RESUMEN
BACKGROUND: Alpha-lipoic acid, epalrestat, and mecobalamin are widely used as monotherapies for diabetic peripheral neuropathy. However, whether a triple-combination therapy with these three drugs is superior to monotherapy or dual therapy remains debatable. METHODS: Nine randomized controlled trials were identified through a search on electronic databases such as PubMed, Web of Science, and Cochrane Library. The trial participants (N = 1153) were divided into the experimental group who received the triple-combination therapy and the control group who received conventional or dual therapy with the aforementioned drugs. RESULTS: Therapeutic outcomes were better in the experimental group than in the control group (odds ratio: 3.74; 95 % confidence interval: 2.57-5.45; I2 = 0 %; p < 0.00001). No statistic difference was noted in adverse effects. Compared with the control group, the experimental group exhibited significant improvements in median motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), peroneal MNCV, peroneal SNCV, and vibration perception thresholds (VPT) in the left and right lower limbs. In the control group, a subgroup analysis by treatment strategy revealed similar improvements in total efficacy, MNCV, and SNCV. CONCLUSIONS: For diabetic peripheral neuropathy, the triple-combination therapy may be more effective than monotherapy or dual therapy.
Asunto(s)
Neuropatías Diabéticas , Quimioterapia Combinada , Ensayos Clínicos Controlados Aleatorios como Asunto , Ácido Tióctico , Neuropatías Diabéticas/tratamiento farmacológico , Humanos , Ácido Tióctico/uso terapéutico , Ácido Tióctico/administración & dosificación , Vitamina B 12/uso terapéutico , Vitamina B 12/administración & dosificación , Vitamina B 12/análogos & derivados , Rodanina/análogos & derivados , Rodanina/uso terapéutico , Rodanina/administración & dosificación , Resultado del Tratamiento , Conducción Nerviosa/efectos de los fármacos , Conducción Nerviosa/fisiología , TiazolidinasRESUMEN
A high salt diet (HSD) is among the most important risk factors for many diseases. One mechanism by which HSD aggravates cerebral ischemic injury is independent of blood pressure changes. The direct role of HSD in inflammation after cerebral ischemia is unclear. In this research, after twenty-one days of being fed a high salt diet, permanent focal ischemia was induced in mice via operation. At 12 h and 1, 3 and 5 days postischemia, the effects of HSD on the lesion volume, microglia polarization, aldose reductase (AR) expression, and inflammatory processes were analyzed. We report that in mice, surplus dietary salt promotes inflammation and increases the activation of classical lipopolysaccharide (LPS)-induced microglia/macrophages (M1). This effect depends on the expression of the AR protein in activated microglia after permanent middle cerebral artery ligation (pMCAL) in HSD mice. The administration of either the AR inhibitor Epalrestat or a p38-neutralizing antibody blocked the polarization of microglia and alleviated stroke injury. In conclusion, HSD promotes polarization in pro-inflammatory M1 microglia by upregulating the expression of the AR protein via p38/MAPK, thereby exacerbating the development of ischemia stroke.
