Endrin-induced histopathological changes and lipid peroxidation in livers and kidneys of rats, mice, guinea pigs and hamsters.

Endrin toxicity may be due to an oxidative stress associated with increased lipid peroxidation, decreased glutathione content, and inhibition of glutathione peroxidase activity. Extensive interspecies variability exists in sensitivity towards endrin. Therefore, histopathological changes and lipid peroxidation in the livers and kidneys of rats, mice, hamsters, and guinea pigs were examined 24 hr after the administration of 4 mg endrin/kg body weight orally in corn oil. Degeneration and necrotic changes with inflammatory cell infiltration were observed in livers and kidneys, and interspecies variability occurred. Fatty changes in the form of hepatic foam cells with cytoplasmic vacuolation were present. Lipofuscin pigments, associated with lipid peroxidation, were observed in hepatocytes and Kupffer cells. These histopathological conditions were prevented in rats which had been pretreated with butylated hydroxyanisole, vitamins E and C, or cysteine, antioxidants and free radical scavengers which have previously been shown to inhibit lipid peroxidation. The extent of endrin-induced lipid peroxidation correlated well with the degree of histopathological changes. Thus, histological changes consistent with the induction of an oxidative stress were observed following the administration of endrin to various animal species.     

Protective effect of curcumin on cypermethrin-induced oxidative stress in Wistar rats

The aim of present study was to investigate the protective effect of curcumin on cypermethrin-induced changes in blood biochemical markers and tissue antioxidant enzyme in rats. Rats were divided into six groups of six each: group I used as control and II and III groups were used as vehicle control. While, groups IV, V and VI were orally treated with curcumin (100 mg/kg body weight), cypermethrin (25 mg/kg body weight) and cypermethrin plus curcumin, respectively for 28 days. Serum biochemical markers were measured in the serum, and the levels of lipid peroxidation and antioxidant enzyme activity were determined in the liver, kidney and brain. Cypermethrin administration caused elevated level of blood biochemical markers in serum and lipid peroxidation in liver, kidney and brain. While the activities of non-enzymatic and enzymatic antioxidants levels were decreased except superoxide dismutase in liver, kidney and brain tissues. The presence of curcumin with cypermethrin significantly decreased the blood biochemical markers and lipid peroxidation but significantly increased the reduced glutathione, catalase and glutathione peroxidase level and preserved the normal histological architecture of the liver, kidney and brain. Our results indicate that curcumin can be potent protective agent against cypermethrin-induced biochemical alterations and oxidative damage in rats.     

Renal damage induced by uranyl nitrate and oestradiol-17beta in Japanese quail and Wistar rats

Morphological alterations occurred in the kidneys of Japanese quail and Wistar rats 18 h after giving uranyl nitrate solution i.v. Dosages of 50 micromol U/kg body weight produced more extensive and more severe damage than did 0.15 micromol U/kg. Degeneration and necrosis of tubular epithelium was prominent in the proximal tubules in rats and in the distal tubules in quail. Less extensive damage occurred in glomeruli and collecting ducts. Protein deposits were seen in the kidneys of both rats and quail. Calcification of degenerating epithelial cells, calcified casts in the tubules, and damage to collecting ducts were seen in quail but not in rats. Oestradiol-17beta (160 micromol/kg body weight, i.m.) induced renal lesions in quail but not in rats. Quail and rat renal lesions induced by the combination of oestradiol plus uranium were more severe than lesions induced by either toxicant singly.     

Protective effect of alprazolam against sleep deprivation-induced behavior alterations and oxidative damage in mice

