Cellular apoptosis and cardiac dysfunction in STZ‐induced diabetic rats attenuated by anthocyanins via activation of IGFI‐R/PI3K/Akt survival signaling

Anthocyanins are known cyto‐protective agents against various stress conditions. In this study cardio‐protective effect of anthocyanins from black rice against diabetic mellitus (DM) was evaluated using a streptozotocin (STZ)‐induced DM rat model. Five‐week‐old male Wistar rats were administered with STZ (55 mg kg^?1, IP) to induce DM; rats in the treatment group received 250 mg oral anthocyanin/kg/day during the 4‐week treatment period. DM and the control rats received normal saline through oral gavage. The results reveal that STZ‐induced DM elevates myocardial apoptosis and associated proapoptotic proteins but down‐regulates the proteins of IGF1R mediated survival signaling mechanism. Furthermore, the functional parameters such as the ejection‐fraction and fraction‐shortening in the DM rat hearts declined considerably. However, the rats treated with anthocyanins significantly reduced apoptosis and the associated proapoptotic proteins and further increased the survival signals to restore the cardiac functions in DM rats. Anthocyanin supplementation enhances cardiomyocyte survival and restores cardiac function.     

Anti-diabetic and renoprotective effects of aliskiren in streptozotocin-induced diabetic nephropathy in female rats

Since chronic kidney disease due to diabetic nephropathy (DN) is becoming an ever larger health burden worldwide, more effective therapies are desperately needed. In the present study, the anti-diabetic and renoprotective effects of aliskiren have been evaluated in streptozotocin (STZ)-induced DN in rats. DN was induced by a single intraperitoneal injection of STZ (65 mg/kg). Three weeks after STZ, rats were divided into four groups; normal, diabetic, diabetic treated with gliclazide (10 mg/kg/day) for 1 month, and diabetic treated with aliskiren (50 mg/kg/day) for 1 month. At the end of the experiment, mean arterial blood pressure and heart rate were recorded. Rats were then euthanized and serum was separated for determination of glucose, insulin, kidney function tests, superoxide dismutase activity (SOD), adiponectin, and tumor necrosis factor-alpha (TNF-α). One kidney was used for estimation of malondialdehyde (MDA), reduced glutathione (GSH), and nitric oxide (NO) contents. Other kidney was used for histopathological study and immunohistochemical measurement of caspase-3 and transforming growth factor beta (TGF-β). In addition, islets of Langerhans were isolated from normal rats by collagenase digestion technique for in vitro study. Aliskiren normalized STZ-induced hyperglycemia, increased insulin level both in vivo and in vitro, normalized kidney function tests and blood pressure, and alleviated STZ-induced kidney histopathological changes. This could be related to the ability of aliskiren toward preserving hemodynamic changes and alleviating oxidative stress and inflammatory and apoptotic markers induced by STZ in rats. However, aliskiren was more effective than gliclazide in relieving STZ-induced DN. These findings support the beneficial effect of aliskiren treatment in DN which could be attributed to its anti-diabetic, renoprotective, antioxidant, anti-inflammatory, and anti-apoptotic effects. Moreover, clinical studies are required to establish the effectiveness of aliskiren treatment in patients suffering from hypertension and diabetes.     

The furoxan nitric oxide donor,PRG150, evokes dose‐dependent analgesia in a rat model of painful diabetic neuropathy

Painful diabetic neuropathy (PDN) is a type of peripheral neuropathic pain that is often intractable. Elevated nitric oxide (NO) from neuronal and non‐neuronal sources in the somatosensory system is implicated in the pathobiology of peripheral neuropathic pain. However, in diabetes, nitrergic nerve degeneration to deplete NO bioactivity appears causal in the pathogenesis of irreversible autonomic neuropathy, another long term complication of diabetes. Hence, this study hypothesized that progressive NO depletion may underpin the pathobiology of PDN and that NO donors may alleviate PDN. Diabetes was induced in rats with intravenous streptozotocin (STZ) at 70 mg/kg and confirmed if blood glucose levels (BGLs) on day 10 post‐STZ were ≥15 mmol/L. Analgesic efficacy of subcutaneous (s.c.) bolus doses of the furoxan NO donor, PRG150 was assessed in the STZ‐diabetic rat model of PDN at 10‐, 14‐ and 24‐weeks post‐STZ relative to the sydnominine NO donor, SIN‐1 and its prodrug, molsidomine. PRG150 produced dose‐dependent analgesia in STZ‐diabetic rats whereas SIN‐1 and molsidomine evoked neuro‐excitatory side‐effects, but not analgesia. The 1000‐fold larger doses of PRG150 needed to produce analgesia at 14‐ and 24‐weeks (800 pmol/kg) c.f. 10‐weeks (8 fmol/kg) post‐STZ in rats, suggest that progressive NO depletion is also causal in PDN. Importantly, doses of PRG150 up to 10 000 fold higher than the analgesic dose did not produce hypotension in rats. The 50‐fold greater release of NO by SIN‐1 c.f. PRG150 in vitro, may underpin the neuro‐excitatory rather than analgesic effects of SIN‐1/molsidomine. PRG150 is worthy of further investigation as a potential novel analgesic for PDN.     

