Alloxan-induced Diabetic Rabbits Research Articles

Interaction of Calmodulin with the cSH2 Domain of the p85 Regulatory Subunit.

Calmodulin (CaM) is a calcium sensor protein that directly interacts with the dual-specificity (lipid and protein) kinase PI3Kα through the SH2 domains of the p85 regulatory subunit. In adenocarcinomas, the CaM interaction removes the autoinhibition of the p110 catalytic subunit of PI3Kα, leading to activation of PI3Kα and promoting cell proliferation, survival, and migration. Here we demonstrate that the cSH2 domain of p85α engages its two CaM-binding motifs in the interaction with the N- and C-lobes of CaM as well as the flexible central linker, and our nuclear magnetic resonance experiments provide structural details. We show that in response to binding CaM, cSH2 exposes its tryptophan residue at the N-terminal region to the solvent. Because of the flexible nature of both CaM and cSH2, multiple binding modes of the interactions are possible. Binding of CaM to the cSH2 domain can help release the inhibition imposed on the p110 subunit, similar to the binding of the phosphorylated motif of RTK, or phosphorylated CaM (pCaM), to the SH2 domains. Amino acid sequence analysis shows that CaM-binding motifs are common in SH2 domains of non-RTKs. We speculate that CaM can also activate these kinases through similar mechanisms.

Antioxidant Enzymes and Lipid Peroxidation in Alloxan-Induced Diabetic Rabbits

The study was carried out to evaluate the effect of alloxan–induced diabetes on some oxidative stress markers in rabbits. Ten rabbits weighing between 1.0-1.5kg were used and divided into two groups of five rabbits each. Diabetes was induced in one of the groups, by intraperitonial administration of alloxan at a dosage of 150mg/kg body weight and the control rabbits were administered normal saline (0.9% NaCl). The animals were monitored for 14days after confirmed diabetes in the test group. The fasting plasma glucose, plasma insulin, plasma lipids, the antioxidant enzymes: Superoxide dismutase (SOD), catalase, and lipid peroxidation were assayed for, in the plasma and the brain of the diabetic and non-diabetic rabbits. The results showed a significant decrease in mean body weight of the alloxan-induced diabetic and control rabbits pre and 14days post alloxan-induction. There was a significant (p < 0.01) increase in fasting plasma glucose, a significant (p < 0.01) decrease in the activity of SOD and a significant (p < 0.01) increase in the activity of catalase in the plasma and brain; there was also a significant (p < 0.01) increase in the level of lipid peroxidation, plasma cholesterol and triglycerides in the diabetic rabbits. Culminating a depletion of SOD activity, the altered activity of plasma (or brain) catalase and increased lipid peroxidation is due to the oxidative stress induced by the diabetic condition, hence the present study indicate that alloxan – induced diabetic potentiated oxidative stress in a short term duration. This shows the importance of antioxidant mimetics to be administered at early stage of diabetics in other to increase the antioxidant capacity thus preventing oxidative stress which may lead to complication in diabetes.

Determination of the optimal diabetes duration for bone regeneration experiments in an alloxan-induced diabetic rabbit calvarial defect model.

PurposeThe purpose of this study was to evaluate the optimal diabetes duration for bone regeneration experiments in an alloxan monohydrate (ALX)–induced diabetic rabbit calvarial defect model by evaluating the association between diabetes duration and bone healing capacity.MethodsTwenty-four New Zealand white rabbits were used. Twenty-two rabbits were injected with 100 mg/kg of ALX to induce experimental diabetes. These rabbits were divided into 4 groups, including a control group and groups with diabetes durations of 1 week (group 1), 2 weeks (group 2), and 4 weeks (group 3). Calvarial defects were created at 1, 2, and 4 weeks after ALX injection and in the control rabbits. Cone-beam computed tomography (CBCT) scanning was performed on the day of surgery and at 2 and 4 weeks after surgery. The rabbits were sacrificed 4 weeks after surgery, followed by histological and immunofluorescence analysis.ResultsThe diabetic state of all diabetic rabbits was well-maintained throughout the experiment. Reconstructed 3-dimensional CBCT imaging showed more rapid and prominent bone regeneration in the control group than in the experimental groups. Histological staining showed notable bone regeneration in the control group, in contrast to scarce bone formation in the experimental groups. The appearance and immunoreactivity of receptor activator of nuclear factor-kappa B and osteoprotegerin did not show notable differences among the groups.ConclusionALX administration at 100 mg/kg successfully induced experimental diabetes in rabbits. The effect of diabetes on bone healing was evident when the interval between diabetes induction and the intervention was ≥1 week.