Sleep deprivation is considered as a risk factor for various diseases. Sleep deprivation leads to behavioral, hormonal, neurochemical and biochemical alterations in the animals. The present study was designed to explore the possible involvement of GABAergic mechanism in protective effect of alprazolam against 72 h sleep deprivation-induced behavior alterations and oxidative damage in mice. In the present study, sleep deprivation caused anxiety-like behavior, weight loss, impaired ambulatory movements and oxidative damage as indicated by increase in lipid peroxidation, nitrite level and depletion of reduced glutathione and catalase activity in sleep-deprived mice brain. Treatment with alprazolam (0.25 and 0.5 mg/kg, ip) significantly improved behavioral alterations. Biochemically, alprazolam treatment significantly restored depleted reduced glutathione, catalase activity, reversed raised lipid peroxidation and nitrite level. Combination of flumazenil (0.5 mg/kg) and picrotoxin (0.5 mg/kg) with lower dose of alprazolam (0.25 mg/kg) significantly antagonized protective effect of alprazolam. However, combination of muscimol (0.05 mg/kg) with alprazolam (0.25 mg/kg, ip) potentiated protective effect of alprazolam. On the basis of these results, it might be suggested that alprazolam might produce protective effect by involving GABAergic system against sleep deprivation-induced behavior alterations and related oxidative damage.     

Lipid peroxidation and HSP72/73 expression in rat following cadmium chloride administration: Interactions of magnesium supplementation

Objective: to determine whether magnesium (Mg) supplementation could have a protective effect against the cadmium (Cd)-induced oxidative stress in liver, kidneys and testes of adult male rats. Stress was evaluated by measuring lipid peroxidation by thiobarbituric acid reactive substances (TBARS) and the heat shock protein (HSP) 72/73 expression.

CdCl₂ injections (2.5 mg/day/kg body weight) for 10 days resulted in a time dependent increase of Cd accumulation in liver, kidney and testes, the highest levels being found in liver (400 μg/g dried tissue). At the same time, an increase of lipid peroxidation was observed. The effect was maximal at day 1 of Cd treatment in liver and testes, and later (day 5) in kidney. Then, Cd-induced lipid peroxidation decreased, suggesting the activation of antioxidant defense mechanisms.

Injections of Mg SO₄ (300–600 mg/day/kg body weight) reduced in a dose-dependent manner Cd-induced lipid peroxidation in liver and kidney as well as the accumulation of Cd in liver, kidney and testes. In testes, a protective effect of Mg was found only during the early phase of Cd-poisoning. On days 5 and 10, lipid peroxidation was even increased as compared to controls.

In liver and testes only the constitutive HSP73 was detected whereas in kidney both HSP73 and the inducible HSP72 were expressed. HSP72/73 expression was not significantly increased by Cd and HSP73 was even lowered in kidney, probably due to the strong dose used. These results were not modified by Mg injections.

Conclusion: Mg supplementation can reduce Cd accumulation in organs and lipid peroxidation related to Cd administration.     

Effect of pristine and functionalized multiwalled carbon nanotubes on rat renal cortex

The increasing application of carbon nanotubes (CNTs) within environmental, occupational and consumer settings has raised concerns regarding their biosafety and adverse effects on human health. The present study was designed to investigate the possible adverse effect of pristine and functionalized (amylated and polyethelene glycol coated) multi-walled (MW) CNTs on rat kidney with special concern to the histological alterations and the associated oxidative stress, apoptosis and inflammation. Healthy male albino rats (n?=?40) were randomly divided into 4 groups: group I (control), group II (pristine MWCNTs), group III (amylated MWCNTs) and group IV [polyethelene glycol (PEG)-coated MWCNTs]. Animals of groups II, III and IV received a single dose of 1?mg/kg body weight of MWCNTs via intra-tracheal (IT) instillation at the beginning of the experiment and all rats were sacrificed after 30 days. Rats in groups II and III showed, nearly similar, renal tissue damage (evidenced by thin collapsed glomeruli, packed mesangial and endothelial cells as well as edematous hemorrhagic glomeruli with apoptotic changes) and functional disruptions (indicated by high serum levels of urea and creatinine) probably through induction of oxidative stress [revealed by high level of the lipid peroxidation marker malondialdehyde (MDA) and lower levels of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx)], apoptosis (indicated by high caspase 3 activity), and inflammation (evidenced by high level of IL1β). However, PEG-coated MWCNTs-treated group (group IV) showed nearly normal renal structure and function. It could be concluded that pristine and functionalized amylated MWCNTs have nephrotoxic effect, while PEG-coated MWCNTs had lowest, or none, toxic effects making them safer for therapy and diagnosis of a variety of diseases.     

