrix , Conditioning, Operant/drug effects , Dopamine Agents/pharmacology , Dose-Response Relationship, Drug , Female , Lurasidone Hydrochloride , Male , Mental Recall/drug effects , Protein Binding/drug effects , Pyridines/pharmacology , Pyrimidines/pharmacology , Pyrroles/pharmacology
2.
Behav Brain Res ; 249: 109-15, 2013 Jul 15.
Article in English | MEDLINE | ID: mdl-23608483

ABSTRACT

It is considered that functional deficiency of the NMDA receptors in the prefrontal cortex (PFC) is one of the causes of the cognitive impairment observed in schizophrenia. As non-human primates display more developed PFC than rodents, they are considered to be useful experimental animals for improving the predictive validity of models used to discover new drugs for treating cognitive dysfunction. The aim of this study was to develop a convenient model of the cognitive impairment observed in schizophrenia using common marmosets and the CANTAB system and to test whether a full agonist of the dopamine D1 receptor (SKF-81297) was effective against the cognitive impairment induced in this model. We administered the NMDA receptor antagonist ketamine (1.5-16mg/kg, i.m.) to the marmosets to induce cognitive impairment and then evaluated their working memory function using the CANTAB spatial working memory (SWM) test. The marmosets' working memory was impaired by subanesthetic doses of ketamine. Next, we tested the effect of SKF-81297 (3 or 10mg/kg, p.o.) on this ketamine-induced cognitive dysfunction. The marmosets were administered SKF-81297 30min before the ketamine injection. Pretreatment with SKF-81297 reversed the ketamine-induced cognitive deficiency. In this study, we found that a D1 receptor agonist, which has been reported to enhance cognitive function, reversed ketamine-induced cognitive impairment in marmosets, which suggests that our marmoset model could be a useful tool for predicting the clinical efficacy of cognitive-enhancing drugs.


Subject(s)
Dopamine Agonists/pharmacology , Maze Learning/drug effects , Memory, Short-Term/drug effects , Spatial Behavior/drug effects , Animals , Benzazepines/pharmacology , Callithrix , Ketamine , Memory Disorders/chemically induced , Receptors, Dopamine D1/agonists
3.
Behav Brain Res ; 246: 125-31, 2013 Jun 01.
Article in English | MEDLINE | ID: mdl-23454675

ABSTRACT

Cognitive impairment is one of the major symptoms of schizophrenia, and is considered largely due to dysfunctions in the prefrontal cortex (PFC). Lurasidone, a novel atypical antipsychotic agent with high binding affinity for dopamine D2, serotonin 5-HT7, 5-HT2A and 5-HT1A receptors has been reported to have superior efficacy in rodents' models of cognitive impairment. However, the beneficial effect of lurasidone on cognitive impairment has not been evaluated in non-human primates. In this study, we investigated the effect of lurasidone on executive function, which is one of the cognitive domains, in common marmosets and compared the results to those of other antipsychotics. The effects of lurasidone, haloperidol, olanzapine, risperidone, quetiapine and clozapine on executive function were evaluated in naïve marmosets using the object retrieval with detours (ORD) task. Before drug treatment, marmosets' success rates in the easy trial of the test were almost 90%. However, maximum success in the difficult trial of the task reached only 50% after 8 days of training. Haloperidol, olanzapine and risperidone decreased correct performance even in the easy trial of the task. All drugs, except lurasidone, impaired success rate in the difficult trial. On the other hand, lurasidone dose-dependently increased marmosets' success rates in the difficult trial with significant effect at 10mg/kg. In conclusion, we have shown in this study that lurasidone, unlike conventional antipsychotics, improves cognition associated with executive function in common marmosets. These findings suggest that lurasidone would be more useful for treatment of schizophrenia cognitive impairment than other antipsychotics.


Subject(s)
Antipsychotic Agents/pharmacology , Executive Function/drug effects , Isoindoles/pharmacology , Thiazoles/pharmacology , Animals , Callithrix , Dose-Response Relationship, Drug , Exploratory Behavior/drug effects , Female , Lurasidone Hydrochloride , Male , Spatial Behavior/drug effects , Time Factors
4.
Article in English | MEDLINE | ID: mdl-23367506

