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1.
J Diabetes Res ; 2018: 2967127, 2018.
Article in English | MEDLINE | ID: mdl-30057911

ABSTRACT

In this study, we wanted to extend our investigation of the efficacy of fish oil with or without salsalate on vascular and neural complications using a type 2 diabetic rat model. Four weeks after the onset of hyperglycemia, diabetic rats were treated via the diet with 3 different amounts of menhaden oil with or without salsalate for 12 weeks. Afterwards, vascular reactivity of epineurial arterioles and neuropathy-related endpoints were examined. The addition of salsalate to high-fat diets enriched with 10% or 25% kcal of menhaden oil protected vascular reactivity to acetylcholine and calcium gene-related peptide, motor and sensory nerve conduction velocity, thermal nociception, intraepidermal nerve fiber density, and cornea sensitivity to a greater extent than 10% or 25% menhaden oil alone. Vascular and neural function was maximally protected with diet containing 45% kcal as menhaden oil, and adding salsalate did not provide any additional benefit. Salsalate alone in the high-fat diet of diabetic rats provided minimal protection/improvement of vascular and neural dysfunction. These studies imply that dietary salsalate in combination with lower amounts of menhaden oil can provide greater benefit toward diabetes-induced vascular and neural impairment than menhaden oil alone.


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetic Neuropathies/drug therapy , Diet , Fish Oils/pharmacology , Salicylates/pharmacology , Animals , Blood Glucose , Diet, Fat-Restricted , Diet, High-Fat , Disease Models, Animal , Male , Peripheral Nervous System Diseases , Rats , Rats, Sprague-Dawley , Sciatic Nerve/pathology
2.
Diabetes ; 67(8): 1616-1626, 2018 08.
Article in English | MEDLINE | ID: mdl-29941448

ABSTRACT

Previously, we had shown that a vasopeptidase inhibitor drug containing ACE and neprilysin inhibitors was an effective treatment for diabetic vascular and neural complications. However, side effects prevented further development. This led to the development of sacubitril/valsartan, a drug containing angiotensin II receptor blocker and neprilysin inhibitor that we hypothesized would be an effective treatment for diabetic peripheral neuropathy. Using early and late intervention protocols (4 and 12 weeks posthyperglycemia, respectively), type 2 diabetic rats were treated with valsartan or sacubitril/valsartan for 12 weeks followed by an extensive evaluation of vascular and neural end points. The results demonstrated efficacy of sacubitril/valsartan in improving vascular and neural function was superior to valsartan alone. In the early intervention protocol, sacubitril/valsartan treatment was found to slow progression of these deficits and, with late intervention treatment, was found to stimulate restoration of vascular reactivity, motor and sensory nerve conduction velocities, and sensitivity/regeneration of sensory nerves of the skin and cornea in a rat model of type 2 diabetes. These preclinical studies suggest that sacubitril/valsartan may be an effective treatment for diabetic peripheral neuropathy, but additional studies will be needed to investigate these effects further.


Subject(s)
Aminobutyrates/therapeutic use , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin Receptor Antagonists/therapeutic use , Diabetes Mellitus, Type 2/complications , Diabetic Angiopathies/prevention & control , Diabetic Neuropathies/prevention & control , Tetrazoles/therapeutic use , Valsartan/therapeutic use , Animals , Biphenyl Compounds , Cardiovascular Agents/therapeutic use , Diabetic Angiopathies/drug therapy , Diabetic Angiopathies/physiopathology , Diabetic Neuropathies/drug therapy , Diabetic Neuropathies/physiopathology , Diabetic Retinopathy/drug therapy , Diabetic Retinopathy/physiopathology , Diabetic Retinopathy/prevention & control , Diet, High-Fat/adverse effects , Disease Progression , Drug Combinations , Male , Neprilysin/antagonists & inhibitors , Neprilysin/metabolism , Neural Conduction/drug effects , Neuroprotective Agents/therapeutic use , Protease Inhibitors/therapeutic use , Rats, Sprague-Dawley , Vascular Resistance/drug effects
3.
J Diabetes Investig ; 9(5): 1033-1040, 2018 Sep.
Article in English | MEDLINE | ID: mdl-29412513