Hyperglycemia-induced alterations in synaptosomal membrane fluidity and activity of membrane bound enzymes: beneficial effect of N-acetylcysteine supplementation

Diabetic encephalopathy is characterized by impaired cognitive functions that appear to underlie neuronal damage triggered by glucose driven oxidative stress. Hyperglycemia-induced oxidative stress in diabetic brain may initiate structural and functional changes in synaptosomal membranes. The objective of the present study was to examine the neuroprotective role of N-acetylcysteine (NAC) in hyperglycemia-induced alterations in lipid composition and activity of membrane bound enzymes (Na⁺,K⁺-ATPase and Ca²⁺-ATPase) in the rodent model of type 1 diabetes. Male Wistar rats weighing between 180 and 200 g were rendered diabetic by a single injection of streptozotocin (50 mg/kg body weight, i.p.). The diabetic animals were administered NAC (1.4–1.5 g/kg body weight) for eight weeks and lipid composition along with membrane fluidity were determined. A significant increase in lipid peroxidation was observed in cerebral cortex of diabetic rats. NAC administration on the other hand lowered the hyperglycemia-induced lipid peroxidation to near control levels. The increased lipid peroxidation following chronic hyperglycemia was accompanied by a significant increase in the total lipids which can be attributed to increase in the levels of cholesterol, triglycerides and glycolipids. On the contrary phospholipid and ganglioside levels were decreased. Hyperglycemia-induced increase in cholesterol to phospholipid ratio reflected decrease in membrane fluidity. Fluorescence polarization (p) with DPH also confirmed decrease in synaptosomal membrane fluidity that influenced the activity of membrane bound enzymes. An inverse correlation was found between fluorescence polarization with the activities of Na⁺,K⁺-ATPase (r²=0.416, P<0.05) and Ca²⁺ ATPase (r²=0.604, P<0.05). NAC was found to significantly improve lipid composition, restore membrane fluidity and activity of membrane bound enzymes. Our results clearly suggest perturbations in lipid composition and membrane fluidity as a major factor in the development of diabetic encephalopathy. Furthermore, NAC administration ameliorated the effect of hyperglycemia on oxidative stress and alterations in lipid composition thereby restoring membrane fluidity and activity of membrane bound enzymes.     

Influence of rutin on biochemical alterations in hyperammonemia in rats

Flavonoids are non-nutritive dietary components that are widely distributed in plants. The present study was undertaken to examine the protective influence of rutin, a polyphenolic flavonoid, on oxidative stress during ammonium chloride (AC)-induced hyperammonemia by measuring the levels of oxidative damage as well as antioxidant status. The levels of tissue (liver, brain and kidney) lipid peroxides and the antioxidants (total thiols, catalase, reduced glutathione and glutathione peroxidase) were analyzed. Hyperammonemia was induced by daily intraperitoneal injections of AC at a dose of 100 mg/kg body weight for 8 weeks. Decreased levels of tissue lipid peroxidation accompanied with increased antioxidant levels in hyperammonemic rats were observed during oral administration of rutin (50 mg/kg body weight), which clearly shows the antioxidant property of rutin. The study of induction of the antioxidant status is considered to be a reliable marker for evaluating the antiperoxidative effect of the polyphenolic compound. Our present findings show the protective role of rutin against lipid peroxidation and suggest that rutin possesses antioxidant potential that may be used for therapeutic purposes.     

Renal function and histologic studies in rats treated by floctafenin (author's transl)]

The nephrotoxic action of floctafenin has been studied in rats. When administered orally at 20 or 50 mg/kg/day for 20 or 50 days, this analgesic agent had no effect on the renal function, either in intact rats or in animal with reduced renal parenchyma. There is no histological change in the kidneys of the treated animals except some focal dilatations of the distal tubules. The tubular alterations were more important in treated and untreated rats with nephronic reduction. The whole body autoradiographic studies of rats treated with 14C floctafenin showed that liver and kidney accumulate radioactivity, and that the intake of radiolabeled compounds is twice higher in renal cortex than in medulla. This study suggests that the toxicity of floctafenin for the rat kidney is very low or none.     