Functionalized PVA-silk blended nanofibrous mats promote diabetic wound healing via regulation of extracellular matrix and tissue remodelling.

Chronic cutaneous ulcers, a complex pathophysiological diabetic condition, represent a critical clinical challenge in the current diabetes mellitus pandemic. Consequently, there is a compelling need for bioactive dressings that can trigger healing processes for complete wound repair. Silk fibroin (SF), a natural protein polymer from mulberry and non-mulberry silkworms, has properties that support accelerated wound healing rate. SF from non-mulberry variety possesses additional cell-binding motifs (arginine, glycine, and aspartate), offering cell-material interactions. This study is aimed to investigate wound healing efficacy of dressings made up of various SF varieties blended with poly(vinyl alcohol) biopolymer in alloxan-induced diabetic rabbit model. The nanofibrous mats have been developed using electrospinning and functionalized with growth factors and LL-37 antimicrobial peptide for sustained delivery. Following post 14-day treatment, non-mulberry SF (NMSF)-based dressings healed the wounds faster, in comparison with their mulberry Bombyx mori SF, poly(vinyl alcohol), and control counterparts (p<.01). NMSF-based dressings also supported faster granulation tissue development, angiogenesis, and reepithelialization of wounds. Gene expression study of matrix metalloproteinases and collagen proteins affirmed higher extent of tissue remodelling during the repair process. Furthermore, there was organized extracellular matrix deposition (collagen type I, collagen type III, elastin, and reticulin) and higher wound breaking strength in NMSF compared with other groups after 4weeks. These results validated the potential of NMSF-based bioactive dressings to regulate extracellular matrix deposition leading to faster and complete repair of chronic diabetic cutaneous wounds.

Restoration of plasma markers of liver and kidney functions/integrity in alloxan-induced diabetic rabbits by aqueous extract of Pleurotus tuberregium sclerotia

The effect of aqueous extract of the sclerotia of Pleurotus tuberregium on the plasma electrolytes, and markers of liver and kidney functions/integrity of normal and alloxan-induced rabbits was investigated. Diabetes mellitus was induced by injection of alloxan (120mg/kg body weight), via the marginal ear vein. The extract was administered orally at 100, 200 and 300mg/kg (both to normal and diabetic rabbits), and metformin at 50mg/kg. Gas chromatographic-flame ionization detector analysis of the extract revealed the presence of twelve known phenolic acids, consisting mainly of caffeic acid (80.24%), chlorogenic acid (11.08%), piperic acid (6.11%), sinapinic acid (2.14%) and ferulic acid (0.34%). Compared to test control, the treatment significantly (p<0.05) lowered plasma activities of alkaline phosphatase, gamma glutamyltransferase, and alanine and aspartate transaminases. Also lowered were plasma unconjugated/conjugated bilirubin ratio and concentrations of urea, blood urea nitrogen, creatinine, sodium, and total and unconjugated bilirubin. It however, significantly (p<0.05) raised plasma potassium and calcium levels. Therefore, the modulation of plasma sodium and potassium is an indication of the diuretic potential of the extract. In addition, the extract had no deleterious effect on the liver and kidney of the treated animals, at least at the doses administered in this study.

Pioglitazone attenuates atrial remodeling and vulnerability to atrial fibrillation in alloxan-induced diabetic rabbits.

