RESUMO
To rigorously explore the role of omega-3 polyunsaturated fatty acids (PUFA) in the treatment of diabetic peripheral neuropathy (DPN), we have created a transgenic mouse utilizing a Cre-lox promoter to control overexpression of human 15-lipoxygenase-1 (15-LOX-1). In this study, we sought to determine the effect of treating type 2 diabetic wild-type mice and transgenic mice ubiquitously overexpressing 15-LOX-1 with menhaden oil on endpoints related to DPN. Wild-type and transgenic mice on a C57Bl/6J background were divided into three groups. Two of each of these groups were used to create a high-fat diet/streptozotocin model for type 2 diabetes. The remaining mice were control groups. Four weeks later, one set of diabetic mice from each group was treated with menhaden oil for twelve weeks and then evaluated using DPN-related endpoints. Studies were also performed using dorsal root ganglion neurons isolated from wild-type and transgenic mice. Wild-type and transgenic diabetic mice developed DPN as determined by slowing of nerve conduction velocity, decreased sensory nerve fibers in the skin and cornea, and impairment of thermal and mechanical sensitivity of the hindpaw compared to their respective control mice. Although not significant, there was a trend for the severity of these DPN-related deficits to be less in the diabetic transgenic mice compared to the diabetic wild-type mice. Treating diabetic wild-type and transgenic mice with menhaden oil improved the DPN-related endpoints with a trend for greater improvement or protection by menhaden oil observed in the diabetic transgenic mice. Treating dorsal root ganglion neurons with docosahexanoic acid but not eicosapentaenoic acid significantly increased neurite outgrowth with greater efficacy observed with neurons isolated from transgenic mice. Targeting pathways that will increase the production of the anti-inflammatory metabolites of omega-3 PUFA may be an efficacious approach to developing an effective treatment for DPN.
Assuntos
Araquidonato 15-Lipoxigenase/fisiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Óleos de Peixe/uso terapêutico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Animais , Araquidonato 15-Lipoxigenase/genética , Diabetes Mellitus Tipo 2/complicações , Neuropatias Diabéticas/etiologia , Ácidos Docosa-Hexaenoicos/sangue , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doenças do Sistema Nervoso Periférico/etiologiaRESUMO
OBJECTIVE: The lack of effective treatments against diabetic sensorimotor polyneuropathy demands the search for new strategies to combat or prevent the condition. Because reduced magnesium and increased methylglyoxal levels have been implicated in the development of both type 2 diabetes and neuropathic pain, we aimed to assess the putative interplay of both molecules with diabetic sensorimotor polyneuropathy. METHODS: In a cross-sectional study, serum magnesium and plasma methylglyoxal levels were measured in recently diagnosed type 2 diabetes patients with (n = 51) and without (n = 184) diabetic sensorimotor polyneuropathy from the German Diabetes Study baseline cohort. Peripheral nerve function was assessed using nerve conduction velocity and quantitative sensory testing. Human neuroblastoma cells (SH-SY5Y) and mouse dorsal root ganglia cells were used to characterize the neurotoxic effect of methylglyoxal and/or neuroprotective effect of magnesium. RESULTS: Here, we demonstrate that serum magnesium concentration was reduced in recently diagnosed type 2 diabetes patients with diabetic sensorimotor polyneuropathy and inversely associated with plasma methylglyoxal concentration. Magnesium, methylglyoxal, and, importantly, their interaction were strongly interrelated with methylglyoxal-dependent nerve dysfunction and were predictive of changes in nerve function. Magnesium supplementation prevented methylglyoxal neurotoxicity in differentiated SH-SY5Y neuron-like cells due to reduction of intracellular methylglyoxal formation, while supplementation with the divalent cations zinc and manganese had no effect on methylglyoxal neurotoxicity. Furthermore, the downregulation of mitochondrial activity in mouse dorsal root ganglia cells and consequently the enrichment of triosephosphates, the primary source of methylglyoxal, resulted in neurite degeneration, which was completely prevented through magnesium supplementation. CONCLUSIONS: These multifaceted findings reveal a novel putative pathophysiological pathway of hypomagnesemia-induced carbonyl stress leading to neuronal damage and merit further investigations not only for diabetic sensorimotor polyneuropathy but also other neurodegenerative diseases associated with magnesium deficiency and impaired energy metabolism.