ABSTRACT

Lurasidone is a novel antipsychotic agent with high affinity for dopamine D(2) and serotonin 5-HT(7), 5-HT(2A), and 5-HT(1A) receptors. We previously reported that in addition to its antipsychotic action, lurasidone shows beneficial effects on mood and cognition in rats, likely through 5-HT(7) receptor antagonistic actions. In this study, we evaluated binding of lurasidone to 5-HT(7) receptors in the rat brain by autoradiography using [(3)H]SB-269970, a specific radioligand for 5-HT(7) receptors. Brain slices were incubated with 4 nM [(3)H]SB-269970 at room temperature and exposed to imaging plates for 8 weeks before phosphorimager analysis. Using this method, we first investigated 5-HT(7) receptor distribution. We found that 5-HT(7) receptors are abundantly localized in brain limbic structures, including the lateral septum, thalamus, hypothalamus, hippocampus, and amygdala. On the other hand, its distribution was moderate in the cortex and low in the caudate putamen and cerebellum. Secondly, binding of lurasidone, a selective 5-HT(7) receptor antagonist SB-656104-A and an atypical antipsychotic olanzapine to this receptor was examined. Lurasidone, SB-656104-A (10­1000 nM), and olanzapine (100­10,000 nM) showed concentration-dependent inhibition of [(3)H]SB-269970 binding with IC(50) values of 90, 49, and 5200 nM, respectively. Similar inhibitory actions of these drugs were shown in in vitro [(3)H]SB-269970 binding to 5-HT(7) receptors expressed in Chinese hamster ovary cells. Since there was no marked species difference in rat and human 5-HT(7) receptor binding by lurasidone (K(i) = 1.55 and 2.10 nM, respectively), these findings suggest that binding to 5-HT(7) receptors might play some role in its beneficial pharmacological actions in schizophrenic patients.


Subject(s)
Antipsychotic Agents/pharmacokinetics , Brain/drug effects , Isoindoles/pharmacokinetics , Receptors, Serotonin/metabolism , Thiazoles/pharmacokinetics , Animals , Autoradiography , Brain/metabolism , CHO Cells , Cricetinae , Lurasidone Hydrochloride , Male , Radioligand Assay , Rats , Rats, Sprague-Dawley
5.
Behav Brain Res ; 244: 66-9, 2013 May 01.
Article in English | MEDLINE | ID: mdl-23376699

ABSTRACT

Lurasidone is a novel atypical antipsychotic with high affinity for dopamine D2, serotonin 5-HT7 and 5-HT2A receptors. We previously reported that lurasidone and the selective 5-HT7 receptor antagonist, SB-656104-A improved learning and memory deficits induced by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, in the rat passive avoidance test. In this study, we first examined the role of the 5-HT7 receptor antagonistic activity of lurasidone in its pro-cognitive effect to ameliorate MK-801-induced deficits in the rat passive avoidance test. The 5-HT7 receptor agonist, AS19, (2S)-(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino) tetralin, (3 mg/kg, s.c.) completely blocked the attenuating effects of lurasidone (3 mg/kg, p.o.), highlighting the importance of 5-HT7 receptor antagonism in the pro-cognitive effect of lurasidone. AS19 (3 mg/kg, s.c.) also blocked the ameliorating effect of SB-656104-A (10 mg/kg, i.p.) in the same experimental paradigm. To further extend our observation, we next tested whether 5-HT7 receptor antagonism still led to the amelioration of MK-801-induced deficits when combined with D2 and 5-HT2A receptor antagonists, and found that SB-656104-A (10 mg/kg, i.p.) significantly ameliorated MK-801-induced deficits even in the presence of the D2 receptor antagonist raclopride (0.1 mg/kg, s.c.) and 5-HT2A receptor antagonist ketanserin (1 mg/kg, s.c.). Taken together, these results suggest that the 5-HT7 receptor antagonistic activity of lurasidone plays an important role in its effectiveness against MK-801-induced deficits, and may contribute to its pharmacological actions in patients with schizophrenia.


Subject(s)
Avoidance Learning/drug effects , Dizocilpine Maleate/antagonists & inhibitors , Isoindoles/pharmacology , Memory/drug effects , Serotonin Antagonists/pharmacology , Thiazoles/pharmacology , Animals , Antipsychotic Agents/antagonists & inhibitors , Antipsychotic Agents/pharmacology , Dizocilpine Maleate/pharmacology , Dopamine Antagonists/pharmacology , Isoindoles/antagonists & inhibitors , Ketanserin/pharmacology , Lurasidone Hydrochloride , Male , Phenols/pharmacology , Pyrazoles/pharmacology , Pyrrolidines/pharmacology , Raclopride/pharmacology , Rats , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/pharmacology , Tetrahydronaphthalenes/pharmacology , Thiazoles/antagonists & inhibitors
6.
Bioorg Med Chem Lett ; 21(7): 1978-82, 2011 Apr 01.
Article in English | MEDLINE | ID: mdl-21377875

ABSTRACT

In our search for new PPARα/γ agonists, we designed and synthesized a series of benzoylazole-based carboxylic acids. Compound 9 showed potent PPARγ partial agonistic activity with modest PPARα agonistic activity. The sodium salt of 9 (9Na) demonstrated potent efficacy in lowering both blood glucose and lipids in an animal model without causing significant body weight gain, a well-known side effect associated with PPARγ full agonists.