Recent evidence indicates that peroxisome proliferator-activated receptor (PPAR)-γ activators exert anti-inflammatory and antioxidant actions. However, the underlying mechanisms by which these agents prevent atrial remodeling in diabetes are not completely elucidated. We sought to investigate the potential effects of pioglitazone, a PPAR-γ activator, on atrial remodeling and atrial fibrillation (AF) inducibility in diabetic rabbits. Alloxan-induced diabetic rabbits were randomly divided into three groups: diabetes only, diabetes treated with low-dose pioglitazone (4mg/day/kg), or diabetes treated with high-dose pioglitazone (8mg/day/kg) (n=24 for each group). A total of 24 healthy rabbits served as controls. Eight weeks later, hemodynamic, echocardiographic, and electrophysiological parameters were recorded. Left atrial whole-cell patch-clamp studies, histological examination, and Western blot analysis were also performed. In the DM group (6/8 vs 1/8, P<.05), higher AF inducibility, increased amount of fibrosis, lower INa , and higher ICaL were observed in the DM group compared to controls. Western blot analysis showed that DM increased the expression of extracellular signal-regulated kinase 2 (ERK2), phosphorylation ERK, transforming growth factor beta-1, Toll-like receptor 4, nuclear factor-κB p50, and heat-shock protein 70. All of these electrophysiological, histological, ion current density, and protein expression changes were all reduced by pioglitazone. Pioglitazone attenuates diabetes-induced structural and electrophysiological remodeling in the atria, thereby reducing the vulnerability to AF.

Effects of diabetes mellitus on biomechanical properties of the rabbit cornea

To investigate the effects of diabetes on the biomechanical behavior of cornea in alloxan-induced diabetic rabbits. Diabetes mellitus (DM) was induced in 20 rabbits using alloxan, while another 20 age- and weight-matched non-diabetic rabbits served as controls. Eyes were enucleated after 8 weeks of inducing diabetes and the whole cornea was removed with a 3 mm wide scleral ring and tested under inflation conditions with an internal pressure range of 2.0–30.0 mmHg to determine their stress-strain behavior using an inverse analysis process. The blood glucose level (BG), advanced glycosylation end products (AGEs), central corneal thickness (CCT) and intraocular pressure (IOP) increased significantly in the DM group. There were statistically significant correlations between BG and AGEs (r = 0.768, p = 0.00), and between AGEs and CCT variation upon induction of DM (r = 0.594, p = 0.00). The tangent modulus (Et) of the cornea at four stress levels (1–4 kPa, equivalent to approximately IOP of 7.5, 15, 22.5 and 30 mmHg, respectively) was significantly higher in diabetic rabbits than in the control group (p < 0.05). Further, Et at stress of 2 kPa (which corresponded to the average IOP for the control group) was significantly correlated with BG (r = 0.378, p < 0.05), AGEs (r = 0.496, p < 0.05) and CCT variation upon induction of DM (r = 0.439, p < 0.05). IOP, as measured by contact tonometry, was also significantly correlated with both CCT (r = 0.315, p < 0.05) and Et at 2 kPa (r = 0.329, p < 0.05), and even after correcting for the effects of CCT and Et, IOP still significantly increased with both AGEs (r = 0.772, p = 0.00) and BG (r = 0.762, p = 0.00). The cornea of diabetic rabbits showed a significant increase in mechanical stiffness as evidenced by increases in corneal thickness and tangent modulus. The Et increase may be explained by a non-enzymatic cross-linking of collagen fibrils mediated by AGEs due to the high blood glucose levels in diabetes. The study also found significant IOP increases with higher blood glucose level even after controlling the effects of both corneal thickness and tangent modulus.

