Lipid Peroxidation In Rat Brain Research Articles

A model of aluminum exposure associated with lipid peroxidation in rat brain.

We have developed a rat model to investigate the relationship between aluminum exposure and aluminum accumulation, and with oxidative damage in brain tissues. Intraperitoneal injections of aluminum lactate for 7 wk (the total aluminum dosage per rat was approx 100 mg) significantly increased aluminum levels in the brain. The concentration of lipid peroxidation products (thiobarbituric acid-reactive substances [TBARS]) also increased in the brain following aluminum lactate injections. No significant correlations between the concentrations of aluminum and of TBARS were found in the whole brain. Subcellular analysis revealed that aluminum lactate injections led to a significant increase in the concentration of aluminum in the mitochondrial fraction but had no significant effect on the concentration of peroxides in any subcellular fraction. These results suggest that aluminum accumulation induced by the aluminum lactate administration associates with the acceleration of lipid peroxidation in rat brain. Furthermore, these data indicate that the pro-oxidant effect of aluminum may be indirect and concentration independent. The experimental conditions used here provide an animal model of aluminum accumulation in the brain that should prove useful for further investigations of the mechanisms of aluminum neurotoxicity.

Preventive effects of Cassia auriculata L. flowers on brain lipid peroxidation in rats treated with streptozotocin.

The effect of aqueous extract of the flowers of Cassia auriculata were examined on antioxidants and lipid peroxidation in the brain of streptozotocin diabetic rats. Significant increase in the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase and reduced glutathione were observed in brain on treatment with Cassia auriculata flower extract (CFEt) and glibenclamide. Both the treated groups showed significant decrease in thiobarbituric reactive substances (TBARS) and hydroperoxide formation in brain, suggesting its role in protection against lipid peroxidation induced membrane damage. Since the study of induction of the antioxidant enzymes is considered to be a reliable marker for evaluating the antiperoxidative efficacy of medicinal plant, these findings are suggestions of possible antiperoxidative role played by Cassia auriculata flower extract.

Differential effects of antipsychotics on expression of antioxidant enzymes and membrane lipid peroxidation in rat brain

Typical and atypical antipsychotics significantly differ in their neurotransmitter receptor affinity profiles, and their efficacy and side effects in schizophrenic patients. Typical antipsychotics have been found to increase the oxidative (i.e. free radical-mediated) cellular injury in rats. Since schizophrenia also involves oxidative injury, the understanding of differential effects of these antipsychotics on expression of antioxidant enzymes and oxidative injury may be very critical. The effect of chronic exposure of haloperidol (HAL), a typical antipsychotic, was compared to effects of risperidone (RIS) or clozapine (CLZ) or olanzapine (OLZ), atypical antipsychotics on antioxidant defense enzymes and lipid peroxidation in the rat brain. The levels of antioxidant enzymes and hydroxyalkenals (HAEs) were measured in rat brain cytosol and fatty acids were measured in brain cell membranes. Chronic HAL treatment for both 45 and 90 days significantly decreased manganese-superoxide dismutase (MnSOD), copper-zinc superoxide dismutase (CuZnSOD) and catalase (CAT) activity with parallel marked increase in (HAEs), a marker of lipid peroxidation in rat brain. The levels of enzymatic activity very well correlated with the levels of enzyme proteins indicating that the changes were probably in the expression of net protein. However, RIS, CLZ and OLZ treatments did not produce any alterations in the levels of antioxidant enzymes and HAEs, both after 45 and 90 days. There were no alterations in the levels of saturated as well as polyunsaturated fatty acids in brain membranes. These findings indicate that chronic administration of HAL, but none of the studied atypicals induce oxidative stress by persistent changes in the levels of antioxidant enzymes and cause membrane lipid peroxidation.

Paraquat- and diquat-induced oxygen radical generation and lipid peroxidation in rat brain microsomes.

NADPH-menadione reductase activity by rat brain microsomes (Ms) was decreased 40-50% by 10 microM dicumarol, a potent inhibitor of DT-diaphorase, whereas no change in NADPH-paraquat (PQ) and -diquat (DQ) reductase activity was observed. NADPH-DQ reductase activity in brain Ms was 2.5-fold higher than NADPH-PQ reductase activity. The formation of PQ and DQ radicals was verified optically and observed directly by ESR spectroscopy in the NADPH-PQ and -DQ reductase reactions by brain Ms under anaerobic conditions. PQ- and DQ-induced superoxide formation was confirmed by the detection of DMPO-OOH ESR signals and followed by chemiluminescence (CL) of a Cypridina luciferin analogue (CLA). The kinetics and intensity of the CL were consistent with the observations that the reduction in DQ is faster than that in PQ. Thiobarbituric acid reactive substances (TBARS) and phospholipid hydroperoxides in brain Ms increased in the presence of NADPH and Fe3+. The generation of both lipid peroxidation products derived from brain Ms decreased with increasing concentrations of PQ and DQ. The inhibitory effect of DQ is more pronounced than that of PQ. The formation of PQ- and DQ-induced reactive oxygen species was not associated with lipid peroxidation in rat brain Ms.