Asunto(s)
Isquemia Encefálica/metabolismo , Macrófagos/fisiología , Microglía/fisiología , Sales (Química)/administración & dosificación , Antagonistas de Receptores Androgénicos/administración & dosificación , Animales , Isquemia Encefálica/patología , Diferenciación Celular , Citocinas/metabolismo , Ingestión de Alimentos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Activación de Macrófagos , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores Androgénicos/metabolismo , Rodanina/administración & dosificación , Rodanina/análogos & derivados , Sales (Química)/efectos adversos , Transducción de Señal , Células TH1/inmunología , Tiazolidinas/administración & dosificación , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND AND OBJECTIVES: Aldose Reductase (AR), a polyol pathway enzyme that mediates diabetic complications is implicated in tumour development and progression. This study was undertaken to determine whether gedunin, a neem limonoid prevents the hallmarks of cancer by inhibiting AR and the associated downstream PI3K/Akt/mTOR/ERK/NF-κB signalling axis in the SCC131 oral cancer cell line. METHODS: The expression of AR and key molecules involved in cell proliferation, apoptosis, autophagy, invasion and angiogenesis was analysed by qRT-PCR, and immunoblotting. ROS generation and cell cycle were analysed by FACS. Alamar blue assay and scratch assay were used to evaluate cell proliferation and migration in the endothelial cell line Eahy926. RESULTS: Gedunin and the AR inhibitor epalrestat inhibited AR expression and ROS generation. Cell cycle arrest at G1/S was associated with cell death by autophagy with subsequent switch over to apoptosis. Furthermore, hypoxia-induced cell migration was inhibited in Eahy926 cells with downregulation of pro-invasive and proangiogenic proteins in SCC131 as well as Eahy926 cells. Co-inactivation of Akt and ERK was coupled with abrogation of IKK/NF-κB signaling. However, the combination of gedunin and epalrestat was more effective than single agents. CONCLUSION: Inhibition of AR-mediated ROS signalling may be a key mechanism by which gedunin and epalrestat exert their anticancer effects. Our results provide compelling evidence that the combination of gedunin and epalrestat modulates expression of key oncogenic signalling kinases and transcription factors primarily by influencing phosphorylation and subcellular localisation. AR inhibitors such as gedunin and epalrestat are novel candidate agents for cancer prevention and therapy.
Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Azadirachta/química , Carcinoma de Células Escamosas/metabolismo , Inhibidores Enzimáticos/farmacología , Limoninas/farmacología , Neoplasias de la Boca/metabolismo , Oncogenes , Rodanina/análogos & derivados , Transducción de Señal/efectos de los fármacos , Tiazolidinas/farmacología , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Inhibidores Enzimáticos/administración & dosificación , Humanos , Limoninas/administración & dosificación , Limoninas/aislamiento & purificación , Neoplasias de la Boca/enzimología , Neoplasias de la Boca/patología , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Rodanina/administración & dosificación , Rodanina/farmacología , Tiazolidinas/administración & dosificaciónRESUMEN
BACKGROUND: Diabetic peripheral neuropathy (DPN) is a common long-term complication of diabetes mellitus, affecting patients in the world. Epalrestat combined with α-lipoic acid (ALA) is the most frequent combine therapy used in the DPN researches. We aim to assess the effectiveness and safety of epalrestat combined with ALA in patients with DPN, compare with epalrestat alone. METHODS: We will search Cochrane Library, PubMed, Wanfang Data, China National Knowledge Infrastructure, VIP Chinese Science and Technology Journals Database, and Chinese Biomedical Database from inception until October 31th, 2017. Inclusion the randomized controlled trials and clinical control trials of combine therapy which evaluate clinical efficacy and side effect in people with DPN. Data extraction and risk of bias assessments will be independently conducted by 2 reviewers. The primary outcome measures will be total effective rate, motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), Toronto clinical scoring system (TCSS), and total symptom score (TSS). All statistical analyses will be performed using RevMan V.5.3 software. RESULTS: This review will evaluate the total effective rate, nerve conduction velocity, TCSS, TSS, and safety of ALA combined with epalrestat for patients with DPN, compare with epalrestat alone. CONCLUSION: Our study will provide evidence to assess whether epalrestat combined with ALA is an optional treatment for patients with DPN.