Effects of Nicotinamide and Its Isomers on Iron-induced Renal Damage

The effects of three isomers of pyridinecarboxamide (picolinamide (2 pyridinecarboxamide), nicotinamide (3 pyridinecarboxamide) and isonicotinamide (4 pyridinecarboxamide)) on iron-induced renal damage were studied. Pyridinecarboxamide (250 mg/kg body weight, ip) was administered 10 min before injection of ferric nitrilo-triacetate (Fe(III)-NTA) (7.5 mgFe/kg body weight, ip). In picolinamide-treated rats, the renal tubular necrosis induced by Fe(III) NTA was attenuated and serum creatinine did not increase. Picolinamide most efficiently suppressed renal lipid peroxidation in vivoinduced by Fe(III) NTA. Non heme iron levels in the kidneys after Fe(III) NTA injection did not differ in groups to which pyridinecarbox-amides were administered. To elucidate the protective effects of picolinamide, we studied the action of pyridinecarboxamides on lipid peroxidation and DNA damage in vitro. These isomers inhibited iron-induced lipid peroxidation of linolenic acid. Picolinamide had no effect on DNA damage, but nicotinamide and isonicotinamide promoted DNA damage by iron, especially when ascorbate was used as a reductant. None of these pyridinecarboxamide isomers changed the chlelate structure of Fe(III) NTA as shown by electronic absorption spectra. Among the three isomers, picolinamide most effectively protected the kidneys against iron-induced renal damage, since it not only inhibited iron-induced lipid peroxidation, but also had little enhancing action on DNA damage by iron.     

Effects of nicotinamide and its isomers on iron-induced renal damage.

The effects of three isomers of pyridinecarboxamide (picolinamide (2-pyridinecarboxamide), nicotinamide (3-pyridinecarboxamide) and isonicotinamide (4-pyridinecarboxamide)) on iron-induced renal damage were studied. Pyridinecarboxamide (250 mg/kg body weight, ip) was administered 10 min before injection of ferric nitrilotriacetate (Fe(III)-NTA) (7.5 mgFe/kg body weight, ip). In picolinamide-treated rats, the renal tubular necrosis induced by Fe(III)-NTA was attenuated and serum creatinine did not increase. Picolinamide most efficiently suppressed renal lipid peroxidation in vivo-induced by Fe(III)-NTA. Non-heme iron levels in the kidneys after Fe(III)-NTA injection did not differ in groups to which pyridinecarboxamides were administered. To elucidate the protective effects of picolinamide, we studied the action of pyridinecarboxamides on lipid peroxidation and DNA damage in vitro. These isomers inhibited iron-induced lipid peroxidation of linolenic acid. Picolinamide had no effect on DNA damage, but nicotinamide and isonicotinamide promoted DNA damage by iron, especially when ascorbate was used as a reductant. None of these pyridinecarboxamide isomers changed the chlelate structure of Fe(III)-NTA as shown by electronic absorption spectra. Among the three isomers, picolinamide most effectively protected the kidneys against iron-induced renal damage, since it not only inhibited iron-induced lipid peroxidation, but also had little enhancing action on DNA damage by iron.     

Influence of cadmium intoxication on hepatic lipid peroxidation, glutathione level, and glutathione S-transferase and gamma-glutamyl transpeptidase activities: correlation with chromosome aberrations in bone marrow cells.

