Influence of streptozotocin-induced diabetes on blood pressure and on renin formation and release

Summary I.v. injection of 40 mg/kg or 65 mg/kg streptozotocin reliably induced diabetes in female Sprague-Dawley rats, but failed to induce hypertension within the following 42 days. In most animals injected with the higher dose and in some animals injected with the lower dose, the tail blood flow was permanently impaired so that no blood pressure signals could be obtained by tail plethysmography. This phenomenon occurred also when the drug was injected into the jugular vein and thus was not due to a local effect of streptozotocin. 15 days after 65 mg/kg streptozotocin, the mean arterial pressure of the rats was similar to that of controls, when measured in the awake state (carotid cannula) or under ether anaesthesia. 42 days after streptozotocin, under pentobarbital anaesthesia, the blood pressure was again normal in the animals given 40 mg/kg of the drug and depressed in the animals given 65 mg/kg of the drug 42 days previously. The increase of blood pressure induced by 1 g/kg (–)-noradrenaline i.v. was similar in the latter group of animals and in controls.The renal cortical renin concentration was much lower than in controls 42 days after either dose of streptozotocin, while the plasma renin activity was normal (40 mg/kg) or increased (65 mg/kg). The low renal renin content may have been due to the diabetic state, rather than to the drug itself. Adrenal medullary dopamine-beta-hydroxylase activity was increased 42 days after the higher dose of streptozotocin.Supported by the Swiss National Science Foundation, grant Nr. 3.410.078     

A study comparing the effects of rosiglitazone and/or insulin treatments on streptozotocin induced diabetic (type I diabetes) rat aorta and cavernous tissues

Our aim was to investigate the role of oxidative stress and inflammation on the functional and biochemical changes caused by hyperglycemia in the aorta and corpus cavernosum tissues of streptozotozin diabetic rats and to determine if rosiglitazone and/or insulin treatment has any preventive effect on organ dysfunction. Wistar Albino rats were divided into 2 groups. I) Control group: a) Vehicle, 0.1 M citrate buffer, the solvent of streptozotocin injected intraperitoneally (i.p) and b) Rosiglitazone group: (4 mg/kg/day, i.p.) for 8 weeks. II) Diabetic group: streptozotocin (60 mg/kg) was administered i.p. to induce diabetes. 48 h after streptozotocin injection, animals were divided into 4 subgroups (n=6 for each group); a) no treatment group (D), b) treated with rosiglitazone (4 mg/kg/day) (DR), c) treated with insulin (6 U/kg/day) (DI) and d) treated with insulin and rosiglitazone (DRI) for 8 weeks. At the end of the experimental period, animals were decapitated and tissue samples were collected for in vitro experiments and biochemical studies. Endothelium dependent relaxation induced by acetylcholine in the aorta and corpus cavernosum tissues were attenuated in the diabetic group, whereas phenylephrine induced contractile responses were reduced. These responses were restored after rosiglitazone and/or insulin treatment, the combination being the most efficient treatment. Malondialdehyde and TNF-α levels were increased in diabetic rats while glutathione levels were decreased. All treatments prevented these changes in biochemical parameters, rosiglitazone and insulin combination again being the most efficient treatment. Our results suggested that supplementing diabetic patients receiving insulin treatment with adjunct therapy of rosiglitazone may have some benefit for controlling diabetic complications.     

Effect of nifedipine on severe experimental cataract in diabetic rats

We examined the effects of Ca(2+)-channel blockers on sugar cataract formation in streptozotocin (65 mg/kg, i.v.)-induced diabetic rats that were given 5% D-glucose as drinking water. The diabetic rats were treated with an L-type Ca(2+)-channel blocker, nifedipine or verapamil, for 9 weeks from the 3rd day of streptozotocin injection. Using the full lens images of the horizontal plane captured with the new digital camera system that we developed recently, the cataract formation was quantitatively assessed in parallel with the conventional scaling method. In the animal model of diabetes mellitus, the cataracts at the peripheral region of the lens were detected 2 weeks after induction of hyperglycemia and progressed depending on the length of the diabetic period. The majority of them developed mature cataracts after 9 weeks of hyperglycemia. Nifedipine slowed the progression rate of diabetic cataracts without affecting the period of time required for the onset of this disease, whereas verapamil had no significant inhibitory effect on the diabetic cataract. These findings suggest that nifedipine may be considered as a candidate drug to suppress the progression of diabetic cataracts.     

