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Showing posts with label FLAVONOID OF Drynaria fortunei. Show all posts
Showing posts with label FLAVONOID OF Drynaria fortunei. Show all posts

Thursday, May 14, 2009

NEPHROPROTECTIVE PLANTS



Cite this: Moona A Latheef Madhukkal, Sithara Ravindran, "NEPHROPROTECTIVE PLANTS", B. Pharm Projects and Review Articles, Vol. 1, pp. 700-745, 2006. (http://farmacists.blogspot.in/)
 



It is greatly to the credit of people of India, that they were acquainted with a far large no. of medicinal plants than the natives of any other country on the face of the earth.2 Many Indian fruits, grains and vegetables employed as useful dietary articles forms a chief factor in the cure of diseases, as well as preservation of health and good nutrition.3 Herbs have always been the principle form of medicine in India and they are becoming popular throughout the world, as people strive to stay healthy in the face of chronic stress and pollution and to treat illness with medicine that work in concert with the body's own defences. Thus medicinal plants play an important role in the lives of rural people.4 A plant is said to be medicinal when "at least one part possesses therapeutic properties."

One may recognize four stages in the development of the implements in the treatment of disease. In the first stage, crude drug were employed, prepared in the roughest manner, such as powered cinchona or metallic antimony. In the next stage, these were converted to more active and more manageable forms, such as extractions or solutions, watery or alcoholic. In the third stage, the pure active principles, separated from the crude drugs were employed Eg: morphine and quinine. In the 4th stage, instead of attempting to extract out medicine from the natural products in which they are contained, such substances are synthesized which possess particular desired actions.2 Medicinal plants have curative properties due to the presence of various complex chemical substances of different composition, which are found as secondary plant metabolites in one or more parts of these plants.



Nephrology is indeed an ancient discipline with a noble and distinguished legacy that spans at least three previous millennia. A bronze artifact closely resembling the human kidney and dating to 1300BC was excavated from the ruins of the temple of kition and at least thirteen references to the kidney can be found in the old tastement. Before the time of the christ, Greek physicians prescribed botanical material to promote diuresis and employed blood letting and other means for removal of excess body fluids. Hyppocrates (460-375BC) was skilled in microscopic detail of urine analysis. Artaeus of Cappadoicia (30-90AD) and Galan (130-200AD) recognized kidney as the organ responsible for urine formation.5 By the middle of 1800, the structural complexity of mammalian kidney was revealed & unraveled through improved optics & microscopy. If a few names had to be chosen among the pioneers, we could mention Marcello Malpighi and Loreuzo Bellin in Italy & Antoine Ferrein in France for the birth of renal anatomy, Sir William Bowman in England & Karl Ludwig in Germany for renal physiology & Richard Bright in London & Pierra Rayer in Paris for the diseases of kidney. Kidney is an important excretory organ in the human body. The function of kidney is not only to excrete metabolic waste products, but also to maintain the acid base balance, endocrine function like erythropoietin production.6































Toxins may directly affect membrane permeability. Eg: with amphotericin & polyene antibiotics. They can act by increasing the activity of membrane phospholipase & by inhibiting normal reconstruction of the membrane. Phospholipid degradation products, lysophospholipids & free fatty acids have membrane detergent properties. Even in the absence of major changes in membrane permeability, the failure of plasma membrane pumps will cause potential injury changes in the cation homeostasis of the cell eg: Na-K-ATPase & Ca ATPase pumps. The activity of each may be affected by limitation of ATP, compromise of function of enzyme protein or changes in the phospholipid microenvironment surrounding the enzyme.12 Toxin may also lead to remodelling of the surface of the renal tubular cell, thus changing the area available for transportation.