We examined whether there was any correlation between chromosome aberrations (CAs) in bone marrow cells with hepatic lipid peroxidation (LPO), reduced glutathione (GSH) level, glutathione S-transferase (GST), and gamma-glutamyl transpeptidase (GGT) activity after cadmium (Cd) intoxication in both a dose- and a time-dependent manner. Cadmium chloride was administered subcutaneously in doses of 0.5, 1.5, 2.5, and 5.0 mg/kg body weight to Swiss albino Balb/c male mice. The animals were exposed for 8, 16, and 24 days, i.e., 4, 8, and 12 doses, respectively. Biochemical parameters were measured in hepatic tissue for a correlation with chromosome aberrations in bone marrow. With the increment of dose and advancement of time points, the biochemical, as well as the cytogenetic, parameters altered significantly. Hepatic lipid peroxidation and GGT activity increased significantly along with an increased percentage of chromosome aberrations in the bone marrow, but the hepatic reduced glutathione level and GST activity were found to decrease following Cd administration. Up to 5.0 mg Cd/kg body weight, lipid peroxidation did not exhibit threshold levels of toxicity as shown by the two-way (fixed effect) analysis of variance test. In contrast, the observed values of reduced glutathione levels, GST and GGT activity, and chromosome aberrations in bone marrow showed threshold activity levels. Therefore, there might be a relationship between an increase in the frequency of chromosome aberrations, elevated lipid peroxidation, and depleted glutathione levels and GST and GGT activity. The clastogenic efficacy of Cd may be mediated through the biochemical pathways.     

Hesperidin protects renal and hepatic tissues against free radical-mediated oxidative stress during DMBA-induced experimental breast cancer

Hesperidin has been reported to have an excellent and wide variety of biological activities. This property has brought the compound to a new stage in the treatment of various oxidative stress-mediated diseases. The present investigation was aimed to evaluate the therapeutic potential of hesperidin by assaying the activities of antioxidant enzymes, lipid peroxidation, membrane bound marker enzymes, adenosine triphosphates, and TCA cycle enzymes, especially in kidney tissues during 7,12-dimethybenz(a)anthracene-induced breast cancer. Daily oral administration of hesperidin (30 mg/kg body wt) to breast cancer-bearing rats for 45 days demonstrated a significant (P < .05) decline in renal lipid peroxidation and membrane bound marker enzymes, as well as a remarkable increase in adenosine triphosphatases, mitochondrial functional enzymes, and renal antioxidants. Furthermore, histological studies of liver and kidney provided evidence of biochemical alterations. Thus, the protective effects of hesperidin on attenuating the peroxidation reaction and membrane bound marker enzyme activities as well as upregulation of adenosine triphosphatases, TCA cycle enzymes, and antioxidants suggest promising uses of flavonoglycoside hesperidin in the future treatment of oxidative stress-mediated diseases.     

Acute effect of aspartame-induced oxidative stress in Wistar albino rat brain

The present study was carried out to investigate the acute effect of aspartame on oxidative stress in the Wistar albino rat brain. We sought to investigate whether acute administration of aspartame (75 mg/kg) could release methanol and induce oxidative stress in the rat brain 24 hours after administration. To mimic human methanol metabolism, methotrexate treated rats were used to study aspartame effects. Wistar strain male albino rats were administered with aspartame orally as a single dose and studied along with controls and methotrexate treated controls. Blood methanol and formate level were estimated after 24 hours and rats were sacrificed and free radical changes were observed in discrete regions by assessing the scavenging enzymes, reduce dglutathione (GSH), lipid peroxidation and protein thiol levels. There was a significant increase in lipid peroxidation levels, superoxide dismutase activity (SOD), glutathione peroxidase levels (GPx), and catalase activity (CAT) with a significant decrease in GSH and protein thiol. Aspartame exposure resulted in detectable methanol even after 24 hours. Methanol and its metabolites may be responsible for the generation of oxidative stress in brain regions. The observed alteration in aspartame fed animals may be due to its metabolite methanol and elevated formate. The elevated free radicals due to methanol induced oxidative stress.     

Protective effects of melatonin on the ionizing radiation induced DNA damage in the rat brain.

Melatonin is an endogenously produced antioxidant with radioprotective actions while ionizing radiation is a well-known cytotoxic and mutagenic agent of which the biological results are attributable to its free radical producing effects. The effect of melatonin on the DNA strand breakage and lipid peroxidation induced by ionizing radiation in the rat brain were investigated in order to clarify its radioprotective ability. The DNA strand breakage in rat brain exposed to 1000 cGy ionizing radiation was assessed by alkaline single cell gel electrophoresis and the lipid peroxidation was evaluated by measuring thiobarbituric acid reactive substances (TBARS) concentrations. A significant increase in DNA damage (p < 0.05) and TBARS concentrations (p < 0.01) was found in the radiation treated rat brain. Pre-treatment of rats with intraperitoneal doses of 100 mg/kg melatonin provided a significant decrease in the DNA strand breakage and lipid peroxidation. Our results indicate that melatonin can protect brain cells from oxidative damage induced by ionizing radiation.     