ABSTRACT

AIMS/INTRODUCTION: Peripheral neuropathy is a common complication of diabetes and also occurs in 30% of human obese individuals with impaired glucose tolerance. Even though peripheral neuropathy affects both sexes, most pre-clinical studies have been carried out using male rodents. The aim of the present study was to create diet-induced obesity and type 2 diabetes in female rats and mice in order to examine the development of peripheral neuropathy. MATERIALS AND METHODS: At 12 weeks-of-age, rats and mice were separated into three groups. Two groups or rats and mice were fed a 60-kcal% high-fat diet for 12 weeks (rats) or 8 weeks (mice). To induce type 2 diabetes, one group of high-fat diet-fed rats and mice were treated with a low dose of streptozotocin. Analyses of multiple neural end-points were carried out 12 weeks later. RESULTS: Glucose utilization was impaired in diet-induced obese female rats and mice, as was a number of neurological end-points including nerve conduction velocity, intraepidermal and subepithelial corneal nerve fiber densities, and thermal and mechanical sensitivity. When female diet-induced obese rats or mice were made hyperglycemic, glucose utilization and sensory nerve density of the skin and cornea, as well as thermal and mechanical sensitivity, were more significantly impaired compared with diet-induced obese female rodents. CONCLUSIONS: These studies show that diet-induced obese and type 2 diabetic female rodents develop peripheral neuropathy that is similar to that occurring in male rodents. However, for female rats, more aggressive treatment is required to induce dietary obesity.


Subject(s)
Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/pathology , Diet, High-Fat/adverse effects , Peripheral Nervous System Diseases/blood , Peripheral Nervous System Diseases/pathology , Animals , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/complications , Diet, High-Fat/trends , Female , Mice , Mice, Inbred C57BL , Peripheral Nervous System Diseases/etiology , Rats , Rats, Sprague-Dawley , Streptozocin , Treatment Outcome
4.
Cornea ; 36(6): 725-731, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28476051

ABSTRACT

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.


Subject(s)
Cornea/innervation , Diabetes Mellitus, Experimental/drug therapy , Diabetic Neuropathies/physiopathology , Diet, High-Fat , Enalapril/administration & dosage , Fish Oils/administration & dosage , Hypesthesia/physiopathology , Thioctic Acid/administration & dosage , Adiponectin/metabolism , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Animals , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/physiopathology , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/physiopathology , Drug Therapy, Combination , Lipids/blood , Male , Peptidyl-Dipeptidase A/metabolism , Rats , Rats, Sprague-Dawley , Streptozocin , Thiobarbituric Acid Reactive Substances/metabolism , Trigeminal Nerve Diseases/physiopathology
5.
Invest Ophthalmol Vis Sci ; 57(6): 2412-9, 2016 05 01.
Article in English | MEDLINE | ID: mdl-27145474

ABSTRACT

PURPOSE: Diagnosis of peripheral neuropathy (PN), which affects approximately 50% of the diabetic population, is subjective, with many patients seeking a diagnosis only after presenting with symptoms. Recently, in vivo confocal microscopy of subepithelial corneal nerve density has been promoted as a surrogate marker for early detection of PN, but imaging of corneal nerves requires sophisticated instrumentation, expertise in confocal imaging, cooperative patients, and automated analysis tools to derive corneal nerve density. As an alternative, we developed a simple screening method that is based on the sensitivity of corneal nerves to cause reflex eyelid squinting in response to hyperosmolar eye drops. METHODS: Eyes of control and type 2 diabetic rats were given an eye drop of a 290- to 900-mOsm solution, and the ocular response was video recorded. Other neuropathic end points including nerve conduction velocity and subepithelial cornea nerve density were determined. RESULTS: Motor and sensory nerve conduction velocity and total nerve fiber length of corneal nerves in the subepithelial layer were significantly decreased in diabetic rats. Applying the hyperosmotic solutions to the ocular surface caused an osmolarity-dependent increase in squinting of the treated eye in control rats. Squinting was almost totally blocked by preapplication of proparacaine or N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide, a transient receptor potential melastatin-8 channel blocker. Squinting in response to the 900-mOsm solution was significantly reduced in diabetic rats. CONCLUSIONS: Preclinical studies show that evaluation of corneal sensitivity may be an alternative method for the early detection of PN and has potential for translation to clinical studies.


Subject(s)
Behavior, Animal , Cornea/innervation , Diabetes Mellitus, Experimental , Diabetic Neuropathies/diagnosis , Early Diagnosis , Nociception/physiology , Saline Solution, Hypertonic/administration & dosage , Animals , Cornea/drug effects , Diabetic Neuropathies/physiopathology , Male , Microscopy, Confocal , Nerve Fibers/drug effects , Ophthalmic Solutions/administration & dosage , Osmolar Concentration , Rats , Rats, Sprague-Dawley
6.
Eur J Pharmacol ; 765: 258-67, 2015 Oct 15.
Article in English | MEDLINE | ID: mdl-26291662

ABSTRACT

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.