In rats given gentamicin, the appearance of cellular necrosis & renal failure is well so related with an increase in Ca in renal cortex & mitochondria. The intracellular metabolism of drugs leads to the formation of reactive metabolites, which are toxic for cell, as are free radicals. The superoxide ion normally formed, during oxidation forms hydroxyl radicals, which lead to lipid peroxidation. This inturn causes oxidative deterioration of polyunsaturated lipids of membranes & causes the dramatic modification of structure & function. The toxic agent reduces the concentration of antioxidants, superoxide dismutase, glutathione, catalase, vit.E, ascorbic acid which are the protective tissues that reacts & remove reactive oxygen species.4 Nephrotoxin induced changes in tubule cells integrity may be sublethal or lethal. Such prelethal changes include development of abnormally enlarged lysosomes & myeloid bodies, loss of brush border membrane & vacuolization & dilation of the endoplasmic reticulum. Enzymuria resulting from loss of some of these damaged membranes in the urine has been used to gauge the occurrence of renal tubule cell injury & to follow it serially.11


Numerous in
vivo & in vitro studies have demonstrated the effect of free radicals like reactive oxygen metabolites viz. superoxide, hydroxyl ions & hydrogen peroxide which are important mediators of tissue injury. Free radicals can be defined as chemical species possessing unpaired electrons, which are formed by hemolytic cleavage of a covalent bond of a molecule, by loss of a single electron from a normal molecule or by the addition of a single electron to a normal molecule. Free radicals may be positively charged (cation radical), negatively charged (anion radical) or neutral These free radicals have very short half-life, high reactivity & damaging activity towards macromolecules like proteins, DNA & lipids. These species may be either oxygen derived reactive oxygen species (ROS) or nitrogen derived reactive nitrogen species (RNS). ROS includes superoxide, hydroxyl, hydroperoxyl, peroxyl, alkoxyl as free radicals & hydrogen peroxide, hypochlorous acid, ozone & singlet oxygen as non-radicals. The RNS are mainly nitric oxide, peroxynitrile, & nitrogen dioxide & dinitrogen trioxide. Free radical injury & oxidative stress have been implicated in many renal diseases like acute renal failure, IgA nephropathy, anaemia of chronic renal failure & ischaemic kidney.









Cisplatin has site-specific nephrotoxic effect on the proximal tubule of the rat. Three distinct segments S1, S2, S3 been
described
for the proximal tubule of the rat by a number of investigators. A focal loss or thinning of the microvillus
brush border was evident at all levels of microscopy. In some cells the brush border was completely obliterated with only a few microvilli remaining. The cytoplasm of many cells appeared condensed. Clumping of nuclear chromatin & increased number of cytoplasmic vesicles could be seen in many of the injured cells. Other cells appeared to round up & lose their normal orientation & often protruded into the tubular lumen. Completely necrotic cells were evident & could be seen sloughing into the tubular lumen. In some areas, only a bare basal lamina remained. Cells adjacent to these areas appeared to flatten out & send long thin cytoplasmic process out to reline the basal membrane.

The exact mechanism of cisplatin nephrotoxicity is unclear. Experimental studies have shown that there is an abrupt fall in the effective renal plasma flow within 3 hrs of the i.p. dose of cisplatin. It is known to be filtered by the glomeruli & concentrated in the glomerular filterate from which it is activated in the presence of a low intra cellular chloride concentration. The low intracellular concentration of chloride facilitates the displacement of chloride by the water molecule yielding a positively charged, hydrated & hydroxylated complex. Hydration of cisplatin induces formation of monochloro monoaquodiamino platin or diaquo diammineplatin. These agents alkylate the purine & pyrimidine bases of nuclear material.12 Renal damage is seen in proximal tubular S3 portion, the distal tubule & collecting duct.


Other proposed explanation of the nephrotoxicity of cisplatin include the possibility that it include generate reactive metabolites that bind covalently to tissue macromolecules. The nephrotoxic effects might also be due to sulphydryl binding of heavy metal. A reduction in sulphydryl groups in the rat renal cortex has been demonstrated; this occurred before any significant change in renal function could be detected, suggesting that this biochemical change may be a primary event. Cell fractionations have shown that the greatest decline of sulphydryl groups occurs in the mitochondrial & cytosol fractions; these also had the highest concentrations of platinum.12 A recent study found that cisplatin induced proximal tubule injury could be ameliorated by the administration of hydroxylradical scavengers. In these studies cisplatin (5mg/kg BW) caused lipid peroxidation. The hydroxyl radical scavenger prevented acute renal failure by altering tubule damage & enhancing the regenerative response of damaged tubule cells protection from cisplatin toxicity has generally focused on providing free radical scavengers.4