Increased lipid peroxidation in tissues of nickel chloride-treated rats

Parenteral administration of nickel chloride (NiCl2) to rats enhanced lipid peroxidation in liver, kidney, and lung (but not in brain, heart, spleen, or testis), as measured by the thiobarbituric acid reaction for malondialdehyde (MDA) and related chromogens in fresh tissue homogenates. After sc injection of NiCl2 (0.75 mmol per kg body wt), MDA concentrations in liver and kidney became significantly increased by nine h and reached peak values at 48 h. For example, in nine rats killed 48 h after the NiCl2 injection, hepatic MDA concentrations averaged 2.5 +/- 1.0 mumol per g dry wt (P less than 0.001 versus 0.5 +/- 0.3 mumol per g in 30 controls). Dose-effect relationships for lipid peroxidation in liver and kidney were observed with NiCl2 dosages ranging from 0.12 to 0.75 mmol per kg, sc. Intrarenal administration of a carcinogenic nickel compound, nickel subsulfide (Ni3S2, 0.36 mmol per kg body wt), did not affect MDA concentrations in the injected kidneys of rats killed one to 20 days post-injection. The results of this study implicate lipid peroxidation as a molecular mechanism for cell injury in acute NiCl2 poisoning, but they do not furnish any evidence that lipid peroxidation is involved in the initiation of nickel carcinogenesis.     

Melatonin ameliorates diabetes-induced brain injury in rats

Diabetic brain is a serious complication of diabetes, and it is associated with oxidative stress and neuronal injury. This study investigated the protective effect of melatonin (MLT) on diabetes-induced brain injury. A rat model of type 2 diabetes mellitus was produced by intraperitoneal injection of nicotinamide 100 mg/kg, followed by intraperitoneal injection of streptozotocin 55 mg/kg. The diabetic rats were orally administered MLT 10 mg/kg of body weight for 15 days. MLT remarkably downregulated serum glucose levels. It also improved levels of the lipid peroxidation product 4-hydroxynonenal, improved levels of antioxidants including glutathione, glutathione peroxidase and glutathione reductase in the brains of the diabetic rats, and this is indicative of the antioxidant potential of MLT. MLT also prevented increase in homocysteine, amyloid-β42 and tau levels in diabetic rats, and this suggests that it can reduce the risk of dementia. This is associated with reduction in the levels of the dopamine, serotonin, and glutamate and is indicative of the regulatory effect of MLT on neurotransmitters. Treatment with MLT improved diabetes-induced structural alteration in the hippocampus and cerebral cortex. MLT significantly reduced caspase-3 and Bax as well as significantly increase Bcl-2 protein and GFAP-positive astrocytes indicating its anti-apoptotic effect. MLT showed remarkable ameliorative effect against biochemical and molecular alterations in the brains of diabetic rats most likely through its antioxidant property.     

Preliminary study on the protective effect of vitamin C on monosodium glutamate-induced hepatotoxicity in rats

Monosodium glutamate (MSG) is a food additive with a wide range of biological effects but its high dose and prolonged use can cause a toxic effect on the liver. Therefore, the present study was aimed at investigating the role of vitamin C in MSG-induced hepatotoxicity in rats. MSG was administered to rats (by gavage) at a dose of 6 mg/g body weight for 10 days to induce hepatotoxicity, and vitamin C at a dose of 500 mg/kg body weight was coadministered to evaluate its ameliorating effect by measuring alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in serum; superoxide dismutase (SOD) and catalase activities in liver fraction; lipid peroxidation; and liver weight. It was found that MSG significantly (P?<?0.05) induced lipid peroxidation (LPO), increased liver weight, and increased activity of SOD and catalase in the liver of animals. The activity of ALT and AST was also increased in the serum on MSG administration. Vitamin C (500 mg/kg) coadministered with MSG significantly reduced LPO and liver weight and decreased the hepatic activity of catalase, but the activity of SOD was not reduced significantly. Also, a significant reduction in ALT and AST activity was observed. MSG induced oxidative stress and hepatic toxicity in the experimental animals at a dose of 6 mg/g body weight. Vitamin C significantly reduced the oxidative stress and hepatic toxicity induced by MSG, thereby providing a protective effect against the MSG-induced hepatotoxicity. The protective effect is associated with decreased LPO and liver weight and decreased activities of catalase, ALT, and AST.     