Effect of aqueous extract of &lt;i&gt;Thymus serpyllum&lt;/i&gt; on lipid profile and some liver enzymes in alloxan-induced diabetic rabbit

&lt;p class="Abstract"&gt;The present study was designed to evaluate the effects of aqueous extract of&lt;em&gt; Thymus serpyllum&lt;/em&gt; on lipid profile and some liver enzymes level in the diabetic rabbit. Rabbits were made diabetic with a single intravenous injection of alloxan and were divided into groups. Group 1 and 2 served as normal and diabetic control, respectively. Group 3 and 4 were given standard drugs glibenclamide and acarbose respectively while Group 5 was treated with 500 mg/kg of extract for 30 days. Blood samples were taken on day 0 and 30. The extract significantly reduced the level of serum cholesterol, triglyceride, LDLs, VLDLs, alkaline phosphatase and transaminases without affecting the HDLs level. Total cholesterol/HDL-cholesterol ratio was significantly reduced as compared to diabetic control. It is conceivable that&lt;em&gt; T. &lt;/em&gt;serpyllum possesses antihyperlipidemic and hepatoprotective effects in diabetic rabbit.&lt;/p&gt;

Antidiabetic and renoprotective effect of Fagonia cretica L. methanolic extract and Citrus paradise Macfad. juice in alloxan induced diabetic rabbits

Context: Fagonia cretica is a medicinal herb reported to have flavanoids of potential therapeutic value and Citrus paradisi is a fruit, whose juice is of great therapeutic value due to its anti-hyperglycemic effects. Aims: To determine anti-hyperglycemic and renal protective effect of methanolic extract of Fagonia cretica and Citrus paradisi juice (grapefruit juice) in alloxan induced diabetic rabbits. Methods: Diabetes was induced in rabbits by alloxan monohydrate (150 mg/kg, i.p.). The therapies including Fagonia cretica methanolic extract (500 mg/kg), Citrus paradisi juice (7 mL/kg) and sitagliptin (10 mg/kg) were administered (p.o.) to diabetic groups for 14 days. The biochemical parameters, glucose, creatinine, urea, bilirubin, albumin, total protein, globulins and albumin/globulin ratio were estimated. Results: Fagonia cretica extract and grapefruit juice therapy significantly (p&lt;0.05) reduced glucose levels in diabetic rats. Fagonia cretica extract was more effective anti-hyperglycemic agent than Citrus paradisi juice and sitagliptin. Significant (p&lt;0.05) improvement in kidney function was observed in treated groups, the plant extract showing significant improvement as compared to the other two treatments. The histopathological results verified improvement in structural damage of kidney, liver and pancreas with these treatments. Conclusions: Fagonica cretica and Citrus paradisi juice therapy markedly improved hyperglycemia and kidney functions in alloxan-induced diabetic rabbits.

Oleuropein improves insulin resistance in skeletal muscle by promoting the translocation of GLUT4.

As the beneficial effects of the Mediterranean diet on human health are well established, the phenolic compounds in olive oil have been gaining interest. Oleuropein, a major phenolic compound in olives, is known to reduce the blood glucose levels in alloxan-induced diabetic rats and rabbits, however, its effect on type 2 diabetes caused by obesity is not clear. The purpose of this study is clarifying the effect of oleuropein on the glucose tolerance in skeletal muscle under the condition of lipotoxicity caused by type 2 diabetes. Oleuropein enhanced glucose uptake in C2C12 cells without insulin. Translocation of glucose transporter 4 (GLUT4) into the cell membrane was promoted by activation of adenosine monophosphate-activated protein kinase (AMPK) but not protein kinase B (Akt). Physiological concentration of oleuropein (10 µM) was sufficient to express beneficial effects on C2C12 cells. Oleuropein prevented palmitic acid-induced myocellular insulin resistance. Furthermore, in gastrocnemius muscles of mice fed a high fat diet, oleuropein also induced the GLUT4 localization into cell membrane. These results suggest the possibility of oleuropein to be effective for type 2 diabetes by reducing insulin resistance in skeletal muscles.