The first step involved in the pathogenesis is the transport of the drug into proximal tubular cells where they become concentrated & where they exert their toxic influence. The second step involves the deleterious interaction of these agents with one or more intracellular metabolic processes, which ultimately is expressed as a depression of renal function. With regard to gentamicin, chronic exposure of cultured fibroblast to high levels of gentamicin, lead to accumulation of the antibiotic within lysosomes accompanied by inhibition of lysosomal sphingomylinase & a marked generalized phopholipidosis. The development of large lysosomes & myeloid bodies during gentamicin nephrotoxicity has been well documented and inhibition of kidney sphingomyelinase has been reported. Gentamicin induces inhibition of renal cortical mitochondrial oxidative phosphorylation before histological evidence of severe proximal cellular damage. There is significant reduction in whole kidney ATP levels, ADP dependant and dinitrophenol (DNP) uncoupled respiration.16 Gentamicin treatment in vivo increased renal cortical MDA levels decreased the total glutathione, increased the GSSH/GSH ratio, sharply reduces levels of esterified arachidonic acid and induced a generalized shift from polyunsaturated fattyacids. Gentamicin also decreased the activities of catalase & SOD.11




Flavanoids are phenolic compounds widely distributed in fruits, vegetables, plant extracts as well as plant derived beverages Eg : tea & red wine. These have generated interest because of their broad pharmacological effects such as vasoprotective, anti-inflammatory, antiviral & antifungal actions. Many of these affects are related to their antioxidant properties, which may be due to their ability to scavenge free radicals & to synergestic effects of other antioxidant. Another mechanism not yet extensively studied, may result from interaction between flavanoid & metal ions (esp iron & copper) leading to chelates. For Eg: it has been reported that concomitant administration of quercetin with cisplatin showed considerable decreases in levels of marker for nephrotoxicity & lipid peroxide & increased ATPase activities compared to CDDP treated group. Glutathione content & antioxidant enzyme activities were significantly increased.









 The effects of glycyrrhizin (200 mg/kg/day) on renal function in association with the regulation of aquaporin 2 water channel in rats with gentamicin (100 mg/kg/day)-induced acute renal failure was investigated. Polyuria in rats with gentamicin-induced acute renal failure was associated with down-regulation of renal aquaporin 2 in the inner and outer renal medulla, and cortex. Glycyrrhizin administration restored the expression of aquaporin 2 with paralleled changes in urine output. Changes in renal functional parameters, such as creatinine clearance, urinary osmolality, and solute-free reabsorption, accompanying acute renal failure were also partially restored after administration of glycyrrhizin. Histological changes in rats with gentamicin-induced acute renal failure were also abrogated by glycyrrhizin treatment. The above results suggest that glycyrrhizin treatment could ameliorate renal defects in rats with acute renal failure induced by gentamicin.

The effect of Ginkgo biloba (EGb), a plant extract with an antioxidant effect, has been studied on gentamicin-induced nephrotoxicity in male wistar rats. Ginkgo biloba extract (300 mg/kg BW) was administered orally concurrently with gentamicin (80 mg/kg BW). Estimations of urine creatinine, glucose, blood urea, serum creatinine, plasma and kidney tissue MDA were carried out after gentamicin treatment. Kidneys were examined using histological techniques. Blood urea and serum creatinine were increased with gentamicin. Creatinine clearance was significantly decreased with gentamicin. Changes in blood urea, serum creatinine and creatinine clearance induced by gentamicin were significantly prevented by Ginkgo biloba extract. There was a rise in plasma and kidney tissue MDA with gentamicin, which were significantly reduced to normal with Ginkgo biloba extract. Histomorphology showed necrosis and desquamation of tubular epithelial cells in renal cortex with gentamicin, while it was normal with Ginkgo biloba extract. These data suggest that supplementation of Ginkgo biloba extract may be helpful to reduce gentamicin nephrotoxicity.