Altered neuroexcitability in experimental diabetic neuropathy: effect of acetyl-L-carnitine.

Sciatic nerve conduction velocity (NCV) is reduced in rats made hyperglycaemic with streptozotocin (STZ). This neurophysiological dysfunction has been associated with increased nerve sorbitol and reduced nerve inositol. Treatment of STZ diabetic rats with aldose reductase inhibitors (ARIs) which reduce sorbitol and increase inositol in the nerve results in normalization of NCVs. Male Wistar rats were made diabetic with 50 mg/kg of streptozotocin given intraperitoneally. Those animals with blood glucose > 300 mg/dl two weeks later were included in this study. The STZ-diabetic rats were treated with either the ARI sorbinil (40 mg/kg per day), or acetyl-L-carnitine (ALC) (300 mg/kg per day) or sterile 0.15% aqueous NaCl for 16 weeks after 4 or 8 weeks of untreated hyperglycaemia. A control group of non-diabetic rats received no treatment during the interval. Sciatic-nerve sorbitol was elevated (1.08 +/- 0.13 nanomol/mg wet weight vs. 0.19 +/- 0.03 nm/mg wet weight) and inositol was reduced (1.21 +/- 0.12 nm/mg ww vs. 2.02 +/- 0.08 nm/mg ww) in the STZ diabetic rats, which were untreated for 4 weeks. Treatment with sorbinil was associated with normalization of the tissue sorbitol (0.10 +/- 0.05 nm/mg ww), while ALC treatment also significantly reduced the nerve sorbitol but only to a level (0.34 +/- 0.08 nm/mg ww) more elevated than the normal level. The nerves of STZ animals treated with sorbinil or ALC had inositol levels no different from untreated diabetic rats. Thus, hyperglycaemic animals treated with either ALC or sorbinil had similar improvements in NCVs as the diabetic, even though the effect on nerve sorbitol was different and nerve inositol was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sertraline and cocaine-induced locomotion in mice

The effects of repeated treatment with the serotonin uptake blocker sertraline on cocaine-induced locomotion in female C57BL/6ByJ mice were examined in three paradigms. First, when animals were treated for 2 weeks with a daily injection of 8 mg/kg IP of sertraline (or placebo) and challenged with cocaine (25 mg/kg IP) 1 h after the final sertraline injection, their cocaine-induced locomotion was the same as that of placebo-pretreated controls. Second, animals were treated for 2 weeks with cocaine (25 mg/kg IP once a day) (or saline) and then for 2 weeks with sertraline (8 mg/kg IP once a day) (or placebo). Locomotion induced by cocaine (25 mg/kg IP) administered 1 h after the final sertraline (placebo) injection was higher in cocaine- than saline-pretreated mice (sensitization), but there was no difference between sertraline- and placebo-pretreated animals. Third, daily treatment with sertraline (8 mg/kg IP) did not change the locomotor stimulatory effect of cocaine (25 mg/kg IP) administered after a 3-week continuous infusion of cocaine (22 mg/kg/day SC) by osmotic minipumps or after three, four, or seven injections of cocaine (15 or 25 mg/kg IP). After cocaine administration (25 mg/kg IP), animals pretreated repeatedly with sertraline (8 mg/kg IP once a day for 2 weeks) had the same plasma or brain levels of cocaine as those pretreated with placebo; there was no difference between cocaine- and saline-treated mice in brain levels of sertraline or desmethylsertraline.     

Effect of scoparia dulcis (Sweet Broomweed) plant extract on plasma antioxidants in streptozotocin-induced experimental diabetes in male albino Wistar rats

Clinical research has confirmed the efficacy of several plants in the modulation of oxidative stress associated with diabetes mellitus. Scoparia dulcis plant extract is tried for prevention and treatment of diabetes mellitus induced experimentally by streptozotocin injection. A single dose of streptozotocin (45 mg/kg body weight) produced decrease in insulin, hyperglycemia, increased lipid peroxidation (Thiobarbituric reactive substances and lipid hydroperoxides) and decreased antioxidant levels (vitamin C, vitamin E, reduced glutathione, ceruloplasmin). Oral administration of an aqueous extract of Scoparia dulcis plant (200 mg/kg body weight) for 6 weeks to diabetic rats significantly increased the plasma insulin and plasma antioxidants and significantly decreased lipid peroxidation. The effect of Scoparia dulcis plant extract at 200 mg/kg body weight was better than that of glibenclamide, a reference drug.     