Morphine hyposensitivity in streptozotocin‐diabetic rats: Reversal by dietary l‐arginine treatment

Painful diabetic neuropathy (PDN) is a long‐term complication of diabetes. Defining symptoms include mechanical allodynia (pain due to light pressure or touch) and morphine hyposensitivity. In our previous work using the streptozotocin (STZ)‐diabetic rat model of PDN, morphine hyposensitivity developed in a temporal manner with efficacy abolished at 3 months post‐STZ and maintained for 6 months post‐STZ. As this time course mimicked that for the temporal development of hyposensitivity to the pain‐relieving effects of the furoxan nitric oxide (NO) donor, PRG150 (3‐methylfuroxan‐4‐carbaldehyde) in STZ‐diabetic rats, we hypothesized that progressive depletion of endogenous NO bioactivity may underpin the temporal loss of morphine sensitivity in STZ‐diabetic rats. Furthermore, we hypothesized that replenishment of NO bioactivity may restore morphine sensitivity in these animals. Diabetes was induced in male Dark Agouti rats by intravenous injection of STZ (85 mg/kg). Diabetes was confirmed on day 7 if blood glucose concentrations were ≥15 mmol/L. Mechanical allodynia was fully developed in the bilateral hindpaws by 3 weeks of STZ‐diabetes in rats and this was maintained for the study duration. Morphine hyposensitivity developed in a temporal manner with efficacy abolished by 3 months post‐STZ. Administration of dietary l ‐arginine (NO precursor) at 1 g/d to STZ‐diabetic rats according to a 15‐week prevention protocol initiated at 9 weeks post‐STZ prevented abolition of morphine efficacy. When given as an 8‐week intervention protocol in rats where morphine efficacy was abolished, dietary l ‐arginine at 1 g/d progressively rescued morphine efficacy and potency. Our findings implicate NO depletion in the development of morphine hyposensitivity in STZ‐diabetic rats.     

Deep sea minerals ameliorate diabetic‐induced inflammation via inhibition of TNFα signaling pathways

It has been well‐documented that the consumption of deep sea water (DSW) has beneficial effects on myocardial hypertrophy and cardiac apoptosis induced by hypercholesterolemia. However, the molecular mechanisms for the anti‐inflammatory effects of DSW on diabetic cardiomyopathy are still largely unclear. The main purpose of this present study was to test the hypothesis that DSW exerts anti‐inflammatory effects through the suppression of the TNF‐α‐mediated signaling pathways. IP injection of streptozotocin (STZ) at the dose of 65 mg/kg was used to establish a diabetes rat model. DSW mineral extracts that diluted in desalinated water were prepared in three different dosages and administered to the rats through gavages for 4 weeks. These dosages are DSW‐1X (equivalent to 37 mg Mg²⁺/kg/day), 2X (equivalent to 74 mg Mg²⁺/kg/day) and 3X (equivalent to 111 mg Mg²⁺ mg/kg/day). Immunofluorescence staining and Western blot showed that the protein expression level of TNF‐α was markedly higher in the STZ‐induced diabetic rat hearts than in the control group. Consequently, the phosphorylation levels of the TNF‐α‐modulated downstream signaling molecules and P38 mitogen‐activated protein kinases (MAPKs) were notably elevated in heart tissues of STZ‐induced diabetes. These higher phosphorylation levels subsequently upregulated NF‐κB‐modulated inflammatory mediators, such as cyclooxygenase (COX)‐II and inducible nitric oxide synthase (iNOS). However, treatment with DSW as well as MgSO₄, the main mineral in DSW, significantly reversed all the alterations. These findings suggest that DSW has potential as a therapeutic agent for preventing diabetes‐related cardiovascular diseases.     