Subject(s)
Azoles/chemical synthesis , Azoles/pharmacology , PPAR alpha/agonists , PPAR gamma/agonists , Animals , Azoles/chemistry , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/pharmacology , Mice , Models, Animal , Models, Molecular
7.
Behav Brain Res ; 220(1): 83-90, 2011 Jun 20.
Article in English | MEDLINE | ID: mdl-21277905

ABSTRACT

We have previously reported that lurasidone, a novel atypical antipsychotic with potent serotonin 5-HT(7) antagonist and 5-HT(1A) partial agonist activities, is superior to other antipsychotics in improving the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801-induced learning and memory impairment in the passive avoidance (PA) and Morris water maze (MWM) tests in rats. In this study, we investigated the effects of selective antagonists of 5-HT(7) and 5-HT(1A) receptors (SB-656104-A and WAY-100635, respectively) on MK-801-induced learning and memory impairment in the same tests. In the PA test, either pre-training (3 and 10mg/kg, p.o.) or post-training (0.3mg/kg, i.v.) administration of lurasidone significantly reversed the test response impaired by MK-801, consistent with our previous reports. Pre-training administration of either SB-656104-A (10 and 30 mg/kg, i.p.) or WAY-100635 (1mg/kg, s.c.) also significantly reversed MK-801-induced memory impairment. Furthermore, post-training administration of either SB-656104-A (0.3mg/kg, i.v.) or WAY-100635 (0.01 mg/kg, i.v.) counteracted the effect of MK-801, which suggested that both 5-HT receptor subtype-selective antagonists could restore the memory consolidation process. In the MWM test, SB-656104-A (3mg/kg, i.p.) reversed learning impairment induced by MK-801. On the other hand, WAY-100635 (0.3 and 1mg/kg, i.p.) did not have any effect on the MK-801-induced learning impairment. Taken together, our results showed that 5-HT(7) and 5-HT(1A) receptor antagonists mimic the effect of lurasidone in whole or in part, respectively, to reverse MK-801-induced learning and memory impairment, which warrants further investigation of the interaction of lurasidone with these serotonin receptors as a possible mechanism underlying its procognitive effects in these animal models.


Subject(s)
Avoidance Learning/physiology , Isoindoles/therapeutic use , Maze Learning/physiology , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Serotonin/metabolism , Thiazoles/therapeutic use , Animals , Avoidance Learning/drug effects , Disease Models, Animal , Dizocilpine Maleate/adverse effects , Dose-Response Relationship, Drug , Drug Interactions , Excitatory Amino Acid Antagonists/adverse effects , Learning Disabilities/chemically induced , Learning Disabilities/drug therapy , Lurasidone Hydrochloride , Male , Maze Learning/drug effects , Memory Disorders/chemically induced , Memory Disorders/drug therapy , Rats , Rats, Wistar , Reaction Time/drug effects , Serotonin Agents/pharmacology , Time Factors
8.
Bioorg Med Chem Lett ; 21(1): 220-4, 2011 Jan 01.
Article in English | MEDLINE | ID: mdl-21130649

ABSTRACT

Starting with a subtle blood glucose-lowering effect of a TGF-ß inhibitor, we designed and synthesized a series of benzoylpyrrole-based carboxylic acids as PPARs activators. Among these compounds, 10sNa exhibited favorable blood glucose-lowering effect without body weight gain. We assume that the beneficial effect of 10sNa is attributed to not only its compound PPARα agonistic activity but also its PPARγ partial agonistic activity.