In vivo recovery effect of silibinin treatment on streptozotocin-induced diabetic mice is associated with the modulations of Sirt-1 expression and autophagy in pancreatic β-cell

Improper adjustments of autophagy and silent information regulator 1 (Sirt-1) expression were reported to be closely associated with metabolic disorders. In this study, we examined the roles of Sirt-1 and autophagy in streptozotocin-induced diabetes mellitus, assessed the relationship between autophagy and Sirt-1, and investigated the protective mechanism of silibinin. Diabetes was induced in 6-week-old mice by intravenous injection of streptozotocin (150?mg/kg/day, for 2 weeks). In the treatment groups, silibinin (50?mg/kg/day, intramuscular injection, for 8 weeks) or inhibitors (50?mg/kg/day, subcutaneous injection, for 8 weeks) were given. Diabetic control animals received vehicle for the same time. Compared with diabetic controls, silibinin or autophagy inhibitor, 3-methyladenine, treated mice showed decreased levels of glycosylated hemoglobin A1C (P?相似文献   

Effects of gamma-vinyl GABA (vigabatrin) on blood pressure and body weight of hypertensive and normotensive rats

Summary Inactivation of GABA was inhibited by -vinyl GABA (GVG) and the effects of the increased GABA level in the brain on blood pressure and body weight of spontaneously hypertensive rats (SHR) and normotensive rats (WKY) were investigated.When started at the age of 8 weeks or 5 weeks, treatment of SHR and WKY with GVG (150 mg/kg, s.c.) for several weeks did not influence systolic blood pressure. In 1-week old SHR, treatment with GVG (up to 150 mg/kg, s.c.) abolished the rise in blood pressure until animals were 8 weeks old. Thereafter, arterial blood pressure started to increase but it remained distinctly lower than that in untreated animals. When started at the age of 1 week, treatment with GVG for 7 weeks did not influence arterial blood pressure in WKY. GVG delayed increase in body weight in SHR and WKY, irrespective of their age. GVG greatly increased GABA levels in the hypothalamus, frontal cortex, brainstem and rest of the brain in both WKY and SHR.It is concluded that an increase in the GABA level in the brain leads to a delay in the development of hypertension in young SHR. Hence, development of genetic hypertension seems to be susceptible to activation of the GABAergic system in a very early critical phase only. Send offprint requests to N. Singewald at the above addressThis work was supported by the Fonds zur Förderung der wissenschaftlichen Forschung     

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.     

Effects of antidiabetic drugs in high-fat diet and streptozotocin-nicotinamide-induced type 2 diabetic mice

Based on previously established methods, we developed an easily available type 2 diabetic mouse model that exhibits obesity and insulin resistance. We investigated the effects of several antidiabetic drugs on this new model, which was induced by a high-fat diet in combination with streptozotocin and nicotinamide injection. Male ICR mice were fed a high-fat diet (45% of calories as fat) for 3weeks and then intraperitoneally administered with nicotinamide (1000mg/kg) and streptozotocin (150mg/kg). These diabetic mice exhibited hyperglycemia and glucose intolerance as a result of the loss of early-phase insulin secretion. The mice also developed significant insulin resistance, hyperlipidemia and obesity. A single dose of mitiglinide, glibenclamide, sitagliptin, insulin, metformin and voglibose significantly improved glucose tolerance during a liquid meal tolerance test. Repeated administration of sitagliptin and rosiglitazone also improved hyperglycemia and insulin resistance. These results demonstrate that a high-fat diet combined with nicotinamide and streptozotocin injection induces a diabetic mouse model that replicates the metabolic characteristics of human type 2 diabetes. This diabetic model, which exhibits impaired insulin secretion, glucose intolerance, insulin resistance, and obesity, may be suitable to evaluate antidiabetic agents for the treatment of type 2 diabetes.     