Tropisetron ameliorates early diabetic nephropathy in streptozotocin‐induced diabetic rats

It has been well established that oxidative stress and inflammation are involved in the pathogenesis of diabetic nephropathy. It has been shown that tropisetron exerts anti‐inflammatory and immunomodulatory properties. The current study was designed to investigate protective effects of tropisetron on early diabetic nephropathy in streptozotocin‐induced diabetic rats. Rats were divided into six groups: (i) untreated diabetic (streptozotocin group); (ii) untreated control; (iii) diabetic rats treated with tropisetron (3 mg/kg); (iv) normal rats treated with tropisetron (3 mg/kg); (v) diabetic rats treated with granisetron (3 mg/kg); and (vi) normal rats treated with granisetron (3 mg/kg); rats began receiving treatment at the time of diabetes induction for 2 weeks. At the termination of the experiments, bodyweight, kidney index, urinary albumin excretion, and glomerular filtration rate were measured. The levels of oxidative stress markers and tumour necrosis factor‐α were also determined. Streptozotocin‐treated animals showed significant loss of bodyweight and renal enlargement and dysfunction. Diabetic rats also exhibited an increase in malondialdehyde along with a significant decrease in glutathione, superoxide dismutase activity, and catalase activity. Furthermore, the diabetic animals demonstrated a significant rise in renal cortical, urinary tumour necrosis factor‐α, and urinary albumin excretion. Both granisetron and tropisetron decreased blood glucose in diabetic animals, but this decrease was not significant for granisetron. Treatment with tropisetron, but not granisetron, prevented increases in oxidative stress and tumour necrosis factor‐α, decreased urinary cytokine excretion and albuminuria, and improved renal morphological damage. In conclusion, the present study suggests that tropisetron may be a protective agent in early diabetic nephropathy, and its action is mediated, at least in part, by anti‐oxidative and anti‐inflammatory mechanisms that appear to be independent of the 5‐HT₃ receptor.     

Hesperidin,a flavanoglycone attenuates experimental diabetic neuropathy via modulation of cellular and biochemical marker to improve nerve functions

Aim: Diabetic neuropathy (DN) is one of the most common long-term complications of diabetes mellitus and clinically can be characterized by an elevated nociceptive response with electrophysiological conduction abnormalities. The present investigation was designed to evaluate the neuroprotective effect of hesperidin against STZ induced diabetic neuropathic pain in laboratory rats.

Materials and methods: DN was induced in Sprague–Dawley rats (150–200?g) by intraperitoneal administration of streptozotocin (STZ) (55?mg/kg, p.o.). Rats were divided into various groups, namely, STZ control (vehicle), hesperidin (25, 50, and 100?mg/kg, p.o.), insulin (10?IU/kg, s.c.), and combination of hesperidin (100?mg/kg, p.o.) with insulin (10?IU/kg, s.c.) for 4 weeks. Various behavioral (allodynia and hyperalgesia), biochemical parameters [oxido-nitosative stress, Na–K–ATPase, aldose reductase (AR)], and molecular changes (TNF-α and IL-1β) along with hemodynamic changes were determined.

Results: Rats treated with hesperidin (50 and 100?mg/kg, p.o., 4 weeks) significantly reduced (p?p?p?Conclusion: In combination with insulin, hesperidin not only attenuated the diabetic condition but also reversed neuropathic pain via control over hyperglycemia as well as hyperlipidemia to down-regulate generation of free radical, release of pro-inflammatory cytokines as well as elevation in membrane bound enzyme.     

Healing effects of sumac (Rhus coriaria) in streptozotocin-induced diabetic rats

Context Sumac [Rhus coriaria L. (RC) (Anacardiaceae)] is used as a folk medicine in the treatment of diabetes in Turkey.

Objective This study investigates the in vivo healing and protective effects of lyophilized extract sumac against streptozotocin (STZ)-induced diabetic complications.