Asunto(s)
Neuropatías Diabéticas/tratamiento farmacológico , Metaanálisis como Asunto , Rodanina/análogos & derivados , Tiazolidinas , Ácido Tióctico , Antioxidantes/administración & dosificación , Antioxidantes/efectos adversos , Quimioterapia Combinada , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Rodanina/administración & dosificación , Rodanina/efectos adversos , Tiazolidinas/administración & dosificación , Tiazolidinas/efectos adversos , Ácido Tióctico/administración & dosificación , Ácido Tióctico/efectos adversos , Resultado del TratamientoRESUMEN
Most treatments for diabetic eye conditions rely on systemic (oral) or intravitreal administration, and there is still a demand of efficient and comfortable ocular dosage forms. Our purpose was to design contact lenses (CLs) suitable for local prophylaxis/treatment of diabetes-related ocular pathologies, by means of the incorporation of bioinspired functional groups that can reversibly interact with epalrestat, an aldose reductase inhibitor. Several sets of silicone hydrogels were synthesized varying the contents in 2-hydroxyethyl methacrylate (HEMA), monomethacryloxypropyl-sym-polydimethylsiloxane hydroxypropyl terminated (MCS-MC12), and aminopropyl methacrylamide (APMA). Epalrestat was incorporated before or after polymerization, and loading and release profiles compared. All sets were evaluated regarding optical properties, oxygen permeability, swelling, cytocompatibility, ocular irritation, and corneal drug penetration (using a drug solution as reference). Designed silicone hydrogels showed adequate properties to be used as CLs. Affinity for epalrestat strongly depended on the content in APMA, which endowed the hydrogels with prolonged release in 0.9% NaCl for one week, both after synthesis and after being re-loaded. Bovine corneal permeability tests demonstrated that epalrestat released from the hydrogels can efficiently accumulate into the cornea in spite the concentrations provided on cornea surface were lower than those attained after instillation of concentrated eyedrops. Epalrestat-loaded hydrogels also demonstrated anti-cataract activity in an in vitro model of diabetic eye. Overall, silicone hydrogel CLs functionalized with bioinspired chemical groups represent a first attempt to design CLs adapted to the needs of diabetic eyes, acting as controlled release platforms of epalrestat, promoting drug accumulation and diffusion through cornea.
Asunto(s)
Complicaciones de la Diabetes/tratamiento farmacológico , Oftalmopatías/tratamiento farmacológico , Hidrogeles/administración & dosificación , Rodanina/análogos & derivados , Siliconas/administración & dosificación , Tiazolidinas/administración & dosificación , Acrilamidas/química , Animales , Bovinos , Lentes de Contacto , Córnea/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Hidrogeles/química , Metacrilatos/química , Soluciones Oftálmicas/administración & dosificación , Soluciones Oftálmicas/química , Permeabilidad , Rodanina/administración & dosificación , Rodanina/química , Siliconas/química , Tiazolidinas/químicaRESUMEN
Diabetic nephropathy (DN) is the leading cause of end stage renal disease worldwide. Increased glucose flux into the aldose reductase (AR) pathway during diabetes was reported to exert deleterious effects on the kidney. The objective of this study was to investigate the renoprotective effects of AR inhibition in high glucose milieu in vitro. Rat renal tubular (NRK-52E) cells were exposed to high glucose (30 mM) or normal glucose (5 mM) media for 24 to 48 hours with or without the AR inhibitor epalrestat (1 µM) and assessed for changes in Akt and ERK1/2 signaling, AR expression (using western blotting), and alterations in mitochondrial membrane potential (using JC-1 staining), cell viability (using MTT assay), and cell cycle. Exposure of NRK-52E cells to high glucose media caused acute activation of Akt and ERK pathways and depolarization of mitochondrial membrane at 24 hours. Prolonged high glucose exposure (for 48 hours) induced AR expression and G1 cell cycle arrest and decreased cell viability (84% compared to control) in NRK-52E cells. Coincubation of cells with epalrestat prevented the signaling changes and renal cell injury induced by high glucose. Thus, AR inhibition represents a potential therapeutic strategy to prevent DN.
Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Diabetes Mellitus Experimental/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Rodanina/análogos & derivados , Tiazolidinas/administración & dosificación , Aldehído Reductasa/metabolismo , Animales , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Inhibidores Enzimáticos/administración & dosificación , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Glucosa/administración & dosificación , Glucosa/metabolismo , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/enzimología , Túbulos Renales Proximales/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/biosíntesis , Ratas , Rodanina/administración & dosificaciónRESUMEN
Epalrestat is clinically applied for the management of diabetic peripheral neuropathy, yet its pharmacokinetic properties are not well understood. In this study, a rapid and sensitive LC-MS/MS method was established for assaying epalrestat in bio-samples of mice. The method was validated and it showed a good linearity over the range of 2-5000ng/mL, a precision of less than 12.3%, and recovery and matrix effects of 112.5-123.6% and 87.9-89.5%, respectively. After administration of a single dose of epalrestat administered, the exposure level of AUC0-∞ was positively dose-dependent and the mean Cmax, AUC0-12h, T1/2, and MRT were 36.23±7.39µg/mL, 29,086.5µg/Lh, 1.2h and 1.8h, respectively. Epalrestat was highly exposed in stomach, intestine, liver and kidney, and only a small amount was detected in brain, urine and feces. Multi-dose of epalrestat significantly increased MRT and apparent volume of distribution (Vd) relative to those of a single-dose.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Inhibidores Enzimáticos/farmacocinética , Rodanina/análogos & derivados , Tiazolidinas/farmacocinética , Administración Oral , Animales , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/sangre , Inhibidores Enzimáticos/orina , Femenino , Límite de Detección , Masculino , Ratones Endogámicos C57BL , Rodanina/administración & dosificación , Rodanina/sangre , Rodanina/farmacocinética , Rodanina/orina , Espectrometría de Masa por Ionización de Electrospray/métodos , Tiazolidinas/administración & dosificación , Tiazolidinas/sangre , Tiazolidinas/orina , Distribución TisularRESUMEN
PURPOSE: Aldose reductase (ALR), the first and rate-limiting enzyme involved in polyol pathway plays a central role in diabetes and its related complications, including diabetic retinopathy (DR). Inhibition of ALR may also be an ideal target for reducing the deleterious effects of DR. Therefore, the purpose of the present study was to investigate the protective effect of epalrestat (EPL), ALR inhibitor on glucose-induced toxicity in ARPE-19 cells. METHODS: ARPE-19 cells were challenged with normal glucose (NG, 5 mM) and high glucose (HG1, 25 mM and HG2, 50 mM) in the presence or absence of EPL. ALR and VEGF165 expression in retinal pigment epithelial (RPE) cells under experimental conditions were quantified by real-time polymerase chain reaction using SYBR Green chemistry. Vascular endothelial growth factor (VEGF) secretion in the cell supernatant was measured by Sandwich ELISA. Cytotoxicity of EPL was assessed by MTT assay. ALR inhibitory activity, apoptosis, and sorbitol accumulation were also investigated. RESULTS: EPL at studied concentration did not show any toxicity to RPE cells and showed as maximum as 65% ALR inhibition under high glucose condition (HG1). The presence of EPL significantly reduced ALR expression and VEGF levels as induced by high glucose in ARPE-19 cells. CONCLUSION: Inhibition of ALR appeared to be beneficial in reducing diabetes-related complications in RPE cells under high glucose condition.
Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Glucosa/antagonistas & inhibidores , Epitelio Pigmentado de la Retina/efectos de los fármacos , Rodanina/análogos & derivados , Tiazolidinas/farmacología , Aldehído Reductasa/genética , Aldehído Reductasa/metabolismo , Apoptosis/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Glucosa/toxicidad , Humanos , Epitelio Pigmentado de la Retina/patología , Rodanina/administración & dosificación , Rodanina/farmacología , Sorbitol/antagonistas & inhibidores , Sorbitol/metabolismo , Relación Estructura-Actividad , Tiazolidinas/administración & dosificación , Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Important targets for the prevention and treatment of diabetic complications include aldose reductase (AR) inhibitors (ARIs) and inhibitors of advanced glycation endproduct (AGE) formation. Here we evaluate the