Subject(s)
Acetates/chemistry , Carboxylic Acids/chemistry , Hypoglycemic Agents/chemistry , PPAR alpha/agonists , PPAR gamma/agonists , Pyrroles/chemistry , Acetates/pharmacokinetics , Acetates/therapeutic use , Animals , Carboxylic Acids/pharmacokinetics , Carboxylic Acids/therapeutic use , Hyperglycemia/drug therapy , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Male , Mice , Mice, Obese , Obesity/drug therapy , PPAR alpha/metabolism , PPAR gamma/metabolism , Pyrroles/pharmacokinetics , Pyrroles/therapeutic use , Rats , Structure-Activity Relationship
9.
Biol Pharm Bull ; 32(12): 1991-6, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19952417

ABSTRACT

The number of patients with chronic kidney disease (CKD) has continuously grown worldwide. Treatment with antihypertensive agents reduces the rate of progression of CKD, however, there is still a large unmet need to develop strategies for the treatment of CKD. Although we have previously reported that the antifibrotic agent, SMP-534 inhibits the progression of CKD, it is unknown whether combination therapy with SMP-534 and antihypertensive agent shows additive effects on CKD. In present study, we examined whether combination therapy with SMP-534 and the antihypertensive agent, lisinopril is more effective than single therapy with SMP-534 or lisinopril on five-sixths nephrectomized (5/6Nx) rat model. Combination therapy with SMP-534 (50 mg/kg) and lisinopril (5 mg/kg) significantly decreased urinary albumin excretion, blood urea nitrogen (BUN) and serum creatinine and increased creatinine clearance in 5/6Nx rats. On the other hands, single treatment with SMP-534 or lisinopril did not improve renal function at this dose. In addition, combination therapy with SMP-534 and lisinopril significantly decreased extracellular matrix (ECM) accumulation in renal glomeruli and tubulointerstitial injury. These data suggest that combination therapy with an antifibrotic agent and an antihypertensive agent may offer a new therapeutic option for suppressing the progression of CKD.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antihypertensive Agents/therapeutic use , Benzamides/therapeutic use , Kidney Failure, Chronic/drug therapy , Kidney/drug effects , Lisinopril/therapeutic use , Protective Agents/therapeutic use , Albuminuria , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Antihypertensive Agents/pharmacology , Benzamides/pharmacology , Blood Urea Nitrogen , Creatinine/blood , Creatinine/pharmacokinetics , Disease Models, Animal , Drug Therapy, Combination , Extracellular Matrix/metabolism , Kidney/metabolism , Kidney Failure, Chronic/metabolism , Lisinopril/pharmacology , Male , Nephrectomy , Protective Agents/pharmacology , Rats , Rats, Sprague-Dawley
10.
Biochem Biophys Res Commun ; 388(2): 311-6, 2009 Oct 16.
Article in English | MEDLINE | ID: mdl-19664596

ABSTRACT

Metformin is widely used as a hypoglycemic agent for the treatment of type 2 diabetes. Both metformin and rotenone, an inhibitor of respiratory chain complex I, suppressed glucose-6-phosphatase (G6pc), a rate limiting enzyme of liver glucose production, mRNA expression in a rat hepatoma cell line accompanied by a reduction of intracellular ATP concentration and an activation of AMP-activated protein kinase (AMPK). When yeast NADH-quinone oxidoreductase 1 (NDI1) gene was introduced into the cells, neither inhibition of ATP synthesis nor activation of AMPK was induced by these agents. Interestingly, in contrast to rotenone treatment, G6pc mRNA down-regulation was observed in the NDI1 expressing cells after metformin treatment. Since NDI1 can functionally complement the complex I under the presence of metformin or rotenone, our results indicate that metformin induces down-regulation of G6pc expression through an inhibition of complex I and an activation of AMPK-independent mechanism.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Electron Transport Complex I/antagonists & inhibitors , Glucose-6-Phosphatase/antagonists & inhibitors , Hypoglycemic Agents/pharmacology , Metformin/pharmacology , Saccharomyces cerevisiae Proteins/antagonists & inhibitors , Animals , Cell Line, Tumor , Down-Regulation , Glucose-6-Phosphatase/biosynthesis , Mice , Rats
11.
Biomed Res ; 30(3): 177-82, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19574719

ABSTRACT

Pulmonary fibrosis is a progressive and lethal lung disease characterized by accumulation of ECM and loss of pulmonary function. However, no cure exists for this disease, and current treatments often fail to slow its progression or relieve its symptoms. We have previously reported that the anti-fibrotic agent SMP-534 has beneficial effects on renal fibrosis in animal model of nephropathy. In this study, we examined whether SMP-534 has beneficial effects on pulmonary fibrosis in bleomycin-treated hamsters. Treatment with SMP-534 [low dose (70 mg/kg) or high dose (110 mg/kg)] counteracted inhibition of body weight increase induced by bleomycin. In addition, SMP-534 significantly inhibited bleomycin-induced increase in lung hydroxyproline level, an index of collagen formation. Moreover, SMP-534 significantly ameliorated histological pulmonary fibrotic changes induced by bleomycin. The results of this study indicate that the anti-fibrotic agent SMP-534 may offer a new therapeutic option for the treatment of pulmonary fibrosis.