Materials and methods Toxicity test was conducted in three different dosages (250, 500 and 1000?mg/kg of plant extracts, respectively). Six groups of seven rats each were used in experiments. Groups were designed as Normal control, Diabetic (DM), DM?+?AC-20?mg/kg, DM?+?Extract-100?mg/kg, DM?+?Extract 250?mg/kg and DM?+?Extract 500?mg/kg group. Experimental diabetes [50?mg/kg, intraperitoneal (i.p.)] was induced by STZ. The effects of oral administration of the extract for 21 d on the level of serum glucose, insulin, C-peptide, lipid profile (LP), hepatic and renal damage biomarkers (HRDB), diabetic serum biomarkers (DSB), glycosylated haemoglobin (HbA1c), antioxidant defence system constituents (ADSCs), malondialdehyde (MDA) and α-glucosidase activity in small intestine tissue were evaluated.

Results The extract decreased the levels of blood glucose in diabetic groups (an average of 31%). Triglyceride, total cholesterol, high-density lipoprotein and low-density lipoprotein levels were balanced by plant extract (500?mg/kg) supplementation in the diabetic group. Decreased levels of aspartate aminotransferase (89%), alanine aminotransferase (91%), lactate dehydrogenase (35%), alkaline phosphatase (47%), creatinine (25%) and urea (29%) were detected in plant extract (500?mg/kg) supplemented diabetic group. Additionally, a considerable increase in the HRDB, DSB, LP, MDA and fluctuated ADSC levels were restored in RC-extract supplemented groups.

Conclusion RC lyophilized extract has a healing effect on diabetes and diabetes-related complications.     

Argirein alleviates corpus cavernosum dysfunction by suppressing pro‐inflammatory factors p66Shc and ER stress chaperone Bip in diabetic rats

Objectives The aim was to investigate whether argirein, which releases rhein and l ‐arginine after medication, could improve erectile dysfunction (ED) in diabetic rats through normalising the abnormalities of nitric oxide synthase (NOS), p66Shc and immunoglobulin heavy‐chain binding protein (Bip), in the corpus cavernosum (CC). Methods SD rats were randomly divided into six groups. Except for the control group, rats were injected with streptozotocin (STZ) (60 mg/kg, i.p.) once. During weeks 5–8 following STZ injection, except for STZ‐injected untreated rats, others were treated with aminoguanidine (AMG; 100 mg/kg/day, i.g.), or argirein at three doses (50, 100 and 200 mg/kg/day, i.g.). The vascular activity and biomarkers of the cavernosum were examined. Key findings Constrictive and dilative activity was abnormal in the CC, associated with decreased nitric oxide (NO) in serum in the diabetic (DM) group. Increased expression of p66Shc, Bip and inducible nitric oxide synthase (iNOS) and decreased endothelial nitric oxide synthase (eNOS) in the CC were significant in DM rats. Argirein and AMG improved these abnormities significantly. Conclusions We concluded that vascular activity of the cavernosal tissue was impaired due to upregulated p66Shc and Bip in the diabetic CC. Argirein alleviates the vascular dysfunction of the CC by suppressing these upregulated pro‐inflammatory proteins caused by diabetic lesions.     

Effects of adrenergic drugs on isolated and perfused hearts of streptozotocin-induced diabetic rats

To examine the myocardial contractile response of the diabetic heart, effects of isoproterenol (ISO) and norepinephrine (NE) on perfused hearts isolated from streptozotocin (STZ)-induced diabetic rats and insulin-treated diabetic rats were evaluated. Male Sprague-Dawley rats, weighing 200-260 g, were divided into the control (C)-group, diabetes mellitus (DM)-group and diabetes mellitus treated with insulin (DMI)-group. The C group was injected with buffered vehicle. DM and DMI groups were injected intravenously with 60 mg/kg STZ on the first day. Three days after STZ injection, the DMI group was subsequently treated with 4 U of Lente insulin subcutaneously every day. At 45 days after injection of STZ, experiments were performed using a Langendorff perfused heart preparation. The heart was paced at 300 beats/min, and myocardial developed tension (T) was measured isometrically. Plasma glucose values (mg/dl) were 142.4 +/- 8.7 in C, 499.3 +/- 15.6 in DM and 370.6 +/- 27.6 in DMI group. The order of percent increase in T induced by ISO (3 X 10(-9) - 3 X 10(-8) g) was C = DMI much greater than DM, and that by NE (10(-7) - 10(-6) g) was C greater than DMI greater than DM. On the other hand, the percent increase in T induced by CaCl2 (1.1 X 10(-4) - 2.2 X 10(-3) g) and aminophylline (AMI, 0.31 X 10(-3) - 5.00 X 10(-3) g) was not significantly different among three groups. These results indicate that adrenergic receptor-mediated contractile response was significantly depressed in the diabetic heart.     

