The effect of curcumin on myocardial infarction (MI) in the cat and the rat has been investigated (94-97). Dikshit et al. examined the prevention of ischemia-induced biochemical changes by curcumin in the cat heart (94). Myocardial ischemia was induced by ligation of the left descending coronary artery. Curcumin (100 mg/kg, i.p.) was given 30 min before ligation. Hearts were removed 4 hr after coronary artery ligation. Levels of glutathione (GSH), malonaldelhyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), catalase, and lactate dehydrogenase (LDH) were estimated in the ischemic and nonischemic zones. Curcumin protected the animals against decrease in the heart rate and blood pressure following ischemia. In the ischemic zone, after 4 h of ligation, an increase in the level of MDA and activities of MPO and SOD (cytosolic fraction) were observed. Curcumin pretreatment prevented the ischemia-induced elevation in MDA contents and LDH release but did not affect the increase in MPO activity. Thus curcumin prevented ischemia-induced changes in the cat heart.
Nirmala and Puvanakrishnan investigated the effect of curcumin on lysosomal hydrolases (h-glucuronidase, h-N-acetylglucosaminidase, cathep-sin B, cathepsin D, and acid phosphatase) in serum and heart after isopro-terenol (ISO)-induced MI (95). Rats treated with ISO (30 mg/100 g body weight) showed a significant increase in serum lysosomal hydrolase activities, which were found to decrease after curcumin treatment. ISO administration to rats resulted in decreased stability of the membranes, which was reflected by the lowered activity of cathepsin D in mitochondrial, lysosomal, and microsomal fractions. Curcumin treatment returned the activity levels almost to normal, showing that curcumin restored the normal function of the membrane. Histopathological studies of the infarcted rat heart also showed a decreased degree of necrosis after curcumin treatment. Nirmala and Puvanakrishnan also examined the effect of curcumin on the biochemical changes induced by ISO administration in rats (96). ISO caused a decrease in body weight and an increase in heart weight and water content as well as in the levels of serum marker enzymes, viz. creatine kinase (CK), LDH, and LDH1 isozyme. It also produced electrocardiographic changes such as an increased heart rate, reduced R amplitude, and elevated ST. Curcumin at a concentration of 200 mg/kg, when administered orally, decreased serum enzyme levels, and the electrocardiographic changes were restored toward normalcy. MI was accompanied by the disintegration of membrane polyun-saturated fatty acids expressed by an increase in TBARS, a measure of lipid peroxides, and by the impairment of natural scavenging, characterized by a decrease in the levels of SOD, catalase, glutathione peroxidase, ceruloplas-min, a-tocopherol, GSH, and ascorbic acid. Oral pretreatment with curcumin 2 days before and during ISO administration decreased the effect of lipid peroxidation. Curcumin has a membrane-stabilizing action by inhibiting the release of h-glucuronidase from nuclei, mitochondria, lysosome, and micro-somes. Curcumin given before and during treatment decreased the severity of pathological changes and thus could have a protective effect against the damage caused by MI.
Nirmala et al. showed that curcumin treatment modulates collagen metabolism in ISO-induced myocardial necrosis in rats (97). This study evaluated whether curcumin had any specific role in the synthesis and degradation of collagen in rat heart with myocardial necrosis induced by ISO. The effect of curcumin (200 mg/kg) was examined on ISO-induced myocardial necrosis and collagen metabolism. The incorporation of [14C] proline into collagen was studied as an index of collagen synthesis. The heart weight/body weight ratio, heart RNA/DNA ratio, and protein were found to increase significantly in ISO-treated animals. Curcumin given before and during treatment with ISO reversed these changes and attenuated the development of cardiac hypertrophy 2 weeks after the second dose of ISO. Increased fractional synthesis rate and enhanced degradation of newly synthesized collagen were observed in ISO-treated animals. Curcumin before and during treatment with ISO decreased the degree of degradation of the existing collagen matrix and collagen synthesis, 2 weeks after the second dose of ISO. The observed effects could have been due to free-radical-scavenging capacity and inhibition of lysosomal enzyme release by curcumin.
The SOD family of enzymes are key regulators of cellular oxidant stress caused by ischemia-reperfusion. In particular, the mitochondrial-associated Mn-SOD enzyme has been implicated in protection from ischemia-reperfu-sion injury. Shahed et al. investigated the effect of curcumin compounds on expression of antioxidant enzymes mRNA in vivo in rat kidney after ureteral obstruction or ischemia/reperfusion injury (98). Curcumin exhibited reno-protective properties by modulating the expression of Mn-SOD.
Arun and Nalini investigated the efficacy of turmeric and curcumin on blood sugar and polyol pathway in diabetic albino rats (99). Alloxan was used to induce diabetes. Administration of turmeric or curcumin reduced the blood sugar, hemoglobin, and glycosylated hemoglobin levels significantly. Turmeric and curcumin supplementation also reduced the oxidative stress encountered by the diabetic rats, as demonstrated by lower levels of TBARS, which may have been due to the decreased influx of glucose into the polyol pathway leading to an increased NADPH/NADP ratio and elevated activity of the potent antioxdiant enzyme GPx. Moreover, the activity of sorbitol dehydrogenase, which catalyzes the conversion of sorbitol to fructose, was lowered significantly by treatment with turmeric or curcumin. These results also appeared to reveal that curcumin was more effective in attenuating diabetes-mellitus-related changes than turmeric. Srinivasan investigated the effect of curcumin on blood sugar in a diabetic subject (100).