inhibitory activities of prenylated flavonoids isolated from Sophora flavescens, a traditional herbal medicine, on rat lens AR (RLAR), human recombinant AR (HRAR) and AGE formation. Among the tested compounds, two prenylated chalcones--desmethylanhydroicaritin (1) and 8-lavandulylkaempferol (2)--along with five prenylated flavanones--kurarinol (8), kurarinone (9), (2S)-2'-methoxykurarinone (10), (2S)-3beta,7,4'-trihydroxy-5-methoxy-8-(gamma,gamma-dimethylally)-flavanone (11), and kushenol E (13) were potent inhibitors of RLAR, with IC50 values of 0.95, 3.80, 2.13, 2.99, 3.77, 3.63 and 7.74 microM, respectively, compared with quercetin (IC50 7.73 microM). In the HRAR assay, most of the prenylated flavonoids tested showed marked inhibitory activity compared with quercetin (IC50 2.54 microM). In particular, all tested prenylated flavonols, such as desmethylanhydroicaritin (1, IC50 0.45 microM), 8-lavandulylkaempferol (2, IC50 0.79 microM) and kushenol C (3, IC50 0.85 microM), as well as a prenylated chalcone, kuraridin (5, IC50 0.27 microM), and a prenylated flavanone, (2S)-7,4'-dihydroxy-5-methoxy-8-(gamma,gamma-dimethylally)-flavanone (12, IC50 0.37 microM), showed significant inhibitory activities compared with the potent AR inhibitor epalrestat (IC50 0.28 microM). Interestingly, prenylated flavonoids 1 (IC50 104.3 microg mL(-1)), 2 (IC50 132.1 microg mL(-1)), 3 (IC50 84.6 microg mL(-1)) and 11 (IC50 261.0 microg mL(-1)), which harbour a 3-hydroxyl group, also possessed good inhibitory activity toward AGE formation compared with the positive control aminoguanidine (IC50 115.7 microg mL(-1)). Thus, S. flavescens and its prenylated flavonoids inhibit the processes that underlie diabetic complications and related diseases and may therefore have therapeutic benefit.
Asunto(s)
Aldehído Reductasa/efectos de los fármacos , Flavonoides/farmacología , Productos Finales de Glicación Avanzada/metabolismo , Sophora/química , Aldehído Reductasa/metabolismo , Animales , Chalconas/administración & dosificación , Chalconas/aislamiento & purificación , Chalconas/farmacología , Flavonas/administración & dosificación , Flavonas/aislamiento & purificación , Flavonas/farmacología , Flavonoides/administración & dosificación , Flavonoides/aislamiento & purificación , Guanidinas/administración & dosificación , Guanidinas/farmacología , Humanos , Concentración 50 Inhibidora , Medicina Tradicional , Extractos Vegetales/farmacología , Quercetina/administración & dosificación , Quercetina/farmacología , Ratas , Ratas Sprague-Dawley , Rodanina/administración & dosificación , Rodanina/análogos & derivados , Rodanina/farmacología , Tiazolidinas/administración & dosificación , Tiazolidinas/farmacologíaRESUMEN
AIMS: The long-term efficacy of epalrestat, an aldose reductase inhibitor, in improving subjective symptoms and nerve function was comprehensively assessed to identify patients with diabetic peripheral neuropathy who responded to epalrestat treatment. METHODS: Stratified analyses were conducted on data from patients in the Aldose Reductase Inhibitor-Diabetes Complications Trial (ADCT). The ADCT included patients with diabetic peripheral neuropathy, median motor nerve conduction velocity > or = 40 m/s and with glycated haemoglobin (HbA(1c)) < or = 9.0%. Longitudinal data on HbA(1c) and subjective symptoms of the patients for 3 years were analysed (epalrestat n = 231, control subjects n = 273). Stratified analyses based on background variables (glycaemic control, grades of retinopathy or proteinuria) were performed to examine the relationship between subjective symptoms and nerve function. Multiple logistic regression analyses were conducted. RESULTS: Stratified subgroup analyses revealed significantly better efficacy of epalrestat in patients with good glycaemic control and less severe diabetic complications. In the control group, no improvement in nerve function was seen regardless of whether symptomatic benefit was obtained. In the epalrestat group, nerve function deteriorated less or improved in patients whose symptoms improved. The odds ratio of the efficacy of epalrestat vs. control subjects was approximately 2 : 1 (4 : 1 in patients with HbA(1c) < or = 7.0%). CONCLUSION: Our results suggest that epalrestat, an aldose reductase inhibitor, will provide a clinically significant means of preventing and treating diabetic neuropathy if used in appropriate patients.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Neuropatías Diabéticas/tratamiento farmacológico , Inhibidores Enzimáticos/administración & dosificación , Rodanina/análogos & derivados , Tiazolidinas/administración & dosificación , Administración Oral , Anciano , Retinopatía Diabética/tratamiento farmacológico , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Cuidados a Largo Plazo , Masculino , Persona de Mediana Edad , Selección de Paciente , Proteinuria/etiología , Rodanina/administración & dosificación , Resultado del TratamientoRESUMEN