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Diabetic Neuropathies/drug therapy , Enalapril/therapeutic use , Fish Oils/therapeutic use , Thioctic Acid/therapeutic use , Animals , Cornea/innervation , Diabetes Mellitus, Experimental/etiology , Diabetes Mellitus, Experimental/physiopathology , Diabetes Mellitus, Type 2/etiology , Diabetes Mellitus, Type 2/physiopathology , Diabetic Neuropathies/etiology , Diet, High-Fat/adverse effects , Dose-Response Relationship, Drug , Drug Therapy, Combination , Enalapril/administration & dosage , Fish Oils/administration & dosage , Glucose Tolerance Test , Male , Neural Conduction/drug effects , Rats, Sprague-Dawley , Sciatic Nerve/blood supply , Streptozocin/administration & dosage , Thioctic Acid/administration & dosage , Vasodilation/drug effects
7.
J Diabetes Res ; 2015: 307285, 2015.
Article in English | MEDLINE | ID: mdl-26229968

ABSTRACT

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.


Subject(s)
Anti-Obesity Agents/therapeutic use , Diabetes Mellitus, Type 2/etiology , Diabetic Neuropathies/prevention & control , Diet, Fat-Restricted , Dietary Supplements , Disease Models, Animal , Obesity/etiology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Biomarkers/blood , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diet therapy , Diabetes Mellitus, Type 2/drug therapy , Diabetic Neuropathies/complications , Diet, High-Fat/adverse effects , Enalapril/therapeutic use , Fish Oils/therapeutic use , Hypoglycemic Agents/therapeutic use , Male , Neuralgia/complications , Neuralgia/prevention & control , Non-alcoholic Fatty Liver Disease/complications , Obesity/complications , Obesity/diet therapy , Obesity/drug therapy , Rats, Sprague-Dawley , Streptozocin/toxicity , Weight Loss/drug effects
8.
J Neurophysiol ; 113(3): 701-8, 2015 Feb 01.
Article in English | MEDLINE | ID: mdl-25376787

ABSTRACT

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.


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetic Neuropathies/drug therapy , Dietary Supplements , Fish Oils/therapeutic use , Hypesthesia/drug therapy , Animals , Diabetes Mellitus, Experimental/complications , Fish Oils/administration & dosage , Fish Oils/pharmacology , Glycated Hemoglobin/metabolism , Hot Temperature , Lipids/blood , Male , Peripheral Nerves/drug effects , Peripheral Nerves/physiopathology , Rats , Rats, Sprague-Dawley , Touch
9.
J Diabetes Res ; 2014: 714273, 2014.
Article in English | MEDLINE | ID: mdl-25371906

ABSTRACT

Recently a new rat model for type 2 diabetes the Zucker diabetic Sprague-Dawley (ZDSD/Pco) was created. In this study we sought to characterize the development of diabetic neuropathy in ZDSD rats using age-matched Sprague-Dawley rats as a control. Rats were examined at 34 weeks of age 12 weeks after the onset of hyperglycemia in ZDSD rats. At this time ZDSD rats were severely insulin resistant with slowing of both motor and sensory nerve conduction velocities. ZDSD rats also had fatty livers, elevated serum free fatty acids, triglycerides, and cholesterol, and elevated sciatic nerve nitrotyrosine levels. The corneas of ZDSD rats exhibited a decrease in subbasal epithelial corneal nerves and sensitivity. ZDSD rats were hypoalgesic but intraepidermal nerve fibers in the skin of the hindpaw were normal compared to Sprague-Dawley rats. However, the number of Langerhans cells was decreased. Vascular reactivity of epineurial arterioles, blood vessels that provide circulation to the sciatic nerve, to acetylcholine and calcitonin gene-related peptide was impaired in ZDSD rats. These data indicate that ZDSD rats develop many of the neural complications associated with type 2 diabetes and are a good animal model for preclinical investigations of drug development for diabetic neuropathy.


Subject(s)
Diabetes Mellitus, Type 2/complications , Diabetic Neuropathies/etiology , Age Factors , Animals , Arterioles/physiopathology , Blood Glucose/metabolism , Cholesterol/blood , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/physiopathology , Diabetic Angiopathies/etiology , Diabetic Angiopathies/physiopathology , Diabetic Neuropathies/blood , Diabetic Neuropathies/pathology , Diabetic Neuropathies/physiopathology , Disease Models, Animal , Fatty Acids, Nonesterified/blood , Fatty Liver/blood , Fatty Liver/etiology , Langerhans Cells/pathology , Male , Neural Conduction , Nociception , Rats, Sprague-Dawley , Rats, Zucker , Sciatic Nerve/metabolism , Sciatic Nerve/physiopathology , Time Factors , Triglycerides/blood , Tyrosine/analogs & derivatives , Tyrosine/metabolism , Vasodilation
10.
Invest Ophthalmol Vis Sci ; 55(3): 1222-30, 2014 Mar 03.
Article in English | MEDLINE | ID: mdl-24519423