Effect of Withania somnifera on insulin sensitivity in non-insulin-dependent diabetes mellitus rats

We investigated the effect of an aqueous extract of Withania somnifera (WS) on insulin sensitivity in non-insulin-dependent diabetes mellitus (NIDDM) rats. NIDDM was induced by single intraperitoneal injection of streptozotocin (100 mg/kg) to 2 days old rat pups. WS (200 and 400 mg/kg) was administered orally once a day for 5 weeks after the animals were confirmed diabetic (i.e. 75 days after streptozotocin injection). A group of citrate control rats (group I) were also maintained that has received citrate buffer on the second day of their birth. A significant increase in blood glucose, glycosylated haemoglobin (HbA(1)c) and serum insulin levels were observed in NIDDM control rats. Treatment with WS reduced the elevated levels of blood glucose, HbA(1)c and insulin in the NIDDM rats. An oral glucose tolerance test was also performed in the same groups, in which we found a significant improvement in glucose tolerance in the rats treated with WS. The insulin sensitivity was assessed for both peripheral insulin resistance and hepatic insulin resistance. WS treatment significantly improved insulin sensitivity index (K(ITT)) that was significantly decreased in NIDDM control rats. There was significant rise in homeostasis model assessment of insulin resistance (HOMA-R) in NIDDM control rats whereas WS treatment significantly prevented the rise in HOMA-R in NIDDM-treated rats. Our data suggest that aqueous extract of WS normalizes hyperglycemia in NIDDM rats by improving insulin sensitivity.     

Possible involvement of facilitated polyol pathway in augmentation of intimal hyperplasia in rabbits with alloxan-induced hyperglycemia

Present experiments were designed to investigate whether the facilitated polyol pathway is involved in the augmentation of intimal hyperplasia with hyperglycemia. Twelve weeks after a single bolus intravenous injection of alloxan (100 mg/kg) or saline, rabbits underwent a unilateral endothelial denudation of the carotid artery. Intimal hyperplasia was evident 4 weeks after denudation and significantly augmented in hyperglycemic animals treated with alloxan. This effect was accompanied by the enhanced accumulation of endogenous NOS inhibitors (N(G)-monomethyl-l-arginine [l-NMMA] and asymmetric, N(G),N(G)-dimethyl-l-arginine [ADMA]) in regenerated endothelial cells, impairment of NO production and release, and enhanced accumulation of endothelin-1 (ET-1) within the vessel wall. Sorbitol levels in aortic endothelial cells and within the smooth muscle layer were significantly increased with hyperglycemia. All these changes associated with hyperglycemia were significantly reduced in animals treated with the selective aldose reductase inhibitor fidarestat (3 mg/kg/d). These findings suggest that the facilitated polyol pathway possibly plays an important role for the augmentation of intimal hyperplasia caused by the hyperglycemic state.     

Changes in glucose metabolism and cardiovascular responses in thyroidectomized streptozotocin treated diabetic rats (author's transl)

Two weeks after streptozotocin i.v. injection, changes in glucose metabolism, levels of serum and urinary calcium, magnesium and copper, and cardiovascular responses were investigated in thyroidectomized streptozotocin treated diabetic rats. These parameters were compared to those of intact rats. Serum and urinary calcium, magnesium and copper concentrations were not influenced by thyroidectomy. Glycosylated hemoglobin (HbA1) in thyroidectomized streptozotocin treated diabetic rats was higher than that in those which were thyroidectomized alone. In thyroidectomized rats that induction of hyperglycemia required dose of streptozotocin than for intact rats. Norepinephrine (0.3125, 0.625, 1.25 micrograms/kg i.v.)-induced pressor response and ACh (0.3125, 0.625, 1.25, 2.5 micrograms/kg i.v)-induced depressor responses were both reduced in streptozotocin treated diabetic rats. These reduced pressor and depressor responses tended to recover after thyroidectomy. These results suggest that hypothyroid states may partially improve glucose metabolism and cardiovascular responses in streptozotocin treated diabetic rats.     