Assuntos
Magnésio/metabolismo , Polineuropatias/metabolismo , Aldeído Pirúvico/metabolismo , Animais , Estudos Transversais , Diabetes Mellitus/metabolismo , Neuropatias Diabéticas/etiologia , Metabolismo Energético , Feminino , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Neurônios/metabolismo , Polineuropatias/fisiopatologia , Córtex Sensório-Motor/metabolismoRESUMO
PURPOSE: To determine whether cornea nerve fiber density and/or corneal function are valid markers for early detection and treatment of peripheral neuropathy in rats modeling prediabetes and type 2 diabetes. METHODS: High-fat feeding combined without or with low-dose streptozotocin was used to create rat models for prediabetes and type 2 diabetes that were longitudinally studied for loss of structure and function of sensory nerves in the cornea and skin as well as nerve conduction velocity and vascular reactivity of epineurial arterioles. There were three time points examined in each of the three conditions with 12 rats per group. The latest time point (24 weeks of high-fat diet with or without 16 weeks of hyperglycemia) was used to examine reversibility of neuro and vascular pathology following 16 weeks of treatment with menhaden oil, a natural source of long-chain omega-3 polyunsaturated fatty acids. The number of rats in the intervention study ranged from 6 to 17. RESULTS: Our longitudinal study demonstrated that vascular and neural dysfunction associated with obesity or type 2 diabetes occur early and are progressive. Decrease in cornea nerve fiber length and function were valid markers of disease in both the pre-diabetic and diabetic rat models and were more sensitive than decrease in intraepidermal nerve fiber density of the skin and thermal nociception of the hindpaw. Late intervention with menhaden oil significantly reversed both vascular and peripheral nerve damage induced by chronic obesity or type 2 diabetes. CONCLUSION: These studies provide support for examination of corneal structure and function as an early marker of peripheral neuropathy in prediabetes and type 2 diabetes. Furthermore, we demonstrate that omega-3 polyunsaturated fatty acids derived from fish oil are an effective treatment for peripheral neuropathy that occurs with chronic obesity or type 2 diabetes.
RESUMO
We tested whether dietary fatty acids alter membrane composition shifting localization of signaling pathways within caveolae to determine their role in vascular function. Wild type (WT) and caveolin-1-deficient mice (cav-1 KO), required for vascular caveolae formation, were fed low fat (LF), high saturated fat (HF, 60% kcal from lard), or high-fat diet with 50:50 lard and n-3 polyunsaturated fatty acid-enriched menhaden oil (MO). HF and MO increased body weight and fat in WT but had less effect in cav-1 KO. MO increased unsaturated fatty acids and the unsaturation index of aorta from WT and cav-1 KO. In LF WT aorta, endothelial nitric oxide synthase (eNOS) was localized to cav-1-enriched low-density fractions which shifted to actin-enriched high-density fractions with acetylcholine (ACh). HF and MO shifted eNOS to high-density fractions in WT aorta which was not affected by ACh. In cav-1 KO aorta, eNOS was localized in low-density non-caveolar fractions but not shifted by ACh or diet. Inducible NOS and cyclooxygenase 1/2 were not localized in low-density fractions or affected by diet, ACh or genotype. ACh-induced dilation of gracilis arteries from HF WT was similar to dilation in LF but the NOS component was reduced. In WT and cav-1 KO, dilation to ACh was enhanced by MO through increased role for NOS and cyclooxygenase. We conclude that dietary fats affect vascular fatty acid composition and membrane localization of eNOS but the contribution of eNOS and cyclooxygenase in ACh-mediated vascular responses is independent of lipid rafts.