PURPOSE: Cardiac scintigraphic studies using 123I-labeled metaiodobenzylguanidine ([123I]MIBG) have demonstrated heterogeneous myocardial accumulation of MIBG in diabetes. The accumulation has been found to correlate with a heterogeneous decrease in the expression of norepinephrine transporter (NET). In diabetic peripheral nerve tissue, polyol pathways are activated and cause nerve dysfunction and degeneration. However, there has been little research on the polyol pathway and cardiac sympathetic nerves. Therefore, to assess the influence of the polyol pathway on cardiac sympathetic nervous function, we investigated the regional accumulation of MIBG and NET protein expression in diabetic model rats treated with aldose reductase inhibitor (ARI) for the blockade of polyol pathways. METHODS: Rats were given a single intravenous injection of streptozotocin (n=76, STZ-D rats). Starting the day after STZ injection, ARI was administered daily to 42 of the rats for 4 weeks (ARI-D rats). To assess the cardiac sympathetic nervous function, [125I]MIBG autoradiographic experiments were carried out. Finally, NET protein expression was assessed with a saturation binding assay. RESULTS: The myocardial sorbitol concentration was significantly higher in STZ-D rats than in ARI-D rats. There was no heterogeneous accumulation of MIBG in ARI-D rats. There was a heterogeneous decrease of NET expression in STZ-D rats, but not in ARI-D or control rats. CONCLUSION: The gathered data indicate that the enhanced polyol pathway correlates with the decrease in regional cardiac sympathetic nervous function, and this impairment may lead to the reduction of NET protein in cardiac sympathetic nerves of the diabetic inferior wall.
Asunto(s)
3-Yodobencilguanidina/farmacocinética , Diabetes Mellitus Experimental/metabolismo , Corazón/inervación , Miocardio/metabolismo , Polímeros/metabolismo , Sistema Nervioso Simpático/metabolismo , Aldehído Reductasa/antagonistas & inhibidores , Animales , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/diagnóstico por imagen , Corazón/diagnóstico por imagen , Corazón/efectos de los fármacos , Masculino , Tasa de Depuración Metabólica , Cintigrafía , Radiofármacos/farmacocinética , Ratas , Ratas Sprague-Dawley , Rodanina/administración & dosificación , Rodanina/análogos & derivados , Transducción de Señal/efectos de los fármacos , Sorbitol/metabolismo , Estreptozocina , Sistema Nervioso Simpático/diagnóstico por imagen , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
PURPOSE: Cardiac scintigraphic studies using (123)I-labeled metaiodobenzylguanidine ([(123)I]MIBG) have demonstrated heterogeneous myocardial accumulation of MIBG in diabetes. The accumulation has been found to correlate with a heterogeneous decrease in the expression of norepinephrine transporter (NET). In diabetic peripheral nerve tissue, polyol pathways are activated and cause nerve dysfunction and degeneration. However, there has been little research on the polyol pathway and cardiac sympathetic nerves. Therefore, to assess the influence of the polyol pathway on cardiac sympathetic nervous function, we investigated the regional accumulation of MIBG and NET protein expression in diabetic model rats treated with aldose reductase inhibitor (ARI) for the blockade of polyol pathways. METHODS: Rats were given a single intravenous injection of streptozotocin (n=76, STZ-D rats). Starting the day after STZ injection, ARI was administered daily to 42 of the rats for 4 weeks (ARI-D rats). To assess the cardiac sympathetic nervous function, [(125)I]MIBG autoradiographic experiments were carried out. Finally, NET protein expression was assessed with a saturation binding assay. RESULTS: The myocardial sorbitol concentration was significantly higher in STZ-D rats than in ARI-D rats. There was no heterogeneous accumulation of MIBG in ARI-D rats. There was a heterogeneous decrease of NET expression in STZ-D rats, but not in ARI-D or control rats. CONCLUSION: The gathered data indicate that the enhanced polyol pathway correlates with the decrease in regional cardiac sympathetic nervous function, and this impairment may lead to the reduction of NET protein in cardiac sympathetic nerves of the diabetic inferior wall.