Lipid Peroxidation in Rat Brain During Focal Cerebral Ischemia: Prevention of Malondialdehyde and Lipid Conjugated Diene Production by a Novel Antiepileptic, Lamotrigine

The effects of Lamotrigine (LTG) which blocks ischemia induced glutamate (Glu) release, on lipid peroxidation have been evaluated in cortical and cerebellar tissues of rat brain during focal cerebral ischemia. A total of 45 rats were randomly assigned into one of four groups; sham operated animals as controls, animals subjected to middle cerebral artery occlusion (MCAO) and treatment groups with LTG (20 mg/kg i.p.) either 30 min before or just after MCAO. Changes in lipid peroxides were expressed as nanomoles of malondialdehyde (MDA) and conjugated diene (CD) per milligram of protein. MDA values following 60 min of ischemia relative to contralateral cortex and CD levels in 0, 10 and 60 min of ischemia were found to be higher in the ipsilateral cortex than those in the contralateral cortex. On the other hand, contralateral cerebellar MDA levels after 0 and 60 min of ischemia and CD levels after 0, 10 and 60 min of ischemia were higher than those in the ipsilateral cerebellum. Pharmacological inhibition of Glu release significantly decreased the MDA and CD production in both cortex and cerebellum. Pre- or post-ischemic administration of LTG did not significantly change CD levels, but MDA levels in contralateral cortex were found to be significantly decreased than those in ischemic cortex in both pre- and post-treated group.

BRAIN LIPID PEROXIDATION AND CHANGES OF TRACE METALS IN RATS FOLLOWING CHRONIC MANGANESE CHLORIDE EXPOSURE

The aim of this study was to investigate the effects of chronic, daily, 30-d administration of manganese chloride (MnCl 2 ) to male Sprague-Dawley rats on lipid peroxidation and changes of trace elements (manganese, iron, copper, zinc) in various brain regions. Rats were intraperitoneally injected with MnCl 2 (20 mg/kg) once daily for 30 consecutive days. The Mn accumulated in frontal cortex, corpus callosum, hippocampus, striatum, hypothalamus, medulla, cerebellum, and spinal cord. Malondialdehyde, an end product of lipid peroxidation, was markedly decreased in frontal cortex and cerebellum. An increased level of Cu was observed in frontal cortex, medulla, and a cerebellum. A decreased Fe level was found only in cerebellum, and a decreased Zn level was observed in hippocampus and striatum. In a second group of animals, Mn (20 mg/kg/d) and glutathione (GSH, 15 mg/kg/d) were administered ip for 30 d. In GSH-Mn-treated rats, compared to Mn-treated rats, MDA concentrations were significantly reduced in frontal cortex, medulla and cerebellum. The changes of trace elements in rat brain were similar to the Mn-treated group. We suggest that Mn is an atypical antioxidant, as well as not involved in oxidative damage in rat brain. Fe and Cu may play roles in the protective effect of Mn against lipid peroxidation in rat brain.

Hypoxia-induced lipid peroxidation in rat brain and protective effect of carnitine and phosphocreatine.

The exposure to hypobaric hypoxia increased lipid peroxidation as indicated by thiobarbituric acid-reactive substances [TBARS] in rat brain. Plasma lactate/pyruvate ratio was used as a marker of hypoxia. We compared the protective effect of alpha-tocopherol with the effect of L-carnitine or phosphocreatine. Rats pretreated with alpha-tocopherol, L-carnitine, or phosphocreatine had lower TBARS levels after the exposure to hypobaric hypoxia. However, lactate/ pyruvate ratio was improved only in rats pretreated with L-carnitine or phosphocreatine. We conclude from our data that, contrary to alpha-tocopherol, protective effects of L-carnitine and phosphocreatine administrations are due to their regulation of metabolic reactions during hypobaric hypoxia rather than to their scavenger activity.

Antioxidant properties of new chalcogenides against lipid peroxidation in rat brain.