Assuntos
Cavéolas/metabolismo , Gorduras na Dieta/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Obesidade/metabolismo , Acetilcolina/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Glicemia/metabolismo , Composição Corporal/efeitos dos fármacos , Composição Corporal/fisiologia , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Caveolina 1/deficiência , Caveolina 1/fisiologia , Dieta Hiperlipídica , Gorduras na Dieta/administração & dosagem , Ácidos Graxos/metabolismo , Óleos de Peixe/farmacologia , Músculo Grácil/irrigação sanguínea , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/fisiopatologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
PURPOSE OF REVIEW: This review will summarize recent findings of the effect of supplemental fatty acids, with an emphasis on omega-3 polyunsaturated fatty acids, as a treatment for diabetic peripheral neuropathy. RECENT FINDINGS: Pre-clinical studies have provided evidence that treating diabetic rodents with δ linolenic acid (omega-6 18:3) and to a greater extent with eicosapentaenoic and docosahexaenoic acids (omega-3 20:5 and 22:6, respectively) improve and even reverse vascular and neural deficits. Additional studies have shown resolvins, metabolites of eicosapentaenoic and docosahexaenoic acids, can induce neurite outgrowth in neuron cultures and that treating type 1 or type 2 diabetic mice with resolvin D1 or E1 provides benefit for peripheral neuropathy similar to fish oil. Omega-3 polyunsaturated fatty acids derived from fish oil and their derivatives have anti-inflammatory properties and could provide benefit for diabetic peripheral neuropathy. However, clinical trials are needed to determine whether this statement is true.
Assuntos
Neuropatias Diabéticas/tratamento farmacológico , Ácidos Graxos/uso terapêutico , Animais , Dieta , Ácidos Graxos/química , Óleos de Peixe/uso terapêutico , HumanosRESUMO
PURPOSE: This study investigated the efficacy of monotherapy versus combination of menhaden oil, α-lipoic acid, and enalapril on corneal sensation and morphometry and other neuropathy-related endpoints in a rat model of type 2 diabetes. METHODS: Male Sprague-Dawley rats (aged 12 weeks) were fed a high-fat diet for 8 weeks followed by 30 mg/kg streptozotocin. After 16 weeks of hyperglycemia, 12-week treatments consisting of menhaden oil, α-lipoic acid, enalapril, or their combination were initiated. Before and after treatments, we performed analyses of multiple neural and vascular endpoints including corneal sensitivity, corneal nerve density, vascular reactivity of epineurial arterioles, motor and sensory nerve conduction velocity, intraepidermal nerve fiber density, and thermal nociception. RESULTS: Before treatment, all the neural and vascular endpoints in diabetic rats were impaired. Treating diabetic rats with monotherapy was effective in improving neural and vascular deficits with menhaden oil being most efficacious. However, the combination therapy provided the greatest benefit and improved/reversed all nerve and vascular deficits. The effect of combination therapy on corneal relative sensitivity and structure (in mm/mm), primary endpoints for this study, for control, diabetic, and diabetic treated rats was 4.2 ± 1.4 and 7.5 ± 0.5, 12.1 ± 1.3* and 3.8 ± 0.2*, and 6.6 ± 2.3 and 7.3 ± 0.5, respectively (*P < 0.05 compared with control rats; P < 0.05 compared with diabetic rats). CONCLUSIONS: These studies suggest that a combination therapeutic approach may be most effective for treating vascular and neural complications of type 2 diabetes.
Assuntos
Córnea/inervação , Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/fisiopatologia , Dieta Hiperlipídica , Enalapril/administração & dosagem , Óleos de Peixe/administração & dosagem , Hipestesia/fisiopatologia , Ácido Tióctico/administração & dosagem , Adiponectina/metabolismo , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Quimioterapia Combinada , Lipídeos/sangue , Masculino , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Sprague-Dawley , Estreptozocina , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Doenças do Nervo Trigêmeo/fisiopatologiaRESUMO
Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD(+) metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP(+) and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/prevenção & controle , Hipoglicemiantes/farmacologia , Niacinamida/análogos & derivados , Obesidade/tratamento farmacológico , Estado Pré-Diabético/tratamento farmacológico , Animais , Glicemia/metabolismo , Córnea/efeitos dos fármacos , Córnea/inervação , Córnea/patologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/patologia , Dieta Hiperlipídica , Insulina/sangue , Resistência à Insulina , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Niacinamida/farmacologia , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Estado Pré-Diabético/etiologia , Estado Pré-Diabético/metabolismo , Estado Pré-Diabético/patologia , Compostos de Piridínio , EstreptozocinaRESUMO
We examined whether reversal of high fat diet, stimulating weight loss, compared to two treatments previously shown to have beneficial effects, could improve glucose utilization and peripheral neuropathy in animal models of obesity and type 2 diabetes. Rats were fed a high fat diet and treated with a low dose of streptozotocin to create models of diet induced obesity or type 2 diabetes, respectively. Afterwards, rats were transferred to a normal diet or treated with enalapril or dietary enrichment with menhaden oil for 12 weeks. Obesity and to a greater extent type 2 diabetes were associated with impaired glucose utilization and peripheral neuropathy. Placing obese rats on a normal diet improved glucose utilization. Steatosis but not peripheral neuropathy was improved after placing obese or diabetic rats on a normal diet. Treating obese and diabetic rats with enalapril or a menhaden oil enriched diet generally improved peripheral neuropathy endpoints. In summary, dietary improvement with weight loss in obese or type 2 diabetic rats was not sufficient to correct peripheral neuropathy. These results further stress the need for discovery of a comprehensive treatment for peripheral neuropathy.
