Targeting apoptosis in the heart of streptozotocin-induced diabetic rats

To address the issue of cardiomyocyte apoptosis as a possible cause of diabetic cardiomyopathy and whether it would be possible to suppress this apoptosis by the use of PPAR gamma agonists [glitazones] and PPAR alpha agonists [fibrates], versus insulin. forty male rats were made diabetic by intraperitoneal [i.p.] streptozotocin [STZ] injection and were divided into four groups: group II [STZ-injected rats], groups III, IV and V [STZ-injected rats treated with insulin, PPAR gamma agonist [rosiglitazone] and PPAR alpha agonist [bezafirate] respectively, for twelve weeks starting one week following STZ injection]. Additionally, ten rats were injected i.p. by a single dose of saline and served as a control for group II. At the end of the experimental period, plasma glucose was measured. Left ventricular [LV] papillary muscles isometric force [developed tension [DT]] was determined. Oxidative stress as assessed by cardiac malondialdehyde [MDA] and reduced glutathione [GSH] concentrations as well as caspase-3 activity as an index of apoptosis were determined. STZ-injection induced diabetes, evidenced by significant higher mean value in plasma glucose concentration in group II compared to that of the control group I. Significant cardiomyopathy could be observed, in the form of significantly decreased DT of LV papillary muscles in group II compared to the control group I. STZ-injection resulted in oxidative stress evidenced by significant higher mean value in cardiac MDA concentration and significant lower mean value in cardiac GSH concentration in group II compared to the control group I. STZ-injection resulted in cardiac apoptosis evidenced by significant higher mean value in cardiac caspase-3 activity in group II compared to the control group I. The use of insulin, rosiglitazone as well as bezafibrate caused a significant decrease in plasma glucose concentration as well as a significant increase in body weight compared to group II. The use of insulin as well as rosiglitazone, but not bezafibrate, decreased cardiac caspase-3 activity and improved oxidative stress parameters evidenced by significant lower mean value in cardiac MDA concentration and significant higher mean value in cardiac GSH concentration compared to group II. Rosigitazone but neither insulin nor bezafibrate resulted in significant improvement of LV papillary muscle DT compared to group II. The results of the present study support the hypothesis that apoptosis plays a key role in the pathophysiology of diabetic cardiomyopathy and demonstrate that the use of PPAR gamma agonists might have a protective role against diabetic cardiomyopathy. We recommend further human studies to evaluate the role of the addition of PPAR gamma agonists to the treatment regimen of diabetes, from the onset of the disease, in protection against diabetic cardiomyopathy. Although the use of PPAR-alpha agonists seems counterintuitive in light of the current findings, the benefit of reduced delivery of fatty acids to the myocardium may outweigh the effects of activating the cardiac PPARalpha pathway in the diabetic patient

