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In recent years, more then 100 medicinal plants are mentioned in the Indian system of medicine including folk medicines for the management of diabetes, which are effective either separately or in combination3. We have under taken a study on combination of plant and making a formulation then evaluating its anti hyperglycemic property along with its antioxidant potential.
Preliminary phytochemical analysis of ethanolic extract of rhizomes of Picrorhiza scrophulariiflora (EEPS) shown the presence of phytochemicals such as glycosides, alkaloids, polysterols, carbohydrates, proteins, phenols, tannins, saponins, and sterols etc.,
Acute oral toxicity study of EEPS did not exhibit mortality or any profound toxic reactions at a dose of 2000mg/kg/p.o. According to the (OECD) 423 guidelines for acute oral toxicity study LD50, dose of 2000mg/kg/p.o of PHF is found to be safe.
The EEPS at a dose 250mg/kg/p.o and 500mg/kg/p.o did not significantly suppress blood glucose level in over night fasted normal animals after 1st,2nd and 3rd hours of oral administration when compared with standard drug like biguanide classes of drugs such as metformin which is anti-hyperglycemic drug. They do not affect blood glucose in normal individuals.68
The EEPS showed significant improvement in glucose tolerance in glucose fed hyperglycemic normal rats. Such an effect may be accounted for, in part, by a decrease in the rate of intestinal glucose absorption, achieved by an extra pancreatic action including the stimulation of peripheral glucose utilization or enhancing glycolytic and glycogenic process62. However the effect was significant when compared to standard drug glibenclamide and metformin.
STZ is the most commonly used drug for the induction of experimental diabetes for both insulin -dependent diabetes mellitus and non-insulin dependent diabetes mellitus. Type II diabetes diabetes is associated with obesity, and obesity itself causes or aggravates insulin resistance which is found to be a major cause of type II diabetes. There is an increasing evidence that streptozotocin causes diabetes by rapid depletion of β-cells, by DNA alkylation and accumulation of cytotoxic free radicals that is suggested to result from initial islet inflammation. It leads to a reduction in insulin release there by a drastic reduction in plasma insulin concentration leading to stable hyperglycemic state69. In this study significant hyperglycemia was achieved within 48 hours after streptozotocin (35mg/kg b.w i.p) injection. Streptozotocin induced diabetic rats with more than 250mg/dl of blood glucose were considered to be diabetic and used for study.
A single dose administration of EEPS at a dose 250mg/kg/p.o and 500mg/kg/p.o significantly reduced the blood glucose levels at 120 and 240min. In the sub-acute study, glibenclamide treatment reduces blood sugar level from the first week to third week. Treatment with EEPS at dose 250mg / k g bw / p.o significantly (P<0.05) decreased the blood glucose level after second week. Treatment with EEPS at dose 500mg/kg/p.o significantly (P<0.01) decreased the blood glucose level after first week. At the end of the study a marked anti hyperglycemic effect was observed with the EEPS treatment. The possible mechanism involved in suppressing of blood glucose levels by EEPS are modulation glucose transport, glucose disposal, secretagogue insulin secretion69 and which in turn to control the hyper glycemic state70.
Histopathological studies showed prominent islet cell hyperplasia and regeneration of islet cells show a proof for possible anti-hyperglycemic property of the EEPS.
Eperimental induction of diabetes with High fat-fed diet with low dose of STZ is associated with the characteristic loss of body weight which is due to increased muscle wasting and due to loss of tissue protein. Diabetic rats treated with EEPS show an increase in the body weight as compared to the diabetic control which may be due to its protective effect in controlling muscle wasting i.e reversal of gluconeogenesis and may also be to the improvement in insulin secretion and glycemic control71.
Glycated heamoglobin is formed throughout the circulatory life of RBC with the addition of glucose to the N-terminal of the hemoglobin beta chain. This process which is nonenzymatic reflects the average exposure of hemoglobin to glucose to an extended period. Glycoheamoglobin is used as an indicator of metabolic control of diabetes72. In the present study, High fat-fed diet with STZ treated clear-cut abnormalities in the HbA1C levels were evident from elevated level of normal glycated heamoglobin. EEPS at the dose of 500mg/kg treatment over 21days significantly reduced the HbA1C levels compared to the diabetic control.
In diabetes hyperlipidimea is found to be pathological state, in which elevated serum total cholesterol and reduced serum HDL cholesterol increase diabetic complications by accelerating cell death and atherosclerosis. In present study, treatment with EEPS at dose 250mg/kg and 500mg/kg significantly (p<0.01), decrease total cholesterol and significantly increase HDL levels. This effect not only due to better glycemic control but could also been due to that drugs direct action on lipid metabolic pathway. Hypolipidemic effect could represent a protective mechanism against the development of atheroscclerisis73. Lipid lowering activity of EEPS at the dose of 500mg/kg related to acitivty of standard drug metformin.
Elevated production of Reactive Oxygen Species ROS leads to cell damage. High level of ROS has been found to play major role in the pathogenisis of type II diabetes. In this form of diabetes hypo-insulinaemia increases the activity of the enzyme, fatty acyl coenzyme A oxidase and initiates β-oxidation of fatty acid that favors to accumulate free radicals resulting in Lipid peroxidation. Increased concentration of lipid peroxidation in the liver impairs membrane functions by decreasing membrane fluidity and changing the activity of membrane-bound enzyme and receptor. Its end product (lipid radical and lipid peroxide) are harmful to the cells in the body and associated with atherosclerosis57.
An increase in the level of MDA concentration in High fat-fed diet with STZ induced type II diabetic rats57. In the present study MDA and hydrogen peroxide levels in liver were high in diabetic animals. The treatment with EEPS, glibenclamide and metformin exerted aprotective against peroxidative damage.
The enzymatic antioxidant defense mechanism contains various forms of SOD, catalase, glutathione peroxidase, glutathione reducatse and glutathione s transferases. Despite the presence of such a delicate cellular antioxidant systems an over production of ROS in both intra and extracellular spaces often occur exposure of cells to certain chemicals like STZ that yield to the pathogenisis of DM in experimental animals. In the present study we have examined the oxidatvioe stress pathway marker in STZ induced diabetes rats. SOD and catalase are the most important enzymes that scavenge the toxic free radicals and form the major anti oxidant system. SOD protects the tissues against oxygen free radicals by catalyzing the removal of superoxide radicals (O2.) into H2O2 plus O2 there by diminishing the toxic effects of the free radicals. Catalase is a heme protein localized in the peroxyzomes or the micro peroxyzomes it is a major determinant of hepatic anti oxidant status. It catalyse the decomposition of hydrogen peroxide to water and oxygen thus protecting the cell from the oxidative damage74. Super oxide dismutase and catalase activity in the in the diabetic control animals was significantly low due to oxidative strees when compared to the normal animals. Treatment with EEPS at a dose 250mg/kg and 500mg/kg a significantly (p<0.050 and(P<0.01), glibenclamide and metformin treated animals increase in the enzyme activity. EEPS at dose of 500mg/kg exhibit pharmacological response related to metformin.
The reduction of hydrogen peroxide is catalysed by glutathione peroxidase into water and oxygen at the expense of GSH. GPx activity is also reduced in diabetic condition. This may be due to inactivation of the enzyme involved in disposal of O2 species and also insufficient availability of GSH75. Glutatathione peroxidase activity in the diabetic control animal was significantly low due to increased oxidative stress when compared to the normal animals. Treatment with EEPS at a dose 250mg/kg and 500mg/kg a significant (p<0.050 and(P<0.01)increase in the hepatic glutathione peroxidase antioxidant enzyme levels.