环烯醚萜对烟酰胺-链脲霉素诱导的2型糖尿病小鼠生精功能的影响

目的:　探讨环烯醚萜对烟酰胺-链脲霉素诱导的2型糖尿病小鼠生精功能的影响。方法: 在本实验研究中,56只雄性小鼠随机分为7组(n=8)：对照组;糖尿病小鼠组;糖尿病小鼠服用格列本脲(0.25mg/kg)治疗组;糖尿病小鼠接受环烯醚萜(20和40mg/kg)治疗组;正常小鼠接受环烯醚萜(20和40mg/kg)治疗组。糖尿病模型制作：由腹腔注射链脲霉素(65mg/kg),15分钟后注射烟碱(120mg/kg)。然后,连续喂服格列本脲和环烯醚萜28天。最后一次治疗24小时后,提取血清样本、睾丸及附睾组织,测定血激素、观察睾丸病理切片、进行精子参数评估。结果: 糖尿病小鼠体重和睾丸质量,精子浓度和活力,血清LH、FSH和T水平明显下降(p < 0.05)。接受环烯醚萜治疗组小鼠前述下降的参数得到明显提升(p < 0.05)。结论: 结果表明,针对糖尿病小鼠应用环烯醚萜可降低氧化损伤的危重程度、有效提升其生育能力, 具有确切的临床应用价值。     

SD大鼠1型糖尿病动物模型的建立

目的探讨制作理想糖尿病动物模型的方法。方法采用空腹腹腔一次性注射65 mg/kg链脲佐菌素的方法,建立SD大鼠1型糖尿病模型。结果造模1周后测血糖均高于16.7 mmol/L。持续观察8周,血糖值始终在建模初期高血糖水平上波动,未见到复转,并出现典型的"三多一少"症状,胰腺符合糖尿病成模动物胰腺病理变化。结论采用空腹腹腔一次性注射65 mg/kg链脲佐菌素的方法复制出1型糖尿病模型,具有造模方法简便、用药量小、药物毒性较低、胰岛B细胞损害特异性高等优点,可应用于糖尿病及其并发症研究的各个领域。     

Action of N-isopropyl-α-(2-methylhydrazino)-p-toluamide hydrochloride (procarbazine hydrochloride) in the germ tissue of mice: dominant lethal effects

A study was carried out on the effects of N-isopropyl--(2-methylhydrazino)-p-toluamide (procarbazine, Natulan^®) in the dominant lethal test in the mouse. Male mice were dosed once and mated with fresh virgin females each week. The utilization of sperm, treated as spermatids or testicular sperm with 100–800 mg/kg, resulted in significant post-and pre-implantation death of embryos. Fertility was markedly reduced after the injection of 200 mg/kg of procarbazine and over. This is probably due to a cell killing effect, the most sensitive stages being differentiating spermatogonia, type A spermatogonia and resting primary spermatocytes. Total sterility was induced for several weeks with doses of 600 and 800 mg/kg. Up to 12 weeks after treatment the number of females with implants was still significantly lower than controls indicating a severe depletion of spermatogonial cells. The spectrum of effects correlates well with the drug's effect on nucleic acid and protein synthesis.     

Low molecular weight chitosan prevents the progression of low dose streptozotocin-induced slowly progressive diabetes mellitus in mice

The present study was designed to clarify the effect of low molecular weight (LMW) chitosan (chitosan lactate, average MW: 20000) on the progression of slowly progressive non-insulin-dependent diabetes mellitus (NIDDM) induced by a single i.p. injection of low dose (100 mg/kg) streptozotocin (STZ) to 8-week-old male ICR mice. The non-fasting serum glucose levels of STZ-treated control mice continued to rise throughout the experimental period until 23 weeks after STZ treatment. The 0.2% or 0.8% chitosan (water solution), given as drinking water from prediabetic stage (2 weeks after STZ treatment), markedly prevented the time course-related rise of serum glucose levels of diabetic mice. In addition, the reduction of relative numbers of insulin-immunoreactive cells (beta-cells) in the islets of diabetic mice at 24 weeks after STZ treatment was markedly prevented by 0.2% or 0.8% chitosan administration. However, the progression of hyperglycemia in diabetic mice was not affected by 0.2% glucosamine, a monosaccharide of chitosan. The glucose levels of normal mice were not affected by 0.8% chitosan administration. When 0.2% chitosan administration was stopped at 20 weeks, these animals had still maintained significantly lower serum glucose levels, compared to control animals, even at 5 weeks after stopping the administration. These results indicate that LMW chitosan prevents the progression of low dose STZ-induced slowly progressive NIDDM.     