Asunto(s)
3-Yodobencilguanidina/farmacocinética , Diabetes Mellitus Experimental/metabolismo , Corazón/inervación , Miocardio/metabolismo , Polímeros/metabolismo , Rodanina/análogos & derivados , Sistema Nervioso Simpático/metabolismo , Simportadores/metabolismo , Aldehído Reductasa/antagonistas & inhibidores , Animales , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/diagnóstico por imagen , Corazón/diagnóstico por imagen , Corazón/efectos de los fármacos , Masculino , Tasa de Depuración Metabólica , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática , Cintigrafía , Ratas , Ratas Sprague-Dawley , Rodanina/administración & dosificación , Transducción de Señal/efectos de los fármacos , Sorbitol/metabolismo , Estreptozocina , Sistema Nervioso Simpático/diagnóstico por imagen , Sistema Nervioso Simpático/efectos de los fármacos , TiazolidinasRESUMEN
AIM: While the mechanism in the pathogenesis of diabetic corneal disease is unclear, aldose reductase has been implicated in corneal disease. The effects of an oral aldose reductase inhibitor (ARI) on the ocular surface of diabetic patients after cataract surgery were studied. METHODS: This clinical trial was designed to be randomised, double blinded, and placebo controlled. Pseudophakic patients with diabetes were randomly assigned to treatment with either oral ARI (ONO-2235) (n=12) or placebo (n=9) for 12 weeks. The vital staining of the ocular surface, tear production and clearance, break up time in tears (BUT), corneal and conjunctival sensation, and symptom score before treatments were examined as well as 4, 8, 12 weeks after the administration. Specular microscopic evaluation was also performed. RESULTS: After a 12 week period of oral ARI administration, fluorescein staining scores (from 2.04 (SD 1.12) to 1.46 (1.18); p=0.016), conjunctival sensation (from 1.15 (0.37) to 1.36 (0.31); p=0.0006), and symptom scores (from 5.38 (1.932) to 4.00 (2.07); p=0.0002) recovered significantly. Fluorescein staining of oral ARI administration also decreased compared with placebo (p=0.017). Rose bengal staining, tear clearance, and corneal sensation were improved although this increase was minor. Tear production, BUT, and specular microscopic evaluation of the corneal epithelium and endothelium did not demonstrate a significant change. CONCLUSION: Oral ARI opposes the ocular surface changes caused by diabetes, by recovery of ocular surface sensitivity as demonstrated through an improvement in vital staining.
Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Extracción de Catarata , Diabetes Mellitus/tratamiento farmacológico , Inhibidores Enzimáticos/administración & dosificación , Epitelio Corneal/efectos de los fármacos , Rodanina/administración & dosificación , Administración Oral , Anciano , Conjuntiva/fisiopatología , Diabetes Mellitus/patología , Método Doble Ciego , Epitelio Corneal/patología , Epitelio Corneal/fisiopatología , Femenino , Fluoresceína , Colorantes Fluorescentes , Humanos , Masculino , Microscopía Fluorescente , Periodo Posoperatorio , Rodanina/análogos & derivados , Rosa Bengala , Sensación , Lágrimas/metabolismo , TiazolidinasRESUMEN
We investigated the effect of inhibition of a polyol pathway on the glucose-induced increase in transforming growth factor-beta (TGF-beta) production and activity of protein kinase C (PKC) in cultured human mesangial cells (MCs). The exposure of MCs to 33 mmol/l glucose resulted in an increase in TGFbeta production, measured by ELISA, compared with 5 mmol/l glucose. The glucose-induced increase in TGF-beta was prevented by concomitant incubation with epalrestat, an aldose reductase inhibitor (ARI), in a dose-dependent manner at a concentration of more than 10(-6) mol/l. Moreover, the glucose-induced enhancement of PKC activity in the membrane fraction of MCs was also abolished by epalrestat. The addition of epalrestat to MCs cultured with 5 mmol/l glucose showed no demonstrable effects on TGF-beta production and PKC activity. These results provide direct evidence for linkages between derangements in polyol pathway and glucose-induced overproduction of TGF-beta and enhancement of PKC activity in MCs. Accordingly, the effect of an ARI on these metabolic abnormalities in MCs may justify its clinical application for treatment of diabetic nephropathy.