ABSTRACT

PURPOSE: Peripheral neuropathy has been shown to exist in prediabetic and diabetic patients and animal models. However, the development of peripheral neuropathy in prediabetes and posthyperglycemia is likely different. The purpose of this study was to examine the progression of peripheral neuropathy in diet-induced obese rats and high-fat-fed rats treated with a low dose of streptozotocin, a model for type 2 diabetes, using standard endpoints as well as corneal sensitivity and innervation. METHODS: Diet-induced obese rats and high-fat/low-dose streptozotocin diabetic rats were used to examine standard peripheral neuropathy endpoints and innervation of the cornea and corneal epithelium using corneal and standard confocal microscopy, respectively, and corneal sensitivity using a Cochet-Bonnet esthesiometer at three different time points. RESULTS: Obese rats and to a greater extent diabetic rats were insulin resistant. Obese and diabetic rats had developed sensory nerve deficits, but only diabetic rats had motor nerve dysfunction as determined by measuring nerve conduction velocity, thermal nociception, and intraepidermal nerve fiber density. In the cornea there was a decrease in corneal nerve fiber length, innervation of the corneal epithelium, and corneal sensitivity in both diet-induced obese and diabetic rats. CONCLUSIONS: These studies demonstrate that changes in corneal nerve innervation and sensitivity occur in both obese and type 2 diabetic rat models that are consistent with development of peripheral neuropathy. Examination of corneal nerve changes may be valuable endpoints for exploring potential treatments for peripheral neuropathy in both prediabetes with insulin resistance and diabetes.


Subject(s)
Cornea/innervation , Diabetes Mellitus, Experimental/complications , Nerve Fibers/pathology , Obesity/complications , Peripheral Nervous System Diseases/etiology , Animals , Cell Count , Cornea/pathology , Cornea/physiopathology , Diabetes Mellitus, Experimental/pathology , Dietary Fats/toxicity , Male , Microscopy, Confocal , Obesity/pathology , Peripheral Nervous System Diseases/pathology , Rats , Rats, Sprague-Dawley , Sensation
11.
Invest Ophthalmol Vis Sci ; 53(13): 8067-74, 2012 Dec 07.
Article in English | MEDLINE | ID: mdl-23169880

ABSTRACT

PURPOSE: Cornea confocal microscopy is emerging as a clinical tool to evaluate the development and progression of diabetic neuropathy. The purpose of these studies was to characterize the early changes in corneal sensitivity and innervation in a rat model of type 1 diabetes in relation to standard peripheral neuropathy endpoints and to assess the effect of Ilepatril, a vasopeptidase inhibitor which blocks angiotensin converting enzyme and neutral endopeptidase, on these endpoints. METHODS: Streptozotocin-diabetic rats 8 weeks duration were treated with or without Ilepatril for the last 6 weeks of the experimental period. Afterwards, standard diabetic neuropathy endpoints, subbasal corneal nerves and innervation of the epithelium, corneal sensitivity using a Cochet-Bonnet esthesiometer, and vascular reactivity of the posterior ciliary artery were examined. RESULTS: Diabetes caused a decrease in nerve conduction velocity, thermal hypoalgesia, and a reduction in intraepidermal nerve fiber profiles. In the cornea there was a decrease in corneal nerve fibers innervating the epithelium and corneal sensitivity, but subbasal corneal nerve fibers was not changed. Vascular relaxation in response to acetylcholine was decreased in the posterior ciliary artery. These defects were partially to completely prevented by Ilepatril treatment. CONCLUSIONS: These studies suggest that in type 1 diabetic rats decreased innervation of the cornea epithelium occurs early in diabetes and prior to a detectable decrease in subbasal corneal nerves and that these and other diabetic neuropathy-related defects can be partially to completely prevented by a vasopeptidase inhibitor.