Effects of garden cress,fenugreek and black seed on the pharmacodynamics of metoprolol: an herb-drug interaction study in rats with hypertension

ContextGarden cress (GC), fenugreek (FG), and black seed (BS) are traditional herbal medicine for managing hypertension.ObjectiveThe effects of the three herbs on the pharmacodynamics of metoprolol tartrate (MT) in hypertensive rats were investigated.Materials and methodsWistar rats were divided in five groups (n = 6). Group I served as normal control group and Group II (hypertensive control group) had rats treated orally with N-nitro L-arginine methyl ester (L-NAME, 40 mg/kg/day) only. Groups III, IV, and V rats were orally treated with L-NAME (40 mg/kg/day) + GC (300 mg/kg, once daily), L-NAME (40 mg/kg/day) + FG (300 mg/kg, once daily) and L-NAME (40 mg/kg/day) + BS (300 mg/kg, once daily), respectively, for 2 weeks, and on the 14th day, blood pressure and heart rate were recorded using a tail-cuff blood pressure-measuring system. On the 16th day, a single dose of MT (10 mg/kg) was orally administered, and the rats’ blood pressure and heart rate were recorded.ResultsGC, FG, and BS decreased systolic blood pressure (SBP) by 8.7%, 8.5%, and 8.7%, respectively, in hypertensive rats. A greater decrease in SBP by 14.5%, 14.8%, and 16.1% was observed when hypertensive rats were treated with L-NAME + GC + MT, L-NAME + FG + MT, and L-NAME + BS + MT, respectively. Similarly, hypertensive rats treated with the combination of herbs and MT had significantly lower diastolic blood pressure (DBP) than those treated with herbs alone and those treated with L-NAME alone.ConclusionsThe combination of investigated herbs and MT had a beneficial effect on hypertension. However, the concurrent administration of drugs, particularly those predominantly cleared through CYP450 2D6-catalyzed metabolism, with the three investigated herbs should be considered with caution.     

Potentiation of the behavioral and convulsant effects of cocaine by chronic administration in the rat

The effect of chronic administration on the behavioral response to cocaine was studied in male Sprague-Dawley rats. In experiment 1 five groups of rats received daily intraperitoneal injections of either saline, 20 mg/kg, or 40 mg/kg cocaine hydrochloride for 10 days, or of higher doses of cocaine until either one or three convulsions occured. Following this initial treatment, all animals were left untreated for seven days, and then sensitivity to cocaine was assessed in all animals by a test injection series (daily injections of increasing doses of cocaine). Animals which had received 40 mg/kg cocaine during the initial treatment exhibited a greater behavioral response (stereotyped behavior) to cocaine during the test injection series than did animals treated with saline; both the 40 mg/kg and one — convulsion treatments during the initial stage of the experiment resulted in greater sensitivity to the convulsant effect of cocaine during the test injection series. In experiment 2 animals were injected intraperitoneally with either saline or 40 mg/kg cocaine for 10 days and then tested with a series of daily cocaine injections of increasing dosage after remaining untreated for 4, 8, 16 or 32 days. The results indicated that the initial treatment with 40 mg/kg cocaine augmented both the behavioral and convulsant effects of cocaine during the subsequent test injection series. The sensitization to the convulsant effect of cocaine was significant at all intervals after initial treatment except 16 days, while the duration of sensitization to the behavioral effects of cocaine could not be determined due to apparent age-related changes in the response of control animals to cocaine. The sensitization which was observed was attributed to the effects of cocaine per se rather than to convulsions produced by the drug.     

Protective effect of pioglitazone against multiple low-dose streptozotocin-induced diabetes in rats

The autoimmune process is one of the etiological factors of diabetes in humans. Thiazolidinediones, which act through peroxisome proliferator-activated receptor-gamma, have been recently used to prevent diabetic-associated complications in patients with diabetes and insulin resistance. In the present study, we investigated the effect of pioglitazone on the diabetes induced by multiple low-dose streptozotocin (MLDS) in rats. When Sprague-Dawley rats were injected intraperitoneally with a sub-diabetogenic dose of streptozotocin (STZ; 40 mg/kg/day) for a period of 5 days, they developed hyperglycemia 2 days after posttreatment. Pioglitazone (6 mg/kg) administered orally for 7 days before the first dose of STZ prevented or delayed the development of MLDS-induced diabetes compared with the group treated only with STZ. Pioglitazone treatment showed no effect on plasma glucose levels in the control group. These findings suggest that pioglitazone prevented the autoimmune process involved in the development of MLDS-induced diabetes by decreasing glucose levels in rats.