NADPH oxidase inhibitor apocynin prevents atrial remodeling in alloxan-induced diabetic rabbits

ObjectivesDiabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF). The role of the NADPH oxidase (NOX) signaling in the setting of DM and the potential benefits of apocynin on diabetic atrial remodeling remain unknown. MethodsSixty Japanese rabbits were randomized into 3 groups as follows: Control group (Control, n=20), alloxan-induced diabetic group (DM, n=20) and apocynin-treated diabetic group (APO, n=20). Rabbits in the APO group were orally administered apocynin (15mg/kg/day) for 8weeks. Serum malonaldehyde (MDA), superoxide dismutase (SOD) levels, and left atrial tissue NADPH oxidase (NOX) activities were measured. Isolated rabbit hearts were Langendorff perfused. Atrial refractory effective period (AERP), atrial effective refractory period dispersion (AERPD), interatrial conduction time (IACT) and vulnerability to AF were assessed. Atrial interstitial fibrosis was evaluated by Masson's trichrome staining. The protein expression of NF-κB, TGF-β, p38, P-p38, JNK, P-JNK, ERK and P-ERK was measured by Western blot analysis. ResultsThere were no significant differences regarding SBP, DBP, LVEDP and AERP in the three groups. Compared with the Control group, AF inducibility was increased in the DM group (46/450 vs. 5/450, P<0.05), and markedly reduced by apocynin (46/450 vs. 12/450, P<0.05). Apocynin also attenuated atrial structural remodeling in diabetic rabbits. Western-blot analysis indicated that apocynin reduced the DM-induced increased protein expression of TGF-β, NF-κB, P-p38, P-JNK, ERK and P-ERK. ConclusionsApocynin, a NADPH oxidase inhibitor, prevents AF and attenuates atrial remodeling in alloxan-induced diabetic rabbits.

Lycium barbarum polysaccharides ameliorates renal injury and inflammatory reaction in alloxan-induced diabetic nephropathy rabbits

AimsThis study was aimed to investigate the effect of Lycium barbarum polysaccharides (LBP) on renal function and inflammatory reaction in rabbits with diabetic nephropathy. Main methodsDiabetes was induced by injecting alloxan (ALX). Japanese male white rabbits were randomly assigned into 5 groups: normal control group, diabetic nephropathy (DN) model group, LBP prevention group, positive control group and LBP treatment group. LBP (10mg/kg) was given to the LBP prevention group after diabetes mellitus (DM) model succeeded for 12weeks and to the LBP treatment group after DN model succeeded for 4weeks. Telmisartan (3.7mg/kg) was given to the positive group after DN model succeeded for 4weeks, and the same volume of balanced saline was given to the normal group and DN group for 12weeks. Urea nitrogen (BUN), creatinine (SCr), and C-reaction protein (CRP) in serum were detected at the end of the 12th week. The expression of MCP-1 mRNA and ICAM-1 mRNA extracted from cortex were detected by RT-PCR. Western blot analysis was carried out to examine NF-κB p65 protein expression. Key findingsLBP improves the renal function and alleviates the inflammatory reaction in the kidneys of diabetic rabbits. In addition, the prevention effect of LBP is better than the treatment effect of LBP. SignificanceLBP has obvious protective effect on the diabetic nephropathy rabbits' renal function and postpones the appearance and development of DN. The mechanisms may be related to the reduction the expression of MCP-1mRNA and ICAM-1mRNA by restraining the expression of NF-κB and AngII.

Effect of Honey Bee Venom (Apis mellifera) on Hyperglycemia and Hyperlipidemia in Alloxan Induced Diabetic Rabbits

Introduction: In diabetes therapy, a great attention is paid on lowering blood glucose levels and lipid regulating mechanisms of various medical agents including animal toxins. Honey bee venom reduces blood glucose level through increased insulin secretion and glucose take-up. It also has lipid regulating activity verified in several other studies. For that reason, bee venom could be considered as a potential remedy for diabetes. This study aims to investigate the effect of Mongolian honey bee venom on hyperglycemia and hyperlipidemia in alloxan induced diabetic rabbits. Material and method: Twenty two Chinchilla rabbits were divided into three groups: the control (n=6), the diabetic (n=8), and the bee venom treated (n=8) groups. The diabetic group was injected with a 5% solution of Alloxan monohydrate at100 mg/kg intravenously via the marginal vein behind the ear for 2 minutes to induce the diabetes. The bee venom treated group received a bee sting (a sting contains 0.2-0.5 ml of bee venom) on their hind paw every other day after the confirmation of diabetes. Result: Bee venom treatment (BVT) led to the following changes: compared to the diabetic group, the bee venom treated group’s blood glucose levels decreased by 14.9% -26.5%; blood cholesterol levels reduced by 12.5%- 19.1%; Low Density Lipoproteins (LDL) levels lowered by 11.2%-14.2%; and High Density Lipoproteins (HDL) levels increased by 2.5% - 26.25%. Conclusion: Bee venom lowers blood glucose levels and improves lipid profile in alloxan-induced diabetic rabbits and can be considered as a therapeutic agent for diabetes. Further studies should be carried out to determine the most appropriate bee venom dose for the best therapeutic effect.