Subject(s)
Antibiotics, Antineoplastic/adverse effects , Benzamides/therapeutic use , Bleomycin/adverse effects , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/drug therapy , Animals , Body Weight/drug effects , Cricetinae , Cricetulus , Extracellular Matrix/metabolism , Humans , Hydroxyproline/metabolism , Male , Pulmonary Fibrosis/pathology , Random Allocation
12.
Nephron Exp Nephrol ; 110(4): e99-108, 2008.
Article in English | MEDLINE | ID: mdl-18971587

ABSTRACT

BACKGROUND/AIMS: Chronic kidney disease (CKD) is the common cause of end-stage renal disease. Antihypertensive agents are clinically used to inhibit the progression of CKD. However, these agents cannot completely prevent progression to renal failure. We have previously reported that 5-chloro-2-{(1E)-3-[2-(4-methoxybenzoyl)-4-methyl-1H- pyrrol-1-yl]prop-1en-1-yl}-N-(methylsulfonyl)benzamide (SMP-534) improves renal disease and prevents the production of extracellular matrix in vitro. Additionally, SMP-534 inhibits glomerular fibrosis and provides renoprotection in vivo. In the present study, we investigated the effect of SMP-534 on renal dysfunction in a 5/6 nephrectomized (5/6Nx) rat model. METHOD: Five groups of rats were studied: sham operated, 5/6Nx + vehicle, 5/6Nx + SMP-534 30 mg/kg, 5/6Nx + SMP-534 60 mg/kg and 5/6Nx + SMP-534 90 mg/kg. Treatment with SMP-534 began 13 weeks after surgery, when hypertension and renal insufficiency had developed. Serum creatinine, blood urea nitrogen levels, creatinine clearance and urinary albumin were measured at specific time points. RESULTS: Serum creatinine and blood urea nitrogen levels were significantly reduced in SMP-534-treated groups. In addition, SMP-534 dose-dependently suppressed the increase in urinary albumin excretion observed in 5/6Nx rats. Moreover, survival rates were improved in SMP-534-treated groups. CONCLUSION: We have shown in this study that chronic oral administration of SMP-534 improves renal dysfunction in 5/6Nx rats. These findings indicate that SMP-534 may be a new therapeutic agent for the treatment of CKD.


Subject(s)
Benzamides/administration & dosage , Renal Insufficiency/drug therapy , Animals , Nephrectomy/methods , Rats , Renal Insufficiency/pathology , Renal Insufficiency/physiopathology
13.
J Toxicol Sci ; 33(3): 339-47, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18670165

ABSTRACT

Large-scale clinical studies have shown that the biguanide drug metformin, widely used for type 2 diabetes, to be very safe. By contrast, another biguanide, phenformin, has been withdrawn from major markets because of a high incidence of serious adverse effects. The difference in mode of action between the two biguanides remains unclear. To gain insight into the different modes of action of the two drugs, we performed global gene expression profiling using the livers of obese diabetic db/db mice after a single administration of phenformin or metformin at levels sufficient to cause a significant reduction in blood glucose level. Metformin induced modest expression changes, including G6pc in the liver as previously reported. By contrast, phenformin caused changes in expression level of many additional genes. We used a knowledge-based bioinformatic analysis to study the effects of phenformin. Differentially expressed genes identified in this study constitute a large gene network, which may be related to cell death, inflammation or wound response. Our results suggest that the two biguanides show a similar hypoglycemic effect in db/db mice, but phenformin induces a greater stress on the liver even a short time after a single administration. These findings provide a novel insight into the cause of the relatively high occurrence of serious adverse effect after phenformin treatment.


Subject(s)
Gene Expression Profiling , Hypoglycemic Agents/pharmacology , Liver/drug effects , Metformin/pharmacology , Phenformin/pharmacology , Animals , Blood Glucose/analysis , Computational Biology , Dose-Response Relationship, Drug , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Oligonucleotide Array Sequence Analysis , Phenformin/toxicity
14.
Biomed Res ; 29(3): 147-53, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18614848