Hypoglycaemic effect of Melothria heterophylla in streptozotocin-induced diabetic rats

Context: In the Indian traditional system of medicine, Melothria heterophylla (Lour.) Cogn., (Cucurbitaceae) is prescribed for the treatment of diabetes mellitus.

Objective: In the present study, the antidiabetic effect of ethanol extract of Melothria heterophylla (EEMH), and its active isolated constituents were investigated in streptozotocin (STZ)-induced diabetic Swiss albino rats.

Method: Successive Soxhlet extraction of the dried total aerial parts with petroleum ether for defatting and then with ethanol (95%) to obtain ethanol extract, which was concentrated under reduced pressure. Hyperglycemia was induced in rats by STZ (50 mg/kg, body weight). Twenty-four hours after STZ induction, respective groups of diabetic rats received EEMH (200 and 400 mg/kg, body weight), gallic acid (GA) (2 and 4 mg/kg, body weight), and rutin (RU) (2 and 4 mg/kg, body weight), respectively, orally daily for 15 days. Glibenclamide (0.5 mg/kg, orally) served as reference. Blood glucose levels and change in body weight were measured on every 5^th day during 15 days of treatment. Biochemical parameters, viz., serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP) and serum insulin, were measured.

Results: EEMH and its active constituents significantly (p < 0.01) normalized blood glucose levels and serum biochemical parameters as compared to those of STZ controls. Both GA (4 mg/kg) and RU (4 mg/kg) exhibited maximum glucose lowering effect (69.1 and 66.7%, respectively) in diabetic rats compared to the other dose (2 mg/kg) at the end of the study. EEMH, gallic acid and RU also showed significant increase in serum insulin, and body weight of STZ-induced diabetic rats.

Conclusion: Therefore, ethanol extract of Melothria heterophylla, GA and RU demonstrated remarkable antidiabetic activity in STZ-induced diabetic rats.     

New 1,4‐Dihydropyridines Down‐regulate Nitric Oxide in Animals with Streptozotocin‐induced Diabetes Mellitus and Protect Deoxyribonucleic Acid against Peroxynitrite Action

Diabetes mellitus (DM) and its complications cause numerous health and social problems throughout the world. Pathogenic actions of nitric oxide (NO) are responsible to a large extent for development of complications of DM. Search for compounds regulating NO production in patients with DM is thus important for the development of pharmacological drugs. Dihydropyridines (1,4‐DHPs) are prospective compounds from this point of view. The goals of this study were to study the in vivo effects of new DHPs on NO and reactive nitrogen and oxygen species production in a streptozotocin (STZ)‐induced model of DM in rats and to study their ability to protect DNA against nocive action of peroxynitrite. STZ‐induced diabetes caused an increase in NO production in the liver, kidneys, blood and muscles, but a decrease in NO in adipose tissue of STZ‐treated animals. Cerebrocrast treatment was followed by normalization of NO production in the liver, kidneys and blood. Two other DHPs, etaftorone and fenoftorone, were effective in decreasing NO production in kidneys, blood and muscles of diabetic animals. Furthermore, inhibitors of nitric oxide synthase (NOS) and an inhibitor of xanthine oxidoreductase (XOR) decreased NO production in kidneys of diabetic animals. Treatment with etaftorone decreased expression of inducible NOS and XOR in kidneys, whereas it increased the expression of endothelial NOS. In vitro, the studied DHPs did not significantly inhibit the activities of NOS and XOR but affected the reactivity of peroxynitrite with DNA. These new DHPs thus appear of strong interest for treatment of DM complications.     

Hypoglycemic activity of Erythrina variegata leaf in streptozotocin-induced diabetic rats

Context: Erythrina variegata Linn. (Fabaceae), commonly known as Tiger’s Claw, is a thorny deciduous tree grown in tropical and subtropical regions of Eastern Africa, Southern Asia, and Northern Australia. In India, its leaves are traditionally used for diabetes mellitus.

Objective: To evaluate the hypoglycemic activity of methanol extract of E. variegata leaf (MEEV) in streptozotocin (STZ)-induced diabetic Wistar rats.