Ebselen (2-phenyl- 1,2-benzisoselenazole-3 (2H)-one) is a seleno-organic compound with antioxidant properties, and anti-inflammatory actions. Recently, ebselen improved the outcome of acute ischemic stroke in humans. In the present study, the potential antioxidant capacity of organochalcogenide compounds diphenyl diselenide (PhSe)2, diphenyl ditelluride (PhTe)2, diphenyl disulfide (PhS)2, p-Cl-diphenyl diselenide (pCl-PhSe)2, bis-[S-4-isopropyl 2-phenyl oxazoline] diselenide (AA-Se)2, bis-[S-4-isopropyl 2-phenyl oxazoline] ditelluride (AA-Te)2 and bis-[S-4-isopropyl 2-phenyl oxazoline] disulfide (AA-S)2 was compared with that of ebselen (a classical antioxidant). Spontaneous and quinolinic acid (QA)- (2 mM) and sodium nitroprusside (SNP)- (5 microM)-induced thiobarbituric reactive species (TBARS) production by rat brain homogenates was determined colorimetrically. TBARS formation was reduced by ebselen, (PhSe)2, (PhTe)2, (AA-Se)2, (AA-S)2 and (pCl- PhSe)2 to basal rates. The concentrations of these compounds needed to inhibit TBARS formation by 50% (IC50) are 1.71 microM, 3.73 microM, 1.63 microM, 9.85 microM, >33.3 microM, 23.2 microM and 4.83 microM, respectively for QA. For TBARS production induced by SNP the IC50 was 2.02 microM, 12.5 microM, 2.80 microM, >33.3 microM, 24.5 microM and 7.55 microM, respectively. The compounds (AA-Te)2 and (PhS)2 have no antioxidant activity and pro-oxidant activity, respectively. These results suggest that (AA-Se)2 and (AA-S)2 can be considered as potential pharmaceutical antioxidant agents.

Antioxidative and free radical scavenging activities of pineal indoles.

The antioxidant action, free radical scavenging activity and pro-oxidant effect of pineal indoles were studied. Serotonin, 5-hydroxytryptophol, 5-methoxytryptophol and 5-methoxytryptamine potently inhibited lipid peroxidation in rat brain, liver and kidney homogenates and hemolysis of rat erythrocytes. 5-Methoxyindole-3-acetic acid and 5-hydroxyindole-3-acetic acid potently suppressed superoxide radical formation. 5-Hydroxytryptophol and 5-hydroxyindole-3-acetic acid inhibited hydroxyl radical generation. Serotonin, 5-hydroxytryptophol and 5-hydroxyindole-3-acetic acid exhibited a pro-oxidant action in the bleomycin-Fe system. This study demonstrated that 5-methoxytryptamine, among the various pineal indoles tested, exhibited the most potent antioxidant action and was devoid of pro-oxidant effect. Serotonin, 5-hydroxytryptophol and 5-methoxytryptophol also had high antioxidative activity. By comparison melatonin had a lower antioxidant potency.

Antioxidative property of T-0970, a new ureidophenol derivative

We investigated the antioxidative property of T-0970, a newly synthesized ureidophenol derivative. The inhibitory effect of T-0970 on spontaneous lipid peroxidation in rat brain was 10 times greater than those of well-known antioxidants such as butylhydroxytoluene (BHT), probucol and α-tocopherol. T-0970 also showed dose-dependent free radical scavenging activities in vitro for both superoxide anions and hydroxyl radicals. The radical-scavenging potencies of T-0970 were about 10–30 times stronger than those of BHT. We evaluated the in vivo antioxidative ability of T-0970 in the animal model of acute oxidative tissue injury in rats. Intraperitoneal injection of ferric nitrilotriacetate (Fe/NTA) caused an acute and remarkable increase in the level of thiobarbituric acid-reactive substances (TBARS) in both plasma and the liver, and also resulted in a considerable elevation of the plasma levels of GOT and GPT indicative of hepatic injury. Both oral and intravenous administration of T-0970 dose-dependently depressed these diagnostic parameters. These results indicate that T-0970 may have a therapeutic potential in various diseases associated with oxidative tissue injury.