Systemic proliferative changes and clinical signs in cynomolgus monkeys administered a recombinant derivative of human epidermal growth factor.

Epidermal growth factor (EGF) effects have been explored extensively in vivo in rodents, but little is known about trophic responses in nonhuman primates. A previous publication reports the hyperplastic epithelial/parenchymal changes noted in the digestive tract (tongue, esophagus, stomach, intestine, liver, gallbladder, pancreas, and salivary glands) of adult cynomolgus monkeys treated with recombinant human EGF(1-48) (rhEGF(1-48)). This report documents clinical findings and structural effects in the remaining epithelium-containing tissues of these animals. Two monkeys/sex/dose received rhEGF(1-48) by intravenous bolus at 0 (vehicle), 10, 100, 500 (females only), or 1,000 microg/kg/day (males only) daily for up to 2 weeks. Treatment- and dose-related clinical findings included emesis, fecal alterations (soft feces and diarrhea), lacrimation, nasal discharge, hypoactivity, transient hypotension, and salivation after dosing. Male monkeys administered 1,000 microg/kg became moribund after 5 days of treatment and were necropsied. All other monkeys completed the 2-week treatment period. Necropsy findings in nongastrointestinal tissues were: enlarged, pale kidneys at 100 microg/kg and greater; small thymuses seen sporadically at all doses; and enlarged adrenals and small thyroids in males at 1,000 microqg/kg. Respective organ-to-brain weight ratios at 500 and 1,000 microg/kg for kidneys were 1.5- and 2.6-fold greater and for heart were 1.7- and 1.3-fold greater than controls. Microscopically, pronounced dose-related epithelial hypertrophy and hyperplasia were evident in kidney, urinary bladder, skin (epidermis and adnexa), mammary gland, prostate, seminal vesicles, epididymis, uterus, cervix, vagina, thyroid, thymus, tonsillar crypts, cornea, trachea, and pulmonary airways. Epitheliotrophic effects were conspicuous in many tissues at 100 to 1,000 microg/kg. Changes to renal collecting ducts were present at 10 microg/kg, suggesting that kidneys were a relatively sensitive target. Proliferative alterations were not apparent in testes, intraocular structures, brain ependyma and choroid plexus at any dose. Aside from the noted exceptions, rhEGF(1-48) was a pantrophic epithelial mitogen in cynomolgus monkeys when used intravenously at suprapharmacologic doses.     

Lipoic acid effects on lipid peroxidation level,superoxide dismutase activity and monoamines concentration in rat hippocampus

The purposes of the present work were to verify lipid peroxidation level, superoxide dismutase (SOD) activity and monoamines (dopamine (DA), norepinephrine (NE), serotonin (5-HT)), and their metabolites (3,4-hydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA)) contents in rat hippocampus after lipoic acid (LA) administration. Wistar rats were treated with 0.9% saline (i.p., control group) and LA (10, 20 or 30 mg/kg, i.p., LA10, LA20 and LA30 groups, respectively). After the treatments all groups were observed for 24 h. In LA20 group only there was a significant decrease in lipid peroxidation level. However, no alteration was observed in SOD activity in groups treated with LA. The NE and DA levels were increased only in 20 mg/kg dose of LA in rat hippocampus. Serotonin content and their metabolite 5-HIAA levels was decreased in same dose of LA. On the other hand, DOPAC and HVA levels did not show any significant change. The reduction in lipid peroxidation level and alterations in hippocampal monoamines can be suggested as a possible brain mechanism from this antioxidant. The outcome of the study may have therapeutic implications in the neurodegenerative diseases.