Assuntos
Fármacos Antiobesidade/uso terapêutico , Diabetes Mellitus Tipo 2/etiologia , Neuropatias Diabéticas/prevenção & controle , Dieta com Restrição de Gorduras , Suplementos Nutricionais , Modelos Animais de Doenças , Obesidade/etiologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Biomarcadores/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Neuropatias Diabéticas/complicações , Dieta Hiperlipídica/efeitos adversos , Enalapril/uso terapêutico , Óleos de Peixe/uso terapêutico , Hipoglicemiantes/uso terapêutico , Masculino , Neuralgia/complicações , Neuralgia/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/complicações , Obesidade/complicações , Obesidade/dietoterapia , Obesidade/tratamento farmacológico , Ratos Sprague-Dawley , Estreptozocina/toxicidade , Redução de Peso/efeitos dos fármacosRESUMO
We have previously demonstrated that treating diabetic rats with enalapril, an angiotensin converting enzyme (ACE) inhibitor, α-lipoic acid, an antioxidant, or menhaden oil, a natural source of omega-3 fatty acids can partially improve diabetic peripheral neuropathy. In this study we sought to determine the efficacy of combining these three treatments on vascular and neural complications in a high fat fed low dose streptozotocin treated rat, a model of type 2 diabetes. Rats were fed a high fat diet for 8 weeks followed by a 30 mg/kg dose of streptozotocin. Eight weeks after the onset of hyperglycemia diabetic rats were treated with a combination of enalapril, α-lipoic acid and menhaden oil. Diabetic rats not receiving treatment were continued on the high fat diet. Glucose clearance was impaired in diabetic rats and significantly improved with treatment. Diabetes caused steatosis, elevated serum lipid levels, slowing of motor and sensory nerve conduction, thermal hypoalgesia, reduction in intraepidermal nerve fiber profiles, decrease in cornea sub-basal nerve fiber length and corneal sensitivity and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide in epineurial arterioles of the sciatic nerve. Treating diabetic rats with the combination of enalapril, α-lipoic acid and menhaden oil reversed all these deficits to near control levels except for motor nerve conduction velocity which was also significantly improved compared to diabetic rats but remained significantly decreased compared to control rats. These studies suggest that a combination therapeutic approach may be most effective for treating vascular and neural complications of type 2 diabetes.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Enalapril/uso terapêutico , Óleos de Peixe/uso terapêutico , Ácido Tióctico/uso terapêutico , Animais , Córnea/inervação , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Neuropatias Diabéticas/etiologia , Dieta Hiperlipídica/efeitos adversos , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Enalapril/administração & dosagem , Óleos de Peixe/administração & dosagem , Teste de Tolerância a Glucose , Masculino , Condução Nervosa/efeitos dos fármacos , Ratos Sprague-Dawley , Nervo Isquiático/irrigação sanguínea , Estreptozocina/administração & dosagem , Ácido Tióctico/administração & dosagem , Vasodilatação/efeitos dos fármacosRESUMO
The purpose of this study was to determine the effect of supplementing the diet of a mouse model of type 2 diabetes with menhaden (fish) oil or daily treatment with resolvin D1 on diabetic neuropathy. The end points evaluated included motor and sensory nerve conduction velocity, thermal sensitivity, innervation of sensory nerves in the cornea and skin, and the retinal ganglion cell complex thickness. Menhaden oil is a natural source for n-3 polyunsaturated fatty acids, which have been shown to have beneficial effects in other diseases. Resolvin D1 is a metabolite of docosahexaenoic acid and is known to have anti-inflammatory and neuroprotective properties. To model type 2 diabetes, mice were fed a high-fat diet for 8 wk followed by a low dosage of streptozotocin. After 8 wk of hyperglycemia, mice in experimental groups were treated for 6 wk with menhaden oil in the diet or daily injections of 1 ng/g body wt resolvin D1. Our findings show that menhaden oil or resolvin D1 did not improve elevated blood glucose, HbA1C, or glucose utilization. Untreated diabetic mice were thermal hypoalgesic, had reduced motor and sensory nerve conduction velocities, had decreased innervation of the cornea and skin, and had thinner retinal ganglion cell complex. These end points were significantly improved with menhaden oil or resolvin D1 treatment. Exogenously, resolvin D1 stimulated neurite outgrowth from primary cultures of dorsal root ganglion neurons from normal mice. These studies suggest that n-3 polyunsaturated fatty acids derived from fish oil could be an effective treatment for diabetic neuropathy.