Babu and Srinivasan also examined the influence of dietary curcumin on the progression of experimentally induced diabetes induced by cholesterol feeding in the albino rat (101). A 0.5% curcumin diet or 1% cholesterol diet was given to albino rats that were rendered diabetic with streptozotocin injection. Diabetic rats maintained on curcumin diet for 8 weeks excreted less albumin, urea, creatinine, and inorganic phosphorus. Urinary excretion of the electrolytes sodium and potassium was also significantly lowered under curcumin treatment. Dietary curcumin also partially reversed the abnormalities in plasma albumin, urea, creatine, and inorganic phosphorus in diabetic animals. On the other hand, glucose excretion or the fasting-sugar level was unaffected by dietary curcumin, so also the body weights were not improved to any significant extent. The curcumin diet lowered liver weight and lowered lipid peroxidation in plasma and urine at the end of the study compared to controls. The extent of lipid peroxidation was still higher in cholesterol-fed diabetic groups compared to diabetic rats fed with control diet. Thus, the study reveals that curcumin feeding improves the metabolic status in diabetic conditions, despite having no effect on hyperglycemic status or body weight. The mechanism by which curcumin improves this situation is probably by virtue of its hypocholesterolemic influence and its antioxidant and free-radical-scavenging properties.
In another study, Babu and Srinivasan showed the hypolipidemic action of curcumin in rats with streptozotocin-induced diabetes (102). Rats were maintained on 0.5% curcumin-containing diet for 8 weeks. The diet lowered blood cholesterol significantly exclusively by decreasing the LDL-VLDL fraction. A significant decrease in blood triglyceride and phospholipids was also brought about by dietary curcumin. In a parallel study, wherein diabetic animals were maintained on a high-cholesterol diet, the extents of hypercho-lesterolemia and phospholipidemia were higher than in those maintained on the control diet. Curcumin lowered cholesterol and phospholipid levels in these animals also. Liver cholesterol and triglyceride and phospholipid contents were elevated under diabetic conditions. Dietary curcumin showed a distinct tendency to counter these changes in lipid fractions of liver. This effect of curcumin was also seen in diabetic animals maintained on a high-cholesterol diet. Dietary curcumin significantly countered renal cholesterol and triglyceride elevation in diabetic rats. To understand the mechanism of hypocholesterolemic action of dietary curcumin, activities of hepatic choles-terol-7a-hydroxylase and HMG-CoA reductase were measured. Hepatic cholesterol-7a-hydroxylase activity was markedly higher in curcumin-fed diabetic animals, suggesting a higher rate of cholesterol catabolism.
Suresh and Srinivasan showed amelioration of renal lesions associated with diabetes by dietary curcumin in Wistar rats with streptozotocin-induced diabetes (103). For these studies, curcumin was fed at 0.5% in the diet for 8 weeks. Renal damage was assessed by the amount of proteins excreted in the urine and the extent of leaching of the renal tubular enzymes NAG, LDH, AsAT, A1AT, and alkaline and acid phosphatases. The integrity of the kidney was assessed by measuring the activities of several key enzymes of the renal tissue: glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, and LDH (carbohydrate metabolism); aldose reductase and sorbitol dehydrogenase (polyol pathway); and transaminases, ATPases, and membrane polyun-saturated/saturated fatty acid ratio (membrane integrity). Data on enzymuria, albuminuria, activity of kidney ATPases, and fatty acid composition of renal membranes suggested that dietary curcumin significantly inhibited the progression of renal lesions in diabetes. These findings were corroborated by histological examination of kidney sections. This beneficial influence was possibly mediated through curcumin's ability to lower blood cholesterol levels.
Skeletal muscle is often the site of tissue injury due to trauma, disease, developmental defects, or surgery. Yet to date no effective treatment is available to stimulate the repair of skeletal muscle. Thaloor et al. investigated the kinetics and extent of muscle regeneration in vivo after trauma following systemic administration of curcumin to mice (104). Biochemical and histological analyses indicated a faster restoration of normal tissue architecture in mice treated with curcumin after only 4 days of daily intraperitoneal injection, whereas controls required >2 weeks to restore normal tissue architecture. Curcumin acted directly on cultured muscle precursor cells to stimulate both cell proliferation and differentiation under appropriate conditions. The authors suggested that this effect of curcumin was mediated through suppression of NF-kB; inhibition of NF-nB-mediated transcription was confirmed using reporter gene assays. The authors concluded that NF-kB exerts a role in regulating myogenesis and that modulation of NF-kB activity within muscle tissue is beneficial for muscle repair. The striking effects of curcumin on myogenesis suggest therapeutic applications for treating muscle injuries.
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