Role of oxidative stress in streptozotocin-induced diabetic neuropathy in rats

To assess the contribution of oxidative stress in the pathophysiology of diabetic neuropathy and the possible protective effect of L-carnitine, coenzyme Q 10 [CoQ10] and acetylsalicylic acid [ASA] in streptozotocin-included diabetic neuropathy in rats. We also examined whether the studied drugs can promote satisfactory regeneration of sciatic nerve fibers following sciatic nerve crushing. Twenty rats were used as control and were divided into two groups. 10 rats each: Group I a was injected intraperitoneal [i.p.] by a single dose of saline and served as a control for group II a, group I b similar to group I a but with induced sciatic nerve crushing and served as control for group II b. Eighty rats were made diabetic by i.p streptozotocin [STZ] injection and were divided into: group II a [STZ-injected rats], group II b [STZ-injected rats with sciatic nerve crushing], groups III a, IV a and V a [STZ-injected rats treated with L-carnitine, CoQ1O and ASA respectively, for six weeks starting one week following STZ injection], groups III b, IV b and V b [STZ-injected rats,with sciatic nerve crushing, that received the same drugs as groups III a, IV a and V a]. At the end of the experimental period, distal motor latency [DL], maximum peak and peak to peak amplitude of compound muscle action potential [CMAP] were measured by percutaneous sciatic nerve stimulation. Blood samples were collected for measurement of plasma glucose and malondialdehyde [MDA] concentrations. The sciatic nerve was isolated for measuring reduced glutathione [GSH] concentration. STZ-injection induced diabetes, evidenced by significant higher mean value in plasma glucose concentration in groups IIa and IIb compared to that of the control groups Ia and Ib respectively. Significant sciatic nerve dysfunction could be observed, in the form of significantly prolonged DL and significantly decreased maximum peak and peak to peak amplitude of CMAP, in groups IIa and IIb compared to the control groups Ia and Ib respectively. STZ-injection resulted in oxidative stress evidenced by significant higher mean value in plasma MDA concentration and significant lower mean value in sciatic nerve GSH concentration in groups IIa and IIb compared to the control groups Ia and Ib respectively. Sciatic nerve crushing in group I b resulted in significant prolongation of DL and significant decrease in maximum peak and peak to peak amplitude of CMAP compared to group I a. Sciatic nerve crushing in group I b also resulted in significant lower mean value of sciatic nerve GSH concentration compared to group I a. The use of L-carnitine, CoQ10 as well as ASA, did not cause a significant change in plasma glucose concentration nor in body weight compared to groups IIa and IIb. The use of the above mentioned drugs improved oxidative stress parameters evidenced by significant lower mean value in plasma MDA concentration and significant higher mean value in sciatic nerve GSH concentration compared to groups IIa and IIb. The increase in sciatic nerve GSH concentration in groups III b and IV b that received L-carnitine and CoQ10 respectively, was significant compared to group Vb that received ASA as an antioxidant, whereas no significant difference in plasma MDA was found between different drug-treated groups. The use of the studied drugs resulted in significant improvement of DL as well as significant increase in maximum peak and peak to peak amplitude of CMAP compared to groups IIa and IIb. Group V a showed significant higher mean value in the maximum peak and peak to peak amplitude of CMAP compared to groups III a and IV a. Also group V b showed significant higher mean value in the maximum peak and peak to peak amplitude of CMAP compared to group III b. The results of the present study support the hypothesis that oxidative stress plays a key role in the pathophysiology of diabetic neuropathy and demonstrate that the use of antioxidants might have a protective role against diabetic neuropathy as well as a role in enhancing regeneration of functional nerve fibers. We recommend further human studies to evaluate the role of the addition of natural antioxidants, like L-carnitine or CoQ10, as well as ASA to the treatment regimen of diabetes, from the onset of the disease, in protection against diabetic neuropathy

Effect of L-arginine on the blood levels of matrix metalloproteinase-9, caspase-3 and some liver functions in cadmium chloride-induced hepatic inflammation in rats

The intent of the present work was to study the changes of some hepatic parameters upon exposure to cadmium and to study the role of L-arginine in that experimental model of hepatocellular injury. The study was conducted on thirty two adult male albino rats that were divided into four groups, a control group, a cadmium [Cd] treated group [0.1mg/kg b.w] subcutaneously for 30 days, a cadmium and saline treated group and a cadmium and L-arginine treated group [100mg/kg b.w orally] for 30 days. Cadmium significantly [P<0.05] increased the mean values of the measured parameters, alanine aminotransferase [ALT], aspartate amino transferase [AST], tumor necrosis factor alpha [TNF-a], interleukin-6 [IL-6], hepatic caspase-3 activity and serum matrix metallo-proteinase-9 [MMP-9], compared to control and to [cadmium and L-arginine]- treated rats. Concomitant administration of L-arginine with cadmium prevented the occuranee of these changes. Mean while the reduction of MMP-9 mean values, induced by L-arginine, did not return to basal control value. It was concluded that Cd-hepatocellular dysfunction, in that model, is induced through the activation of apoptosis and increased MMP-9 activity. It was also concluded that L-arginine, through the release of NO, induced a partial hepato-protective effect possibly due to the interaction of other mechanisms which may modulate MMP-9 activity