ABSTRACT

We previously reported that peripheral injection of brain-derived neurotrophic factor (BDNF) exhibits hypophagic and hypoglycemic effects in obese hyperglycemic animals, indicating its antiobesity and antidiabetic effects. Since previous studies were focused on the effect of BDNF on overt diabetic animals with severe hyperglycemia, there was no evidence whether BDNF is effective or not for the development of diabetes in prediabetic animal models. Therefore, we evaluated the effect of BDNF on preventing the development of diabetes in db/db mice. First, we characterized age-related changes in the pathophysiology of diabetes in db/db mice. We chose 8 week-old db/db mice as the early diabetic stage (early intervention study) and 4 week-old db/db mice as the prediabetic stage (prevention study). Next, we examined the effects of BDNF on the progression of diabetes in early diabetic db/db mice. In the early intervention study using 8 week-old db/db mice, intermittent treatment with BDNF prevented the deterioration in hyperglycemia. Lastly, we examined the preventive effects of BDNF on the development of diabetes in prediabetic db/db mice. In the prevention study using 4 week-old db/db mice, treatment with BDNF prevented the age-related increase in blood glucose concentration. These results showed for the first time that BDNF prevents the development of diabetes in prediabetic db/db mice.


Subject(s)
Brain-Derived Neurotrophic Factor/pharmacology , Diabetes Mellitus, Experimental/prevention & control , Prediabetic State/physiopathology , Animals , Blood Glucose/analysis , Brain-Derived Neurotrophic Factor/administration & dosage , Disease Progression , Glucose Tolerance Test , Male , Mice , Mice, Inbred C57BL
15.
J Biosci Bioeng ; 105(4): 395-402, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18499057

ABSTRACT

We previously demonstrated that repetitive administration of brain-derived neurotrophic factor (BDNF) ameliorates glucose metabolism and energy expenditure in obese diabetic db/db mice. However, we have not evaluated in detail the effect of single or intermittent BDNF administration on glucose metabolism in a diabetic animal model. The objectives of this study were to examine the dose-response effect and dosing interval of BDNF administration in db/db mice and to evaluate the effect of intermittent BDNF administration on pancreatic function in db/db mice. We evaluated the dose-response effect of BDNF by single administration in db/db mice. First, single administration of BDNF greater than 70 mg/kg significantly reduced blood glucose concentration one day after administered, and the BDNF effect was maintained for 6 d. Next, the effects of BDNF administered twice a week at 4, 10, 25, and 62.5 mg/kg on blood glucose concentration, and the effects of BDNF administered once a week at 10, 20, 30, 50, and 70 mg/kg on blood glucose concentration were examined in db/db mice. In the intermittent treatment studies, BDNF dose-dependently ameliorated glucose metabolism by not only the twice-a-week administration but also the once-a-week administration. Lastly, because BDNF reduces the food intake of obese hyperphagic diabetic mice, the effects of BDNF administered once or twice a week on the blood glucose concentration and plasma and pancreatic insulin concentrations in db/db mice were compared with those of the vehicle under pair-fed conditions. Under pair-fed conditions, the intermittent administration of BDNF (25 mg/kg, twice a week, or 50 mg/kg, once a week) significantly reduced the blood glucose concentration and increased the plasma and pancreatic insulin concentrations compared with those in the pair-fed vehicle-treated db/db mice. This indicates that the prolonged hypoglycemic effect of BDNF is not simply due to the reduction of food intake. In conclusion, we demonstrated that the intermittent administration of BDNF ameliorates glucose metabolism and prevents pancreatic exhaustion in obese diabetic mice. These findings indicate that BDNF may have potential as a unique hypoglycemic agent for the treatment of diabetes at a fundamental level with good patient compliance.


Subject(s)
Blood Glucose/metabolism , Brain-Derived Neurotrophic Factor/pharmacology , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/drug therapy , Energy Metabolism/drug effects , Hypoglycemic Agents/pharmacology , Pancreas/metabolism , Animals , Dose-Response Relationship, Drug , Eating/drug effects , Insulin/blood , Male , Mice , Mice, Obese , Pancreatic Diseases/blood , Pancreatic Diseases/drug therapy , Time Factors
16.
Nephron Exp Nephrol ; 105(2): e45-52, 2007.
Article in English | MEDLINE | ID: mdl-17139189

ABSTRACT

BACKGROUND/AIMS: Diabetic nephropathy is the main cause of end-stage renal disease. Previously we have demonstrated that SMP-534 (an antifibrotic agent) prevents the development of diabetic nephropathy in db/db mouse and that combined treatment with SMP-534 and losartan (antihypertensive agents) markedly prevents the development of diabetic nephropathy compared with single treatment. SMP-534 or losartan was prophylactically administered to db/db mice before the onset of diabetic nephropathy. In the present study, we evaluated the efficacy of combined treatment when administration was started after the onset of diabetic nephropathy. METHODS: db/db mice were raised untreated until 17 weeks of age, by which time increase of urinary albumin was noted, and then treated with SMP-534 and/or losartan for another 8 weeks. Biochemical and histological analyses were performed at 25 weeks of age. RESULTS: Combined treatment with SMP-534 and losartan markedly prevented the increase of urinary albumin and ameliorated the progression of mesangial matrix expansion, even when administration was started long after the increase of urinary albumin. CONCLUSION: The study results indicate that a combination of SMP-534 and losartan might be a valuable therapeutic approach for the treatment of diabetic nephropathy even when administration is started after the onset of diabetic nephropathy.