Subject(s)
Cranial Nerve Diseases/prevention & control , Diabetes Mellitus, Experimental/prevention & control , Diabetes Mellitus, Type 1/prevention & control , Epithelium, Corneal/innervation , Heterocyclic Compounds, 3-Ring/therapeutic use , Ophthalmic Nerve/drug effects , Prodrugs , Acetylcholine/pharmacology , Animals , Blood Glucose/metabolism , Body Weight , Ciliary Arteries/physiology , Cranial Nerve Diseases/physiopathology , Diabetes Mellitus, Experimental/physiopathology , Diabetes Mellitus, Type 1/physiopathology , Epithelium, Corneal/physiopathology , Lipids/blood , Male , Ophthalmic Nerve/physiopathology , Rats , Rats, Sprague-Dawley , Sensation/physiology , Thiobarbituric Acid Reactive Substances/metabolism , Vasodilation/drug effects , Vasodilator Agents/pharmacology
12.
J Nutr Metab ; 2012: 950517, 2012.
Article in English | MEDLINE | ID: mdl-22988492

ABSTRACT

Aims. To determine the effect of partial replacement of a high-fat diet with menhaden oil on diabetic neuropathy in an animal model of type 2 diabetes. Materials and Methods. High-fat/low-dose streptozotocin diabetic rats were used to examine the influence of replacing 50% of the source of the high-fat diet (lard) with menhaden oil, a natural source of n-3 fatty acids, on diabetic neuropathy. Endpoints included analyses of glucose tolerance, fatty liver disease, serum and liver fatty acid composition, serum lipid and adiponectin levels, motor and sensory nerve conduction velocity, thermal sensitivity and innervation of the hindpaw. Results. Diabetic rats were insulin resistant and menhaden oil did not improve whole animal glucose utilization. Menhaden oil did not improve elevated HbA(1)C levels or serum lipid levels but serum levels of adiponectin were significantly increased and hepatic steatosis was significantly improved. Diabetic rats were thermal hypoalgesic, had reduced motor and sensory nerve conduction velocities and intraepidermal nerve fiber profiles were decreased in the hindpaw and these endpoints were significantly improved with menhaden oil. Conclusions. We found that enrichment of a high-fat diet with menhaden oil improved a number of endpoints associated with diabetic neuropathy.

13.
Invest Ophthalmol Vis Sci ; 53(3): 1182-7, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22273725

ABSTRACT

PURPOSE: Corneal confocal microscopy is emerging as a clinical tool to evaluate the development and progression of diabetic neuropathy. The purpose of these studies was to characterize the changes in corneal sensitivity and innervation in a rat model of type 2 diabetes in relation to standard peripheral neuropathy endpoints. Assessment of diabetes-induced changes in corneal innervation and sensitivity in animal models will be important for determining the usefulness of corneal markers for preclinical studies to test potential new treatments for diabetic neuropathy. METHODS: High-fat/low-dose streptozotocin diabetic rats were used to examine diabetes-induced changes in standard diabetic neuropathy endpoints and innervation of the cornea using confocal microscopy, corneal sensitivity using a Cochet-Bonnet esthesiometer, and vascular reactivity of the posterior ciliary artery. RESULTS: Compared with age-matched control rats, the induction of hyperglycemia in rats fed high-fat diets caused a decrease in nerve conduction velocity, thermal hypoalgesia, and intraepidermal nerve fiber profiles. In the cornea there was a decrease in corneal nerve fiber length and sensitivity. In addition, vascular relaxation in response to acetylcholine was decreased in the posterior ciliary artery. CONCLUSIONS: These studies suggest that in a type 2 diabetic rat model, changes in corneal nerve innervation and sensitivity occur that are consistent with changes seen in diabetic patients. Corneal sensitivity and innervation may be valuable endpoints for examining the potential treatments of diabetic neuropathy in preclinical studies.


Subject(s)
Acetylcholine/pharmacology , Ciliary Arteries/physiopathology , Cornea/innervation , Diabetes Mellitus, Type 2/physiopathology , Diabetic Neuropathies/physiopathology , Sensation/physiology , Vasodilation/drug effects , Animals , Ciliary Arteries/drug effects , Cornea/physiopathology , Diabetes Mellitus, Experimental , Diabetic Neuropathies/pathology , Male , Microscopy, Confocal , Ophthalmic Nerve/blood supply , Ophthalmic Nerve/physiopathology , Rats , Rats, Sprague-Dawley , Vasodilator Agents/pharmacology
14.
Eur J Pharmacol ; 677(1-3): 180-7, 2012 Feb 29.
Article in English | MEDLINE | ID: mdl-22198047