Antioxidative activity of natural products from plants

A variety of flavonoids, lignans, an alkaloid, a bisbenzyl, coumarins and terpenes isolated from Chinese herbs was tested for antioxidant activity as reflected in the ability to inhibit lipid peroxidation in rat brain and kidney homogenates and rat erythrocyte hemolysis. The pro-oxidant activities of the aforementioned compounds were assessed by their effects on bleomycin-induced DNA damage. The flavonoids baicalin and luteolin-7-glucuronide-6′-methyl ester, the lignan 4′-demethyldeoxypodophyllotoxin, the alkaloid tetrahydropalmatine, the bisbenzyl erianin and the coumarin xanthotoxol exhibited potent antioxidative activity in both lipid peroxidation and hemolysis assays. The flavonoid rutin and the terpene tanshinone I manifested potent antioxidative activity in the lipid peroxidation assay but no inhibitory activity in the hemolysis assay. The lignan deoxypodophyllotoxin, the flavonoid naringin and the coumarins columbianetin, bergapten and angelicin slightly inhibited lipid peroxidation in brain and kidney homogenates. It is worth stressing that the compounds with antioxidant effects in this assay, with the exception of tetrahydropalmatin and tanshinone I, have at least one free aromatic hydroxyl group in structure. Obviously, the aromatic hydroxyl group is very important for antioxidative effects of the compounds. None of the compounds tested exerted an obvious pro-oxidant effect.

Effects of trimethazidine on brain metabolism in acute ischemia combined with hypoxia

Trimethazidine in a dose of 25 mg/kg prevents disturbances of energy metabolism and activation of lipid peroxidation in rat brain after acute ischemia and hypoxia.

Effect of piribedil and its metabolite, S584, on brain lipid peroxidation in vitro and in vivo

We studied the effect of piribedil (1-3,4-methylendioxybenzyl-4-(2-pyrimidyl) piperazine) and its catechol metabolite, S584 (1-(3,4-dihydroxybenzyl-4-(2-pyrimidinyl)-piperazine), on rat brain lipid peroxidation (a) in vitro in rat synaptosomes and cortical slices after induction of an oxidative stress and (b) in vivo in mouse brain after short-term exposure (two and three 4-h cycles) to O 2/CO 2 (95%:5%). The metabolite (10 −4–10 −5 M), but not piribedil, prevented Fe 3+-stimulated lipid peroxidation in rat synaptosomes and in rat cortical slices incubated with high oxygen concentrations. Piribedil (7.5 and 30 mg/kg, orally), counteracted the increase in thiobarbituric reactive substances in the brain of mice only when these were exposed to two or three cycles of a high oxygen concentration. S584 (30 mg/kg, orally) reduced thiobarbituric acid reactive substances in brain in mice exposed either to air (control) or to three cycles of a high oxygen concentration. These results suggest that piribedil has an antiperoxidative effect in brain, which may be partly related to the in vivo formation of the catechol metabolite, S584.

The effect of quinolinate on rat brain lipid peroxidation is dependent on iron

Quinolinate, an endogenous excitotoxic metabolite of tryptophan with affinity to the N-methyl- d-aspartate type of glutamate receptor, is known as a stimulator of lipid peroxidation in vitro [Neurochem. Res. (1991) 16, 1139–1143]. To analyse the mechanism of this quinolinate toxicity we used the thiobarbituric acid test to measure malondialdehyde in homogenates of rat cerebral hemispheres incubated in air at 37°C for 30 min in the presence of 0.015–15.0 mM quinolinate, endogenous iron or 0.5–2.0 μM FeSO 4 and with or without 250 μM ascorbate. Quinolinate in the concentrations of 0.15–2.5 mM stimulated lipid peroxidation in the homogenates in the presence of 0.5–2.0 μM Fe 2+. However, quinolinate concentrations higher than 3.0 mM inhibited the lipid peroxidation at all the tested concentrations of iron. In the presence of a potent iron chelator (10 μM deferoxamine) quinolinate completely failed to induce lipid peroxidation in rat brain homogenates. Spectral analysis revealed that quinolinate is able to form a complex with Fe 2+. The results suggest that quinolinate does not have a direct peroxidative effect, but that it modulates lipid peroxidation via its interaction with iron.

The effect of quinolinate on rat brain lipid peroxidation is dependent on iron

The effect of quinolinate on rat brain lipid peroxidation is dependent on iron

Effect of Dopamine Metabolism on Lipid Peroxidation in Rat Brain

Effect of Dopamine Metabolism on Lipid Peroxidation in Rat Brain

Autogenous production of hydroxyl radicals from thiopental.

It is generally believed that barbiturates can protect neural tissues from the damage induced by cerebral hypoxia. One of the mechanisms for protecting neurons is through the inhibition of lipid peroxidation (LPO). We therefore examined LPO in rat brain, liver and kidney by measuring the accumulation of thiobarbituric acid-reactive substances (TBAR) after thiopental administration under 21% O2. We also designed an in vitro study to gain insight into free radical generation leading to the formation of LPO from thiopental by electron spin resonance (ESR). An accumulation of TBAR in the rat liver was observed after the administration of a large dose of thiopental (70 mg/kg intraperitoneally). However, no change in LPO in the brain and kidney was observed. In the in vitro study, thiopental could scavenge superoxide (O2-.) radicals, while it spontaneously generated hydroxyl radicals (.OH) in solution. We conclude that thiopental can scavenge O2-., while producing .OH, subsequently resulting in membrane lipid peroxidation under physiologic O2 conditions. This formation of .OH may damage cell membrane lipids.