Assuntos
Anti-Inflamatórios/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Neuropatias Diabéticas/dietoterapia , Neuropatias Diabéticas/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/farmacologia , Óleos de Peixe/administração & dosagem , Animais , Células Cultivadas , Córnea/inervação , Córnea/patologia , Diabetes Mellitus Experimental/dietoterapia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2 , Neuropatias Diabéticas/patologia , Neuropatias Diabéticas/fisiopatologia , Dieta Hiperlipídica , Suplementos Nutricionais , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/fisiologia , Temperatura Alta , Hiperalgesia/dietoterapia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Camundongos Endogâmicos C57BL , Condução Nervosa/fisiologia , Neuritos/efeitos dos fármacos , Neuritos/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/fisiologia , Fármacos Neuroprotetores/farmacologia , Células Ganglionares da Retina/patologia , Pele/inervação , Pele/patologiaRESUMO
The purpose of this study was to determine the effect of supplementing the diet of type 1 diabetic rats with menhaden oil on diabetic neuropathy. Menhaden oil is a natural source for n-3 fatty acids, which have been shown to have beneficial effects in cardiovascular disease and other morbidities. Streptozotocin-induced diabetic rats were used to examine the influence of supplementing their diet with 25% menhaden oil on diabetic neuropathy. Both prevention and intervention protocols were used. Endpoints included motor and sensory nerve conduction velocity, thermal and mechanical sensitivity, and innervation and sensitivity of the cornea and hindpaw. Diabetic neuropathy as evaluated by the stated endpoints was found to be progressive. Menhaden oil did not improve elevated HbA1C levels or serum lipid levels. Diabetic rats at 16-wk duration were thermal hypoalgesic and had reduced motor and sensory nerve conduction velocities, and innervation and sensitivity of the cornea and skin were impaired. These endpoints were significantly improved with menhaden oil treatment following the prevention or intervention protocol. We found that supplementing the diet of type 1 diabetic rats with menhaden oil improved a variety of endpoints associated with diabetic neuropathy. These results suggest that enriching the diet with n-3 fatty acids may be a good treatment strategy for diabetic neuropathy.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Suplementos Nutricionais , Óleos de Peixe/uso terapêutico , Hipestesia/tratamento farmacológico , Animais , Diabetes Mellitus Experimental/complicações , Óleos de Peixe/administração & dosagem , Óleos de Peixe/farmacologia , Hemoglobinas Glicadas/metabolismo , Temperatura Alta , Lipídeos/sangue , Masculino , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/fisiopatologia , Ratos , Ratos Sprague-Dawley , TatoRESUMO
We previously showed that peripheral neuropathy of the bone marrow was associated with loss of circadian rhythmicity of stem/progenitor cell release into the circulation. Bone marrow neuropathy results in dramatic changes in hematopoiesis that lead to microvascular complications, inflammation, and reduced endothelial repair. This series of events represents early pathogenesis before development of diabetic retinopathy. In this study we characterized early alterations within the bone marrow of streptozotocin (STZ)-induced diabetic rats following treatments that prevent experimental peripheral neuropathy. We asked whether bone marrow neuropathy and the associated bone marrow pathology were reversed with treatments that prevent peripheral neuropathy. Three strategies were tested: inhibition of neutral endopeptidase, inhibition of aldose reductase plus lipoic acid supplementation, and insulin therapy with antioxidants. All strategies prevented loss of nerve conduction velocity resulting from STZ-induced diabetes and corrected the STZ-induced diabetes-associated increase of immunoreactivity of neuropeptide Y, tyrosine hydroxylase, and somatostatin. The treatments also reduced concentrations of interleukin-1ß, granulocyte colony-stimulating factor, and matrix metalloproteinase 2 in STZ-induced diabetic bone marrow supernatant and decreased the expression of NADPH oxidase 2, nitric oxide synthase 2, and nuclear factor-κB1 mRNA in bone marrow progenitor cells. These therapies represent novel approaches to attenuate the diabetic phenotype within the bone marrow and may constitute an important therapeutic strategy for diabetic microvascular complications.