Materials and methods: Hyperglycemia was induced in rats by single intraperitoneal injection of STZ (55?mg/kg body weight). Three days after STZ induction, the hyperglycemic rats were treated with MEEV orally at the doses of 300, 600, and 900?mg/kg body weight daily for 21 days. Glibenclamide (1?mg/kg, orally) was used as reference drug. The fasting blood glucose levels were measured on every 7th day during the 21 days of treatment. Serum biochemical parameters including lipid content were estimated.

Results and discussion: MEEV at the doses of 300, 600, and 900?mg/kg orally significantly (P?<?0.01) and dose-dependently reduced and normalized blood glucose levels as compared to that of STZ control group; the dose 900?mg/kg being the most potent showing complete normalization of blood glucose levels. Serum biochemical parameters including lipid profile were significantly (P?<?0.01) restored toward normal levels in META-treated rats as compared to STZ control animals.

Conclusion: This study concludes that E. variegata leaf demonstrated promising hypoglycemic action in STZ-induced diabetic rats substantiating its ethnomedicinal use.     

Antidiabetic effect of Streblus asper in streptozotocin-induced diabetic rats

Context: In the Indian traditional system of medicine, Streblus asper Lour (Moraceae) is prescribed for the treatment of diabetes mellitus.

Objective: In the present study, α-amyrin acetate isolated from S. asper, and the petroleum ether extract of S. asper stem bark (PESA) was screened for their antidiabetic properties in streptozotocin (STZ)-induced diabetic rats.

Materials and methods: Successive Soxhlet extraction of the dried stem bark with petroleum ether and then with ethanol (95%) yielded petroleum ether and ethanol extracts, respectively, which were concentrated under reduced pressure. Hyperglycemia was induced in rats by STZ (50?mg/kg, b.w.). Twenty-four hours after STZ induction, respective groups of diabetic rats received PESA (100, 250 and 500?mg/kg, b.w.) and α-amyrin acetate (25, 50 and 75?mg/kg, b.w.) respectively, orally daily for 15 days. Glibenclamide (0.5?mg/kg, orally) served as a reference. Blood glucose levels were measured on every 5th day during the 15 days of treatment. The serum lipid profiles and biochemical parameters, viz., serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP), insulin and glycosylated hemoglobin level, were measured.

Results: PESA significantly (p < 0.01) normalized blood-glucose levels and serum biochemical parameters as compared with those of STZ controls. α-Amyrin acetate (75?mg/kg, b.w.) exhibited maximum glucose lowering effect (71.10%) in diabetic rats compared to the other dose (25, 50?mg/kg) at the end of the study. The protective effect was further confirmed by histopathological examination of the liver.

Conclusion: PESA and α-amyrin acetate demonstrated remarkable antidiabetic activity in STZ-induced diabetic rats.     

Anti‐inflammatory properties of resveratrol in the retinas of type 2 diabetic rats

Resveratrol (trans‐3,5,4′‐trihydroxystilbene) is a nutritional supplement with anti‐inflammatory properties. The present study investigated the long‐term anti‐inflammatory property of resveratrol in the retinas of type 2 diabetic rats. Male Wistar rats were divided into four groups: normal control, diabetic control, resveratrol‐treated normal rats and resveratrol‐treated diabetic rats. Type 2 diabetes was induced by a single dose injection of streptozotocin (50 mg/kg; i.p.) 15 min after the administration of nicotinamide (110 mg/kg; i.p.) in 12‐h fasted rats (the streptozotocin–nicotinamide type 2 diabetic model). Oral resveratrol administration (5 mg/kg per day for 4 months) significantly improved glucose tolerance, and alleviated hyperglycemia and weight loss in diabetic rats. Furthermore, resveratrol administration significantly decreased the elevated levels of nuclear factor‐κB activity, and mRNA expression, tumour necrosis factor alpha level and apoptotic cells in the retinas of the diabetic rats. Furthermore, resveratrol did not significantly affect plasma insulin levels. Long‐term resveratrol administration has beneficial anti‐inflammatory properties in a rat model of diabetes. However, whether resveratrol exerts its effects directly or through reducing blood glucose levels requires further investigation.     