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Mesangio Glomerular/efectos de los fármacos , Mesangio Glomerular/enzimología , Proteína Quinasa C/efectos de los fármacos , Proteína Quinasa C/metabolismo , Factor de Crecimiento Transformador beta/efectos de los fármacos , Aldehído Reductasa/antagonistas & inhibidores , Células Cultivadas , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Mesangio Glomerular/citología , Glucosa/administración & dosificación , Glucosa/farmacología , Humanos , Rodanina/administración & dosificación , Rodanina/análogos & derivados , Rodanina/farmacología , Tiazolidinas , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
This study was conducted to evaluate effects of the aldose reductase inhibitor ONO-2235 on the contractile response to acetylcholine of the urinary bladder dome of streptozotocin-induced diabetes mellitus (DM) rats and simultaneously observe the changes in the function and number of muscarinic receptors and the sorbitol content of the bladder. The contractile response to acetylcholine increased 51% in the DM rat bladder dome compared to the normal rats; however, this was attenuated to a 10% increase by administration of 100 mg/kg ONO-2235 for 2 weeks. Treatment with ONO-2235 significantly decreased the specific [3H]quinuclidinyl benzilate binding in DM rats. However there was no significant dose-dependency among the ONO-2235-treated groups. The sorbitol levels of the sciatic nerve and the bladder were higher in the DM rats compared to the control rats; ONO-2235 decreased the level, although it did not completely reverse them to the control level. These results suggest that an aldose reductase inhibitor attenuates the increase of the muscarinic receptor number and normalizes the enhanced contractile response to acetylcholine caused by hyperglycemia and diuresis, probably through suppression of the polyol-pathway in the DM rat bladder dome.
Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Diabetes Mellitus Experimental/fisiopatología , Inhibidores Enzimáticos/farmacología , Músculo Liso/efectos de los fármacos , Receptores Muscarínicos/efectos de los fármacos , Rodanina/análogos & derivados , Vejiga Urinaria/efectos de los fármacos , Acetilcolina/farmacología , Análisis de Varianza , Animales , Unión Competitiva , Glucemia/análisis , Glucemia/efectos de los fármacos , Diuresis , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Hiperglucemia/fisiopatología , Masculino , Contracción Muscular/efectos de los fármacos , Ratas , Ratas Wistar , Receptores Muscarínicos/metabolismo , Rodanina/administración & dosificación , Rodanina/farmacología , Nervio Ciático/efectos de los fármacos , Nervio Ciático/metabolismo , Sorbitol/metabolismo , Tiazolidinas , Conservación de Tejido , Vejiga Urinaria/enzimologíaRESUMEN
The present study was conducted in order to determine whether an aldose reductase inhibitor (ARI), epalrestat, prevents the progression of diabetic nephropathy in rats. Rats were made diabetic by intravenous injection of streptozotocin (STZ 50 mg/kg) and epalrestat (100 mg/kg) was administered orally through a gastric tube once daily for 4 weeks. Examination by electron microscope revealed that the number of anionic sites (AS) in the lamina rara externa per 1000 nm of glomerular basement membrane (GBM) was significantly decreased in diabetic rats compared to control values (17.6 + or - 0.4 vs. 21.9 + or -0.4, P < 0.01), whereas, significant recovery (20.3 + or - 0.7, P < 0.05) was observed after 4 weeks of epalrestat treatment. Urinary albumin excretion (UAE) rate was markedly increased in diabetic rats and the treatment resulted in its significant suppression from diabetic rats. In conclusion, administration of epalrestat to diabetic rats is capable of preventing a reduction in the number of AS in GBM which would ameliorate an increased permeability of the basement membrane leading to albuminuria.