ABSTRACT

Treating high fat fed/low dose streptozotocin-diabetic rats; model of type 2 diabetes, with ilepatril (vasopeptidase inhibitor, blocks neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE)) improved vascular and neural functions. Next, studies were performed to determine the individual effect of inhibition of NEP and ACE on diabetes-induced vascular and neural dysfunctions. High fat fed rats (8 weeks) were treated with 30 mg/kg streptozotocin (i.p.) and after 4 additional weeks, were treated for 12 weeks with ilepatril, enalapril (ACE inhibitor) or candoxatril (NEP inhibitor) followed by analysis of vascular and neural functions. Glucose clearance was impaired in diabetic rats and was not improved with treatment although treatment with ilepatril or candoxatril partially improved insulin stimulated glucose uptake by isolated soleus muscle. Diabetes caused slowing of motor and sensory nerve conduction, thermal hypoalgesia, reduction in intraepidermal nerve fiber (IENF) profiles and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide (CGRP) in epineurial arterioles of the sciatic nerve. Inhibition of NEP improved nerve conduction velocity and inhibition of NEP or ACE improved thermal sensitivity and protected IENF density. Ilepatril and candoxatril treatments of diabetic rats were efficacious in improving vascular responsiveness to acetylcholine in epineurial arterioles; whereas all three treatments improved vascular response to CGRP. These studies suggest that inhibition of NEP and ACE activity is an effective approach for treatment of type 2 diabetes neural and vascular complications.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Diabetes Mellitus, Experimental/complications , Diabetic Angiopathies/drug therapy , Diabetic Neuropathies/drug therapy , Diet, High-Fat/adverse effects , Neprilysin/antagonists & inhibitors , Peptidyl-Dipeptidase A/metabolism , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Arterioles/drug effects , Arterioles/physiology , Blood Glucose/metabolism , Body Weight/drug effects , Ceramides/metabolism , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/physiopathology , Diglycerides/metabolism , Dose-Response Relationship, Drug , Glucose Tolerance Test , Male , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Nerve Fibers/drug effects , Neural Conduction/drug effects , Nociception/drug effects , Rats , Rats, Sprague-Dawley , Thiobarbituric Acid Reactive Substances/metabolism , Vasodilation/drug effects
15.
Eur J Pharmacol ; 668(3): 497-506, 2011 Oct 15.
Article in English | MEDLINE | ID: mdl-21816138

ABSTRACT

We have previously shown that treating streptozotocin-induced diabetic rats, an animal model of type 1 diabetes, with Ilepatril (an inhibitor of neutral endopeptidase and angiotensin converting enzyme (ACE)) improves vascular and neural functions. In this study we sought to determine the effect of Ilepatril treatment of high fat fed/low dose streptozotocin-diabetic rats, a model for type 2 diabetes, on vascular and neural complications. Following 8 weeks on a high fat diet rats were treated with 30 mg/kg streptozotocin (i.p.) and after 4 additional weeks a group of these rats was treated for 12 weeks with Ilepatril followed by analysis of neural and vascular functions. Included in these studies were age-matched control rats and rats fed a high fat diet and treated with or without Ilepatril. Diabetic and diet induced obese rats have characteristics of insulin resistance, slowing of nerve conduction velocity, thermal hypoalgesia, reduction in intraepidermal nerve fiber density in the hindpaw and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide in epineurial arterioles of the sciatic nerve. Treatment with Ilepatril was efficacious in improving all of these endpoints although improvement of insulin resistance in diabetic rats was minimal. These studies suggest that dual inhibition of angiotensin converting enzyme and neutral endopeptidase activity of type 2 diabetic rats is an effective approach for treatment of diabetic neural and vascular complications.


Subject(s)
Blood Vessels/drug effects , Diabetes Complications/drug therapy , Diabetes Mellitus, Experimental/complications , Diet, High-Fat/adverse effects , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Nervous System/drug effects , Adipose Tissue/drug effects , Animals , Arterioles/drug effects , Arterioles/physiopathology , Blood Glucose/metabolism , Blood Vessels/metabolism , Blood Vessels/pathology , Blood Vessels/physiopathology , Body Weight/drug effects , Carbohydrate Metabolism/drug effects , Diabetes Complications/metabolism , Diabetes Complications/pathology , Diabetes Complications/physiopathology , Dose-Response Relationship, Drug , Enzyme Inhibitors/therapeutic use , Glucose Tolerance Test , Glutathione/metabolism , Heterocyclic Compounds, 3-Ring/therapeutic use , Insulin/blood , Lens, Crystalline/drug effects , Lens, Crystalline/metabolism , Leptin/blood , Male , Muscle, Skeletal/drug effects , Muscle, Skeletal/pathology , Nerve Fibers/drug effects , Nerve Fibers/metabolism , Nerve Fibers/pathology , Nervous System/metabolism , Nervous System/pathology , Nervous System/physiopathology , Nociception/drug effects , Organ Size/drug effects , Rats , Rats, Sprague-Dawley , Sciatic Nerve/drug effects , Sciatic Nerve/metabolism , Sciatic Nerve/physiopathology , Superoxides/metabolism , Thiobarbiturates/metabolism , Tyrosine/analogs & derivatives , Tyrosine/metabolism , Vasodilation/drug effects
16.
Exp Diabetes Res ; 2011: 810469, 2011.
Article in English | MEDLINE | ID: mdl-21822422