Subject(s)
Antihypertensive Agents/pharmacology , Benzamides/pharmacology , Diabetic Nephropathies/drug therapy , Losartan/pharmacology , Albuminuria , Animals , Disease Models, Animal , Drug Therapy, Combination , Fibrosis/drug therapy , Male , Mice
17.
Biomed Res ; 27(4): 191-5, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16971772

ABSTRACT

Growth hormone (GH) replacement therapy has been shown to have beneficial effects on linear growth enhancement in GH-deficient children over the past few decades. SMP-140 is a sterile liquid formation containing rhGH that is expected to improve patient compliance and accuracy of dosing, compared with the commercially available lyophilized form of GH. However, since there are no data showing that SMP-140 influences body elongation in animal models, we studied the effects of SMP-140 on body length in hypophysectomized (HPX) rats, which are used as animal models of GH deficiency. Consistent with the main feature of GH-deficient children, the body length of HPX rats was significantly shorter than that of sham-operated rats at the start of the study. SMP-140 (0.2, 1 and 5 mg/kg) was administered once daily to HPX rats for seven days, and resulted in a dose-dependent increase in body length and in the width of the growth plate cartilage. These results show that SMP-140 administration increases body length in an animal model of GH deficiency, and suggest that SMP-140 will be a useful agent for the treatment of growth-retarded children.


Subject(s)
Growth/drug effects , Human Growth Hormone/pharmacology , Animals , Disease Models, Animal , Growth Hormone/deficiency , Humans , Hypophysectomy , Rats
18.
Metabolism ; 55(10): 1286-92, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16979397

ABSTRACT

We have previously demonstrated that brain-derived neurotrophic factor (BDNF) ameliorates glucose metabolism and energy expenditure in obese diabetic db/db mice. In the present study, the effect of BDNF treatment on pancreatic islets of db/db mice was examined, using vehicle-treated pair-fed db/db mice as controls. Brain-derived neurotrophic factor (10 mg/kg) or vehicle was subcutaneously administered to male db/db mice for 4 weeks. The food intake of vehicle-treated db/db mice was restricted and precisely synchronized with that of BDNF-treated db/db mice using a pellet pair-feeding apparatus because BDNF decreases food intake in hyperphagic mice. Repetitive administration of BDNF significantly lowered the blood glucose concentration compared with pair-fed vehicle-treated db/db mice. The pancreatic insulin and glucagon concentrations were measured in db/db mice to evaluate the effect of BDNF on the pancreas. Although the insulin concentration in the pancreas of pair-fed vehicle-treated db/db mice was lower than in nondiabetic control +m/+m mice, it was higher in BDNF-treated db/db mice than in vehicle-treated pair-fed db/db mice and comparable to the concentration in +m/+m mice. The glucagon concentration in the pancreas of vehicle-treated pair-fed db/db mice was higher than in +m/+m mice, and BDNF partially decreased the glucagon concentration in the pancreas of db/db mice compared with vehicle. Histologic analyses of pancreatic sections were performed to characterize the mechanism through which BDNF modulates the hormonal concentration in the pancreas of db/db mice. Although there were no significant differences in the number and total area of islets between the BDNF- and vehicle-treated groups, immunostaining with an anti-insulin antibody indicated that the islet beta-cell area in BDNF-treated db/db mice was larger than that in vehicle-treated pair-fed db/db mice. Furthermore, immunostaining with an antiglucagon antibody indicated that BDNF normalized the delocalization of non-beta cells in islets of db/db mice. Electron microscopic images of beta cells indicated a decrease in secretory granules in vehicle-treated pair-fed db/db mice; this change was reversed in BDNF-treated db/db mice and reached a level comparable to that found in +m/+m mice. These findings suggest that BDNF prevents exhaustion of the pancreas in diabetic mice by maintaining the histologic cellular organization of beta cells and non-beta cells in pancreatic islets and restoring the level of insulin-secreting granules in beta cells.