Assuntos
Medula Óssea/patologia , Diabetes Mellitus Experimental/terapia , Neuropatias Diabéticas/prevenção & controle , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Hipoglicemiantes/uso terapêutico , Inflamação/prevenção & controle , Tecido Adiposo/fisiologia , Animais , Citocinas/genética , Citocinas/metabolismo , Óleos de Peixe/administração & dosagem , Óleos de Peixe/uso terapêutico , Regulação da Expressão Gênica , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Hipoglicemiantes/administração & dosagem , Imidazolidinas/uso terapêutico , Insulina/administração & dosagem , Insulina/uso terapêutico , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , NADPH Oxidase 2 , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Neuropeptídeo Y , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Medição da Dor , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Somatostatina , Células-Tronco , Estreptozocina , Ácido Tióctico/uso terapêutico , Tirosina 3-Mono-OxigenaseRESUMO
Mitochondrial-targeted analogs of coenzyme Q (CoQ) are under development to reduce oxidative damage induced by a variety of disease states. However, there is a need to understand the bioenergetic effects of these agents and whether or not these effects are related to redox properties, including their known pro-oxidant effects. We examined the bioenergetic effects of two mitochondrial-targeted CoQ analogs in their quinol forms, mitoquinol (MitoQ) and plastoquinonyl-decyl-triphenylphosphonium (SkQ1), in bovine aortic endothelial cells. We used an extracellular oxygen and proton flux analyzer to assess mitochondrial action at the intact-cell level. Both agents, in dose-dependent fashion, reduced the oxygen consumption rate (OCR) directed at ATP turnover (OCR(ATP)) (IC50 values of 189 ± 13 nM for MitoQ and 181 ± 7 for SKQ1; difference not significant) while not affecting or mildly increasing basal oxygen consumption. Both compounds increased extracellular acidification in the basal state consistent with enhanced glycolysis. Both compounds enhanced mitochondrial superoxide production assessed by using mitochondrial-targeted dihydroethidium, and both increased H2O2 production from mitochondria of cells treated before isolation of the organelles. The manganese superoxide dismutase mimetic manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin did not alter or actually enhanced the actions of the targeted CoQ analogs to reduce OCR(ATP). In contrast, N-acetylcysteine mitigated this effect of MitoQ and SkQ1. In summary, our data demonstrate the important bioenergetic effects of targeted CoQ analogs. Moreover, these effects are mediated, at least in part, through superoxide production but depend on conversion to H2O2. These bioenergetic and redox actions need to be considered as these compounds are developed for therapeutic purposes.