ABSTRACT

We sought to determine the effect of dipeptidyl peptidase IV (DPP-IV) inhibition on streptozotocin diabetes-induced vascular and neural dysfunction. After 4 weeks of untreated diabetes, rats were treated for 12 weeks with Alogliptin (DPP-IV inhibitor). Diabetes caused a slowing of motor and sensory nerve conduction velocity, thermal hypoalgesia, reduction in intraepidermal nerve fiber density in the hindpaw, and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide in epineurial arterioles. Treatment significantly improved motor nerve conduction velocity and thermal response latency. Sensory nerve conduction velocity was marginally improved with treatment of diabetic rats, and treatment did not improve the decrease in intraepidermal nerve fiber density. Vascular relaxation by epineurial arterioles to calcitonin gene-related peptide but not acetylcholine was significantly improved with treatment. These studies suggest that some but not all vascular and neural complications associated with type 1 diabetes can be improved with the inhibition of DPP-IV activity.


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 1/drug therapy , Diabetic Angiopathies/drug therapy , Diabetic Neuropathies/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Piperidines/pharmacology , Uracil/analogs & derivatives , Animals , Blood Glucose/drug effects , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/physiopathology , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/physiopathology , Diabetic Angiopathies/blood , Diabetic Angiopathies/etiology , Diabetic Angiopathies/physiopathology , Diabetic Neuropathies/blood , Diabetic Neuropathies/etiology , Diabetic Neuropathies/physiopathology , Male , Motor Neurons/drug effects , Neural Conduction/drug effects , Oxidative Stress/drug effects , Pain Measurement , Pain Threshold/drug effects , Rats , Rats, Sprague-Dawley , Sensory Receptor Cells/drug effects , Time Factors , Uracil/pharmacology , Vasodilation/drug effects , Weight Gain/drug effects
17.
J Obes ; 20112011.
Article in English | MEDLINE | ID: mdl-20847891

ABSTRACT

The objective of this study was to determine the effect of AVE7688, a drug that inhibits both angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) activity, on neural and vascular defects caused by diet induced obesity (DIO). Rats at 12 weeks of age were fed a standard or high fat diet with or without AVE7688 for 24 weeks. DIO rats had impaired glucose tolerance and developed sensory neuropathy. Vascular relaxation to acetylcholine and calcitonin gene-related peptide was decreased in epineurial arterioles of DIO rats. Rats fed a high fat diet containing AVE7688 did not become obese and vascular and sensory nerve dysfunction and impaired glucose tolerance were improved. DIO is associated with increased expression of NEP in epineurial arterioles. NEP degrades vasoactive peptides which may explain the decrease in neurovascular function in DIO.

18.
Eur J Pharmacol ; 650(2-3): 556-62, 2011 Jan 15.
Article in English | MEDLINE | ID: mdl-21040718

ABSTRACT

We have previously shown that treating streptozotocin-induced diabetic rats, an animal model of type 1 diabetes, with Ilepatril (an inhibitor of neutral endopeptidase and angiotensin converting enzyme (ACE)) improves vascular and neural function. In this study we sought to determine the individual effect of inhibition of neutral endopeptidase and ACE on diabetes-induced vascular and neural dysfunction. After 4 weeks of untreated diabetes, rats were treated for 12 weeks with Ilepatril, Enalapril (ACE inhibitor) or Candoxatril (neutral endopeptidase inhibitor) followed by analysis of neural and vascular function. Diabetes caused slowing of motor and sensory nerve conduction, thermal hypoalgesia, reduction in intraepidermal nerve fiber density in the hindpaw and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide in epineural arterioles of the sciatic nerve and to atrial natriuretic peptide and calcitonin gene-related peptide in renal arteries. Inhibition of neutral endopeptidase or ACE improved neural function; however, dual inhibition of neutral endopeptidase and ACE with Ilepatril tended to have the greatest efficacy. Ilepatril and Candoxatril treatment of diabetic rats was more efficacious in improving vascular responsiveness in epineurial arterioles than treatment with Enalapril. Ilepatril, Enalapril or Candoxatril treatment of diabetic rats were all efficacious in renal arteries. These studies suggest that combination therapy may be the most effective approach for treatment of diabetic neural and vascular complications.