Subject(s)
Brain-Derived Neurotrophic Factor/pharmacology , Diabetes Mellitus/genetics , Diabetes Mellitus/pathology , Islets of Langerhans/drug effects , Islets of Langerhans/pathology , Obesity/drug therapy , Obesity/pathology , Animals , Blood Glucose/metabolism , Brain-Derived Neurotrophic Factor/therapeutic use , Glucagon/blood , Glucagon/metabolism , Immunohistochemistry , Insulin/blood , Insulin/metabolism , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/ultrastructure , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Microscopy, Electron , Pancreas/metabolism , Pancreas/pathology , Recombinant Proteins/pharmacology , Recombinant Proteins/therapeutic use
19.
Comb Chem High Throughput Screen ; 9(3): 187-96, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16533152

ABSTRACT

Hypothalamic hormones physiologically regulate pulsatile release of growth hormone (GH) from the anterior pituitary gland. Since the discovery of these hormones in the 1970s, several new chemically synthesized peptidyl and non-peptidyl derivatives have been proved to stimulate and amplify GH secretion, and this series of molecules has been named the growth hormone secretagogues (GHSs). One of these compounds led to the discovery of a GPCR-type receptor for GHSs (GHS-R), and subsequently the endogenous ligand for the receptor has been identified, and is referred to as ghrelin. The identification of GHSs as physiological regulators of GH secretion encouraged us to examine our GHSs pharmacologically. We previously reported that novel oxindole derivatives have been identified as GHS-R agonists from our internal chemical library. Among these derivatives, (+)-6-carbamoyl-3-(2-chlorophenyl)-(2-diethylaminoethyl)-4-trifluoromethyloxindole (SM-130686, 37S) was found to have potent activity in vitro with a good pharmacokinetic profile in rats (bioavailability of 28%). In this article, we review the synthesis and pharmacological evaluation of SM-130686. SM-130686 binds specifically to GHS-R and increases the Ca(2+) concentration in Chinese hamster ovary cells expressing recombinant GHS-R. Maximal enhancement of the intracellular Ca(2+) concentration induced by SM-130686 treatment was approximately 55% that induced by ghrelin, suggesting that SM-130686 may be a partial GHS-R agonist. Also, in in vivo studies, oral administration of SM-130686 increased body length and fat-free mass gain. We compare the pharmacological profile of SM-130686 with other GHSs, including GHRH and ghrelin, and discuss the therapeutic usefulness of GHSs against several disorders, as well as for treatment of GH deficiency.


Subject(s)
Ethylamines/chemical synthesis , Ethylamines/pharmacology , Growth Hormone/metabolism , Indoles/chemical synthesis , Indoles/pharmacology , Administration, Oral , Animals , Calcium/metabolism , Ethylamines/administration & dosage , Humans , Hypophysectomy , Indoles/administration & dosage , Male , Rats , Sodium Glutamate/administration & dosage
20.
Am J Nephrol ; 26(1): 50-8, 2006.
Article in English | MEDLINE | ID: mdl-16508247

ABSTRACT

BACKGROUND/AIMS: Diabetic nephropathy is now the most common cause of end-stage renal disease. It is also clear that the current therapy, angiotensin II blockage, cannot prevent the progression of diabetic nephropathy. We had previously demonstrated that an antifibrotic agent, SMP-534, reduced extracellular matrix production induced by transforming growth factor-beta in vitro, and that SMP-534 prevented renal fibrosis and urinary albumin in diabetic db/db mice via a nonantihypertensive mechanism. We expected that combined use of SMP-534 and losartan would produce a more highly renoprotective action. METHODS: We examined the effects of combined treatment with SMP-534 and losartan on urinary albumin and glomerular fibrosis in db/db mice. Diet containing these agents was provided from age 9 to 25 weeks. Blood and urine analyses were performed at 8, 17, and 25 weeks. At the end of the study, kidney tissues were histologically analyzed. RESULTS: SMP-534 significantly suppressed an increase in urinary albumin excretion and ameliorated the progression of glomerular fibrosis in db/db mice, whereas losartan did not. Combined treatment with SMP-534 and losartan markedly prevented the increase of urinary albumin excretion compared with treatment with either SMP-534 or losartan alone. In contrast, renal histological analysis revealed that combined treatment did not significantly prevent an increase of mesangial expansion in the kidney compared with treatment with SMP-534 alone. CONCLUSION: A combination of the two agents, SMP-534 and losartan, might be a valuable therapeutic approach for the treatment of diabetic nephropathy.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/administration & dosage , Benzamides/administration & dosage , Diabetic Nephropathies/drug therapy , Losartan/administration & dosage , Albuminuria , Animals , Drug Therapy, Combination , Fibrosis/drug therapy , Kidney/pathology , Kidney Glomerulus/pathology , Male , Mice
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