The ethanol extract of the roots of Cassia auriculata was studied for its nephroprotective activity in cisplatin- and gentamicin-induced renal injury in male albino rats. In the cisplatin model, the extract at doses of 300 and 600 mg/kg body wt. reduced elevated blood urea and serum creatinine and normalized the histopathological changes in the curative regimen. In the gentamicin model, the ethanol extract at a dose of 600 mg/kg body wt. reduced blood urea and serum creatinine effectively in both the curative and the preventive regimen. The extract had a marked nitric oxide free-radical-scavenging effect. The findings suggest that the probable mechanism of nephroprotection by C.auriculata against cisplatin- and gentamicin-induced renal injury could be due to its antioxidant and free-radical-scavenging property.




In this work, tested whether oral treatment of rats with N. sativa oil (0.5, 1.0 or 2.0 ml/kg/day) would ameliorate nephrotoxicity of GM (80 mg/kg/day im) concomitantly with the oil. Nephrotoxicity was evaluated histopathologically and by measurement of concentrations of urea, creatinine and total antioxidant status (TAS) in plasma and reduced glutathione (GSH) and TAS in kidney cortex. The results indicated that GM treatment caused moderate proximal tubular damage, significantly increased the concentrations of creatinine and urea, and decreased that of TAS and GSH. Treatment with N. sativa oil produced a dose-dependent amelioration of the biochemical and histological indices of GM nephrotoxicity that was significant at the two higher doses used, and it increased GSH and TAS concentrations in renal cortex and enhanced growth. The results suggest that N. sativa may be useful in ameliorating signs of GM nephrotoxicity in rats.

9 FLAVONOID OF Drynaria fortunei PROTECTS AGAINST ARF25


Ginsenoside-Rd has been proved to decrease the severity of renal injury induced by cisplatin, in which proximal urinaferous tubules represent the main site of injury. When ginsenoside-Rd was given orally at a dose of 1 or 5 mg/kg body weight/day prior to cisplatin injection, the activities of the antioxidation enzymes superoxide dismutase and catalase were higher, while malondialdehyde levels in serum and renal tissue were lower in the treated rats than in the controls. The levels of urea nitrogen and creatinine in serum were decreased in rats given ginsenoside-Rd. Decreased urinary levels of glucose, sodium and potassium reflected a protective action against the renal dysfunction caused by cisplatin. In addition, it was demonstrated that ginsenoside-Rd affected cultured proximal tubule cells exposed to cisplatin.



Crude water extract of R. Stricta leaves (0.25, 0.5 and 1 g/Kg) was given orally to rats and thereafter, concomitantly with GM (80 mg/Kg/day). Nephrotoxicity was evaluated histopathologically and biochemically by measuring the concentrations of urea and creatinine in serum, reduced glutathione (GSH), lipid peroxidation and superoxide dismutase (SOD) activity in kidney cortex. The results suggested that a dose-related amelioration in the indices of toxicity was noted when the two higher doses of the plant extract were given. The two higher doses, significantly and dose-dependently increased SOD activity and GSH concentration, and decreased that of lipid peroxides in the kidney cortex. These results suggest that R. stricta water extract may contain compounds that could potentially ameliorate GM nephrotoxicity in rats.



This study was conducted to establish the nephroprotective activity of plants. Various models have been used to substantiate the nephroprotective activity of herbals. They were GM in albino rats, cisplatin in rabbits, mercuric chloride in mice, ethylene glycol in mice etc. These nephrotoxic agents caused nephropathy mainly due to their free radical generation in kidney tissues. And the kidney damage was indicated by changes in renal function parameters like creatinine, BUN, and the enzymes suchn as GPx, SOD and was also confirmed histopathologically. Above works certified that, by ameliorating all the allied effects, mainly due to antioxidant property the plants like A.lanata, P.pinnata, C.auriculata, S.radix, G.glabra, G.biloba, N.sativa, D.fortunei, T.terrestris, C.nurvala, O.sanctum, S.nigrum, V.vinifera have nephroprotective activity.
Cite this: Moona A Latheef Madhukkal, Sithara Ravindran, "NEPHROPROTECTIVE PLANTS", B. Pharm Projects and Review Articles, Vol. 1, pp. 700-745, 2006. (http://farmacists.blogspot.in/)

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