Study of Blood Glucose and SGPT lowering effect of Eucalyptus Lanceolata Linn. in Induced Diabetic Rabbits

The part of the plant to curing the diabetes mellitus and improves available data on plants with hypoglycemic effects. Antidiuretic potential of eucalyptus extracts has been evaluated in alloxan-induced diabetic rabbit. Here we used, plants extract about 256 kg were mix with 1000 ml methanol and keep in Flask. After filtering the extracts were exposed to rotary evaporator machine that methanol separated from plant extract. In the Nine rabbit were divided into three different groups. The body weight was recorded on every 6 days interval. The data obtained revealed that eucalyptus extracts reduced the glucose level effectively. Such treatment with extracts decreased the SGPT level. Therefore, it is concluded that the eucalyptus possesses significant antidiabetic activity. And finally, we recommend this plant for medicinal uses and for pharmaceutical industries to isolate pure drugs.

Homogenous demineralized dentin matrix and platelet-rich plasma for bone tissue engineering in cranioplasty of diabetic rabbits: biochemical, radiographic, and histological analysis

This study evaluated the effects of homogenous demineralized dentin matrix (HDDM) slices and platelet-rich plasma (PRP) in surgical defects created in the parietal bones of alloxan-induced diabetic rabbits, treated with a guided bone regeneration technique. Biochemical, radiographic, and histological analyses were performed. Sixty adult New Zealand rabbits were divided into five groups of 12: normoglycaemic (control, C), diabetic (D), diabetic with a PTFE membrane (DM), diabetic with a PTFE membrane and HDDM slices (DM–HDDM), and diabetic with PTFE membrane and PRP (DM–PRP). The quantity and quality of bone mass was greatest in the DM–HDDM group (respective radiographic and histological analyses: at 15 days, 71.70±16.50 and 50.80±1.52; 30 days, 62.73±16.51 and 54.20±1.23; 60 days, 63.03±11.04 and 59.91±3.32; 90 days, 103.60±24.86 and 78.99±1.34), followed by the DM–PRP group (respective radiographic and histological analyses: at 15 days 23.00±2.74 and 20.66±7.45; 30 days 31.92±6.06 and 25.31±5.59; 60 days 25.29±16.30 and 46.73±2.07; 90 days 38.10±14.04 and 53.38±9.20). PRP greatly enhanced vascularization during the bone repair process. Abnormal calcium metabolism was statistically significant in the DM–PRP group (P<0.001) for all four time intervals studied, especially when compared to the DM–HDDM group. Alkaline phosphatase activity was significantly higher in the DM–HDDM group (P<0.001) in comparison to the C, D, and DM–PRP groups, confirming the findings of intense osteoblastic activity and increased bone mineralization. Thus, HDDM promoted superior bone architectural microstructure in bone defects in diabetic rabbits due to its effective osteoinductive and osteoconductive activity, whereas PRP stimulated angiogenesis and red bone marrow formation.