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Enalapril/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Indans/pharmacology , Neprilysin/antagonists & inhibitors , Neural Conduction/drug effects , Propionates/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/physiopathology , Diabetic Angiopathies/drug therapy , Diabetic Angiopathies/etiology , Diabetic Angiopathies/physiopathology , Diabetic Neuropathies/drug therapy , Diabetic Neuropathies/etiology , Diabetic Neuropathies/physiopathology , Enalapril/therapeutic use , Heterocyclic Compounds, 3-Ring/therapeutic use , Indans/therapeutic use , Male , Propionates/therapeutic use , Rats , Rats, Sprague-Dawley , Sciatic Nerve/drug effects , Sciatic Nerve/physiopathology , Streptozocin
19.
Diabetes Metab Res Rev ; 26(4): 306-18, 2010 May.
Article in English | MEDLINE | ID: mdl-20503263

ABSTRACT

BACKGROUND: The objective of this study was to determine the effect of diet-induced obesity (DIO) on microvascular and neural function. METHODS: Rats were fed a standard or high fat diet for up to 32 weeks. The following measurements were carried out: vasodilation in epineurial arterioles using videomicroscopy, endoneurial blood flow using hydrogen clearance, nerve conduction velocity using electrical stimulation, size-frequency distribution of myelinated fibres of the sciatic nerve, intraepidermal nerve fibre density using confocal microscopy and thermal nociception using the Hargreaves method. RESULTS: Rats fed a high fat diet for 32 weeks developed sensory neuropathy, as indicated by slowing of sensory nerve conduction velocity and thermal hypoalgesia. Motor nerve conduction velocity and endoneurial blood flow were not impaired. Mean axonal diameter of myelinated fibres of the sciatic nerve was unchanged in high fat-fed rats compared with that in control. Intraepidermal nerve fibre density was significantly reduced in high fat-fed rats. Vascular relaxation to acetylcholine and calcitonin gene-related peptide was decreased and expression of neutral endopeptidase (NEP) increased in epineurial arterioles of rats fed a high fat diet. In contrast, insulin-mediated vascular relaxation was increased in epineurial arterioles. NEP activity was significantly increased in the skin of the hindpaw. Markers of oxidative stress were increased in the aorta and serum of high fat-fed rats but not in epineurial arterioles. CONCLUSION: Chronic obesity causes microvascular and neural dysfunction. This is associated with increased expression of NEP but not oxidative stress in epineurial arterioles. NEP degrades vasoactive peptides, which may explain the decrease in microvascular function.


Subject(s)
Arterioles/physiopathology , Nervous System Diseases/etiology , Obesity/complications , Animals , Blood Glucose/metabolism , Blotting, Western , Immunohistochemistry , Nervous System Diseases/physiopathology , Obesity/etiology , Obesity/physiopathology , Rats , Rats, Sprague-Dawley
20.
Exp Diabetes Res ; 2009: 912327, 2009.
Article in English | MEDLINE | ID: mdl-19536347

ABSTRACT

The purpose of this study was to determine whether AVE7688 a drug that inhibits both angiotensin converting enzyme and neutral endopeptidase activity protects vascular and nerve functions in an animal model of metabolic syndrome. Obese Zucker rats at 20 weeks of age were treated for 12 weeks with AVE7688. Vasodilation in epineurial arterioles was measured by videomicroscopy and nerve conduction velocity was measured following electrical stimulation. Treatment with AVE7688 improved vascular relaxation in response to acetylcholine and motor and sensory nerve conduction velocity. In obese Zucker rats superoxide levels and nitrotyrosine staining were elevated in the aorta and treatment corrected both conditions. Obese Zucker rats were hypoalgesic in response to a thermal stimulus and demonstrated signs of impaired tactile response and both conditions were significantly improved with treatment. Even though obese Zucker rats are normoglycemic vascular and neural dysfunctions develop with age and can be improved by treatment with AVE7688.


Subject(s)
Blood Vessels/drug effects , Blood Vessels/physiopathology , Heterocyclic Compounds, 3-Ring/pharmacology , Metabolic Syndrome/physiopathology , Nervous System/drug effects , Nervous System/physiopathology , Obesity/physiopathology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Heterocyclic Compounds, 3-Ring/therapeutic use , Male , Metabolic Syndrome/complications , Neprilysin/antagonists & inhibitors , Nervous System Diseases/drug therapy , Nervous System Diseases/etiology , Nervous System Diseases/physiopathology , Neural Conduction/drug effects , Obesity/complications , Pain Threshold/drug effects , Rats , Rats, Zucker , Vascular Diseases/drug therapy , Vascular Diseases/etiology , Vascular Diseases/physiopathology , Vasodilation/drug effects
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