Assuntos
Células Endoteliais/fisiologia , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Ubiquinona/análogos & derivados , Ubiquinona/metabolismo , Acetilcisteína/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/fisiologia , Bovinos , Respiração Celular/efeitos dos fármacos , Respiração Celular/fisiologia , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Metabolismo Energético/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Glicólise/fisiologia , Peróxido de Hidrogênio/metabolismo , Metaloporfirinas/farmacologia , Mitocôndrias/efeitos dos fármacos , Oniocompostos/farmacologia , Compostos Organofosforados/farmacologia , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Consumo de Oxigênio/efeitos dos fármacos , Consumo de Oxigênio/fisiologia , Plastoquinona/análogos & derivados , Plastoquinona/farmacologia , Prótons , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo , Compostos de Tritil/farmacologia , Ubiquinona/farmacologiaRESUMO
Diabetic neuropathy is a debilitating disorder that occurs in more than 50 percent of patients with diabetes. Evidence suggests that there are at least five major pathways involved in the development of diabetic neuropathy: metabolic, vascular, immunologic, neurohormonal growth factor deficiency, and extracellular matrix remodeling. In light of the complicated etiologies, an effective treatment for diabetic neuropathy has not yet been identified. Hyperglycemia increases tissue angiotensin II, which induces oxidative stress, endothelial damage and other pathologies including vasoconstriction, thrombosis, inflammation and vascular remodeling. Angiotensin converting enzyme inhibition and/or blocking of the angiotensin II receptor are recognized as first line treatment for nephropathy and cardiovascular disease in diabetes patients. A new class of drug in late stages of development is vasopeptidase inhibitors. This drug inhibits both angiotensin converting enzyme activity and neutral endopeptidase. Neutral endopeptidase is a protease that degrades a number of biologically active peptides including vasoactive peptides. However, little information is available about the potential benefits of these drugs on diabetic neuropathy. Pre-clinical studies suggest that these drugs may be useful in treating diabetic complications involving vascular tissue. The purpose of this review is to evaluate the use of angiotensin converting enzyme and vasopeptidase inhibitors in the treatment of diabetic neuropathy.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Neuropatias Diabéticas/tratamento farmacológico , Inibidores de Proteases/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Neuropatias Diabéticas/fisiopatologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Inibidores de Proteases/uso terapêuticoRESUMO
Nutritional supplementation with dehydroepiandrosterone (DHEA) may be a candidate for treating diabetes-induced vascular and neural dysfunction. DHEA is a naturally occurring adrenal androgen that has antioxidant properties and is reportedly reduced in diabetes. Using a prevention protocol, we found that dietary supplementation of streptozotocin-induced diabetic rats with 0.1, 0.25, or 0.5% DHEA caused a concentration-dependent prevention in the development of motor nerve conduction velocity and endoneurial blood flow impairment, which are decreased in diabetes. At 0.25%, DHEA significantly prevented the diabetes-induced increase in serum thiobarbituric acid-reactive substances and sciatic nerve conjugated diene levels. This treatment also reduced the production of superoxide by epineurial arterioles of the sciatic nerve. DHEA treatment (0.25%) significantly improved vascular relaxation mediated by acetylcholine in epineurial vessels of diabetic rats. Sciatic nerve Na+-K+-ATPase activity and myoinositol content was also improved by DHEA treatment, whereas sorbitol and fructose content remained elevated. These studies suggest that DHEA, by preventing oxidative stress and perhaps improving sciatic nerve Na+-K+-ATPase activity, may improve vascular and neural dysfunction in diabetes.
Assuntos
Adjuvantes Imunológicos/farmacologia , Desidroepiandrosterona/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Nervo Isquiático/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Adjuvantes Imunológicos/sangue , Animais , Arteríolas/efeitos dos fármacos , Glicemia , Peso Corporal/efeitos dos fármacos , Desidroepiandrosterona/sangue , Diabetes Mellitus Experimental/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Estrogênios/sangue , Masculino , Estresse Oxidativo/fisiologia , Nervos Periféricos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/fisiologia , Superóxidos/metabolismoRESUMO
Previously we have demonstrated that diabetes causes impairment in vascular function of epineurial vessels, which precedes the slowing of motor nerve conduction velocity. Treatment of diabetic rats with aldose reductase inhibitors, aminoguanidine or myo-inositol supplementation have been shown to improve motor nerve conduction velocity and/or decreased endoneurial blood flow. However, the effect these treatments have on vascular reactivity of epineurial vessels of the sciatic nerve is unknown. In these studies we examined the effect of treating streptozotocin-induced rats with sorbinil, aminoguanidine or myo-inositol on motor nerve conduction velocity, endoneurial blood flow and endothelium-dependent vascular relaxation of arterioles that provide circulation to the region of the sciatic nerve. Treating diabetic rats with sorbinil, aminoguanidine or myo-inositol improved the reduction of endoneurial blood flow and motor nerve conduction velocity. However, only sorbinil treatment significantly improved the diabetes-induced impairment of acetylcholine-mediated vasodilation of epineurial vessels of the sciatic nerve. All three treatments were efficacious in preventing the appropriate metabolic derangements associated with either activation of the polyol pathway or increased nonenzymatic glycation. In addition, sorbinil was shown to prevent the diabetes-induced decrease in lens glutathione level. However, other markers of oxidative stress were not vividly improved by these treatments. These studies suggest that sorbinil treatment may be more effective in preventing neural dysfunction in diabetes than either aminoguanidine or myo-inositol.