GW26-e2501 Xanthine oxidase inhibition prevents atrial remodeling and atrial fibrillation in alloxan-induced diabetic rabbits

GW26-e2501 Xanthine oxidase inhibition prevents atrial remodeling and atrial fibrillation in alloxan-induced diabetic rabbits

Biofunctional properties of Eruca sativa Miller (rocket salad) hydroalcoholic extract

Eruca sativa Miller is a worldwide common alimentary plant (rocket leaves). The aim of this study was to correlate the potential in vitro scavenging activity of the E. sativa hydroalcoholic extract (HAE) with its in vivo hypoglycaemic effect. In DDPH free radical (DFR) and ferric-reducing antioxidant power assays, HAE in a concentration dependent manner (25–100 μg/mL) displayed a strong scavenging activity with maximum effect of 88% and 75% at 100 μg/mL, respectively. Daily administration of HAE (50 mg/kg; p.o.) in the in vivo model of alloxan-induced diabetic rabbits for 28 days showed significant reduction in glycaemia, also supported by recovery of body weight. In conclusion, our results give preliminary information on the potential use of this plant as a nutraceutical, useful to control and/or prevent a hyperglycaemic status.

Glycaemic Evaluation of Murraya koenigii in Alloxan-induced Diabetic Rabbits

Glycaemic Evaluation of Murraya koenigii in Alloxan-induced Diabetic Rabbits

Antihyperglycemic and hypolipidemic potential of &lt;i&gt;Caesalpinia decapetala&lt;/i&gt; in alloxan-induced diabetic rabbits

The anti-hyperglycemic, anti-hyperlipidemic, kidney and hepatoprotective potential of Caesalpinia decapetala were evaluated in alloxan-induced diabetic rabbits. The plant extract showed concentration dependant significant (p<0.001) therapeutic potential in diabetic rabbits revealing improvement in lipid profile and liver and kidney functions. 300 mg/kg and 500 mg/kg oral extract were able to reduce average blood glucose levels from 250.6 mg/dL to 204.2 mg/dL and 188.2 mg/dL respectively during 14 days period, in comparison to 183.8 mg/dL of glibenclamide. There was no significant synergistic effect found, upon co-administration of both drug and extract representing the competitive binding to sulphonyl urea (SUR1), revealing possible mechanism of action for compounds in extract. Extract was found to be nephroprotective, hepatoprotective and improved lipid profile of alloxan-treated rabbits. DOI: http://dx.doi.org/10.3329/bjp.v9i4.19961

Probucol prevents atrial remodeling by inhibiting oxidative stress and TNF-α/NF-κB/TGF-β signal transduction pathway in alloxan-induced diabetic rabbits.

Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF). However, the underlying mechanisms for the increased propensity for AF in the setting of DM and the potential effects of probucol on atrial remodeling remain unclear. Eighty Japanese rabbits were randomly assigned to normal/control group (Control, n = 20), alloxan-induced diabetic group (DM, n = 20), probucol-treated group (Control-P, n = 20), and probucol-treated diabetic group (DM-P, n = 20). Rabbits in the DPR and CPR groups were orally administered probucol (1,000 mg/day) for 8 weeks. Serum and left atrial tissue malonaldehyde (MDA), superoxide dismutase (SOD), myeloperoxidase (MPO), and catalase (CAT) levels were assessed. Isolated Langendorff perfused rabbit hearts were prepared to evaluate atrial refractory effective period (AERP) and its dispersion (AERPD), interatrial conduction time (IACT), and vulnerability to AF. Atrial interstitial fibrosis was also evaluated. The mRNA expression levels of TNF-α and TLR4 were analyzed. The protein expressions of NF-κB, HSP70, TGF-β, and ERK in left atrial tissue were analyzed by Western blot. Probucol administration decreased the inducibility of AF in diabetic rabbits and attenuated atrial interstitial fibrosis. The DM-P rabbits exhibited significant alleviation of oxidative stress, evidenced by reduced serum and tissue MDA, compared with diabetic rabbits. Moreover, NF-κB, TGF-β, and HSP70 protein expression and TNF-α mRNA expression were significantly downregulated by probucol treatment in alloxan-induced diabetic rabbits. Probucol prevents atrial remodeling and suppresses AF development in alloxan-induced diabetic rabbits. Its inhibitory effects on oxidative stress, NF-κB, TGF-β, and TNF-α overexpression may contribute to its antiremodeling effects.