Kainate-induced lipid peroxidation in rat brain in vitro is markedly reduced by the endogenous antioxidant melatonin

Generation of reactive oxygen species is a major, well-known cause of heart injury induced by ischemia-reperfusion. This injury is manifested through myocardial stunning, reperfusion and lethal reperfusion injury of cardiocytes. The pyridoindole stobadine has been shown to exhibit significant antioxidant, free-radical scavenging and hypoxic-tissue-protecting properties. The present study examined the effects of stobadine and two novel derivatives, SMe1 and SMe1EC2, which exhibit improved pharmacodynamic and toxicity profiles, on the functional properties and reperfusion dysrhythmias of the isolated rat heart in ischemia-reperfusion conditions. All experiments were performed on isolated Langendorff-perfused hearts isolated from 3-month-old male Wistar rats. After 15 min of stabilization, the hearts were subjected to a 30-minute period of global no-flow ischemia, followed by a 30-minute reperfusion period. Stobadine, SMe1 and SMe1EC2 were applied at a concentration of 1 × 10–5 M 10 min before the onset of ischemia, and during reperfusion through the perfusion medium. As compared to the untreated group, addition of SMe1EC2 during reperfusion significantly increased left ventricular developed pressure, decreased pathologically elevated left ventricular end-diastolic pressure and enhanced recovery of the stunned myocardium after ischemia. Both SMe1 and stobadine failed to influence these parameters; however, all derivatives tested inhibited serious life-threatening reperfusion dysrhythmias such as ventricular tachycardia and ventricular fibrillation. Our findings suggest that SMe1EC2 promotes an improved recovery of the left ventricular function following ischemia compared to either stobadine or SMe1. However, both SMe1EC2 and SMe1 manifested a significant anti-dysrhythmic effect comparable with that of stobadine and partially reduced myocardial ischemia-reperfusion-induced injury.

Ethanol-induced oxygen radical formation and lipid peroxidation in rat brain: effect of chronic alcohol consumption.

The effect of chronic and in vitro ethanol exposure on brain oxygen radical formation and lipid peroxidation was analyzed. Ethanol induces a dose-dependent increase in lipid peroxidation in brain homogenates. The peroxidative effects of alcohol seem to be related to both cytochrome P450 and the ethanol-inducible form of cytochrome P450 (CYP2E1), because preincubation with metyrapone (an inhibitor of cytochrome P450) or with an antibody against CYP2E1 abolished the ethanol-increased lipid peroxidation. Using the formation of dichlorofluorescein, we also demonstrated that both in vitro and chronic alcohol exposure significantly enhanced the formation of oxygen radical species in synaptosomes. Chronic alcohol treatment also leads to an induction of cytochrome P450 (230%), NADPH cytochrome c reductase (180%), NADPH oxidation (184%), and CYP2E1 in brain microsomes. In addition, this treatment produced a decrease in the GSH/GSSG ratio in brain and significantly enhanced the levels of superoxide dismutase and catalase activities. This mechanism could be involved in the toxic effects of ethanol on brain and membrane alterations occurring after chronic ethanol intake.

Developmental changes in the peroxidation potential of rat brain homogenate and mitochondria

Lipid peroxidation, one of the most common expressions of oxidative stress, may be altered during normal physiological states including development. We have examined the changes in lipid peroxidation in rat brain, a tissue highly susceptible to oxidative damage, during this physiological state. In vivo lipid peroxidation was moderate in the foetal and neonatal period and increased during the postnatal development. Lipid peroxidation potential in brain homogenate and mitochondria, in Tris-HCl buffer or with exogenous cofactors, such as ascorbate-Fe 2+, NADPH ADP-Fe 3+ and cumene hydroperoxide, showed significant changes during pre- and postnatal development. In general, brain as well as liver (used as a standard tissue for comparision) seem to have low peroxidation potential in the foetal and neonatal period which then increases at different rates during development to reach adult values at different days. The low peroxidation potential corresponds to the rapid phase of cell proliferation. These results taken together with similar earlier finding in other systems may indicate a possible occurrence of a ‘permissible period’ during which the low levels of lipid peroxidation may be able to yield only low amounts of cytostatic aldehydes and peroxides as byproducts, thereby allowing rapid proliferation of cells.