Protective Effects of d‐Limonene on Lipid Peroxidation and Antioxidant Enzymes in Streptozotocin‐Induced Diabetic Rats

The aim of this study was to evaluate the protective effects of d ‐limonene on the levels of lipid peroxidation by‐products and antioxidant defence systems in the plasma and tissues of normal and streptozotocin (STZ)‐induced diabetes rats. The experimental diabetes was induced in rats by a single dose of STZ (40 mg/kg i.p.) injection, and treatment with d ‐limonene was continued for 45 days. After the treatment period, oxidative stress parameters such as lipid peroxidation by‐products; enzymatic antioxidants such as superoxide dismutase, catalase, glutathione peroxidase and glutathione‐S‐transferase; non‐enzymic antioxidants including reduced glutathione, Vitamins C and E were measured in the plasma and tissues of experimental rats. An increase in the levels of lipid peroxidation by‐products and significant decrease in antioxidant enzymes were observed in untreated diabetic rats. Administration of d ‐limonene to diabetic rats for 45 days caused a significant reduction in the levels of lipid peroxidation by‐products and an increase in the activities of antioxidant enzymes, when compared with the untreated diabetic group. There was no significant difference in normal treated groups, when compared with normal rats. Biochemical observations were substantiated with the help of histopathological examinations through its antioxidant properties and thereby conferred protection against STZ‐induced diabetic rats. The result of this study indicates that d ‐limonene has antioxidant potential in addition to its antidiabetic effect in experimental diabetes.     

Effects of dobutamine and acetylcholine on perfused hearts isolated from streptozocin-induced diabetic rats

In order to study the responsiveness of the diabetic heart to autonomic agents, effects of dobutamine (DOB) and acetylcholine (ACh) on perfused hearts isolated from streptozocin (streptozotocin, STZ)-induced diabetic rats and insulin-treated diabetic rats were evaluated. Male Sprague-Dawley rats, weighing 180-210 g, were divided into control (C) group, diabetes mellitus (DM) group, and diabetes mellitus treated with insulin (DMI) group. C group was injected with buffered vehicle. DM and DMI groups were injected intravenously with 60 mg/kg STZ at the first day. Three days after STZ injection, DMI group was subsequently treated with 4 U of insulin zinc suspension (lente insulin) subcutaneously every day. At 45 days after injection of STZ, experiments were performed using a Langendorff perfused heart preparation. In the evaluation of effect of ACh, heart rate and myocardial developed tension (T) were measured. In the evaluation of effect of DOB, heart was paced at 300 beats/min and T was measured isometrically. Plasma glucose values (mg/dl) were 116.0 +/- 4.9 in C, 482.3 +/- 30.3 in DM, and 204.6 +/- 34.8 in DMI group, respectively. The order of percent increases in T induced by DOB (10(-8)-3 x 10(-6) g) was C greater than DMI greater than DM. The order of percent decreases in T and heart rate by ACh (10(-7)-3 x 10(-6) g) was C greater than DMI greater than DM. These results suggest that both adrenergic receptor-mediated and cholinergic receptor-mediated cardiac responsiveness are significantly depressed in the diabetic heart.     

Does Bosentan Protect Diabetic Brain Alterations in Rats? The Role of Endothelin‐1 in the Diabetic Brain

Diabetes mellitus (DM) is a major problem all over the world, affecting more people in recent years. Individuals with diabetes are more prone to disease than non‐diabetics, especially vascular complications. The aim of this study was to examine the roles of the endothelin (ET)‐1 in brain damage formed in a streptozocin (STZ)‐induced diabetes model, and the effect of bosentan, which is the non‐specific ET1 receptor blocker in the prevention of the diabetes‐induced brain damage. To examine the effects of bosentan (50 mg/kg and 100 mg/kg) in this study, the rats were given the drug for 3 months. The rats were divided into four groups: the sham group (n = 10), the diabetic control group (n = 10), the group of diabetic rats given bosentan 50 mg/kg (n = 10) and the group of diabetic rats given bosentan 100 mg/kg (n = 10). Diabetes was induced in the rats by STZ (60 mg/kg i.p.). On day 91, all rats were killed. Brain tissues of the rats were measured by molecular, biochemical and histopathological methods. Antioxidant levels in the therapy groups were observed as quite near to the values in the healthy group. In this study, while the brain eNOS levels in the diabetic groups decreased, the ET1 and iNOS levels were found to be increased. However, in the diabetes group, hippocampus and cerebellum, pericellular oedema and a number of neuronal cytoretraction were increased in neuropiles, whereas these results were decreased in the therapy group. Based on all of these results, ET1 will not be ignored in diabetes‐induced cerebral complications.