Glutamate uptake in mice bred for ethanol withdrawal severity

Rationale: Withdrawal seizure-prone and withdrawal seizure-resistant mice were selectively bred to exhibit differences in handling-induced convulsion severity during ethanol withdrawal. The glutamatergic system has been implicated in seizure activity as well as ethanol withdrawal symptoms. Objective: This study assessed L-[³H]glutamate uptake into hippocampal synaptosomes prepared from withdrawal seizure-prone and- resistant mice. Methods:Glutamate uptake was characterized following repeated handling-induced convulsions, during acute intoxication, and during peak withdrawal following chronic ethanol exposure. Results: Hippocampal synaptosomal L-[³H]glutamate uptake did not differ between convulsion- and ethanol-naive withdrawal seizure-prone and- resistant mice. Furthermore, exposure to convulsions or to a hypnotic dose of ethanol (4 g/kg) did not alter L-[³H]glutamate uptake. However, withdrawal from 72 h of ethanol exposure significantly increased L-[³H]glutamate uptake in both mouse lines as compared to their respective ethanol-naive controls. Conclusions:These data suggest that glutamate uptake is influenced by chronic ethanol exposure similarly in both withdrawal seizure-prone and- resistant mice. The observed increases in glutamate uptake during withdrawal may be associated with compensatory mechanisms triggered by chronic intoxication and are independent of the selected differences for withdrawal severity. Received: 23 July 1998/Final version: 21 October 1998     

Effects of acute ethanol intoxication,chronic ethanol intoxication,and ethanol withdrawal on magnesium and calcium metabolism in the rat

Effects of ethanol intoxication and withdrawal on magnesium and calcium metabolism were studied in rats. During acute ethanol intoxication, plasma [Mg²⁺] was increased and plasma [Ca²⁺] decreased. During chronic intoxication, plasma [Mg²⁺] was normalized whereas plasma [Ca²⁺] was persistently subnormal. Ethanol withdrawal was followed by a decrease in plasma [Mg²⁺] and a normalization of plasma [Ca²⁺]. These various changes are probably related to changes in systemic pH and to the biochemical effects of ethanol and ethanol withdrawal on intermediary metabolism. Cerebrospinal fluid [Mg²⁺] was unchanged during intoxication and withdrawal and it was concluded that no etiological role can presently be ascribed to the magnesium ion as far as cerebral signs of ethanol intoxication and withdrawal in the rat are concerned. No consistent changes in erythrocyte [Mg²⁺] were encountered during ethanol intoxication and withdrawal in rats.     

浒苔多糖对小鼠肝肾综合征防治作用的研究

目的 观察浒苔多糖对四氯化碳诱导的小鼠肝肾综合征保护作用。方法 用四氯化碳诱导建立小鼠肝肾综合征模型,通过分析小鼠血脂、总抗氧化能力、肝肾功能及肝肾组织病理等变化,阐明浒苔多糖对小鼠肝肾综合征防治的有效性。结果 浒苔多糖有效降低四氯化碳诱导的小鼠血脂水平,提高机体抗氧化能力,改善肝肾功能失调,减轻肝肾组织病变。结论 浒苔多糖对四氯化碳诱导的小鼠肝肾综合征有良好的防治作用,可为今后的临床应用提供理论支持。     

Propolis reverses acetaminophen induced acute hepatorenal alterations: A biochemical and histopathological approach

The present study has been conducted to evaluate the curative effect of propolis extract, a honey bee-hive product, against acetaminophen (APAP) induced oxidative stress and dysfunction in liver and kidney. Animals were challenged with APAP (2 g/kg, p.o.) followed by treatment of propolis extract (100 and 200 mg/kg, p.o.) once only after 24 h. Release of transaminases, alkaline phosphatase, lactate dehydrogenase, and serum bilirubin were increased, whereas hemoglobin and blood sugar were decreased after APAP administration. Antioxidant status in both the liver and kidney tissues were estimated by determining the glutathione, malondialdehyde content and activities of the CYP enzymes, which showed significant alterations after APAP intoxication. In addition, activities of adenosine triphosphatase, acid phosphatase, alkaline phosphatase, and major cell contents (total protein, glycogen and cholesterol) were also altered due to APAP poisoning. Propolis extract successfully reversed the alterations of these biochemical variables at higher dose. Improvements in hepatorenal histoarchitecture were also consistent with biochemical observations. The results indicated that ethanolic extract of propolis has ability to reverse APAP-induced hepatorenal biochemical and histopathological alterations probably by increasing the antioxidative defense activities due to various phenolic compounds present in it.     

Antioxidant and antimicrobial properties of Moltkia petraea (Tratt.) Griseb. flower,leaf and stem infusions

Antioxidant and antimicrobial activities as well as the quantity of phenolic substances (total phenol, flavonoid and phenolic acid contents) were determined in aqueous extracts of leaves, stems and flowers of Moltkia petraea (Tratt.) Griseb. from two mountainous localities (Sveti Jure and Snije?nica) in Croatia. In addition, the profile of phenolic acids was analyzed by UPLC–MS/MS. Antioxidant activities of all extracts in different test systems, namely the DPPH radical scavenging, reducing power assay and chelating activity, increased with extract concentration. Activity of the extracts from Snije?nica in β-carotene-linoleic acid assay did not differ from the activity of standard, BHA. The leaf extracts from Snije?nica demonstrated superior antioxidant activity in most of the assays, while the stem extract from the same locality was the most effective Fe²⁺ ion chelator. In general, the extracts from Snije?nica were more effective antioxidants than the corresponding extracts from Sveti Jure. The aqueous extracts of M. petraea did not show antimicrobial activity against bacteria and fungi tested in the diffusion and dilution assays.     

Tolerance and sensitization to chronic escalating dose heroin following extended withdrawal in Fischer rats: possible role of mu-opioid receptors

Rationale/objectives

Heroin addiction is characterized by recurrent cycles of drug use, abstinence, and relapse. It is likely that neurobiological changes during chronic heroin exposure persist across withdrawal and impact behavioral responses to re-exposure. We hypothesized that, after extended withdrawal, heroin-withdrawn rats would express behavioral tolerance and/or sensitization in response to heroin re-exposure and that these responses might be associated with altered mu-opioid receptor (MOPr) activity.

Methods

Male Fischer rats were exposed chronically to escalating doses of heroin (7.5–75 mg/kg/day), experienced acute spontaneous withdrawal and extended (10-day) abstinence, and were re-exposed chronically to heroin. Homecage behaviors and locomotor activity in response to heroin, as well as somatic withdrawal signs, were recorded. Separate groups of rats were sacrificed after extended abstinence and MOPr expression and G-protein coupling were analyzed using [³H]DAMGO and [³⁵S]GTPγS assays.

Results

The depth of behavioral stupor was lower during the initial days of heroin re-exposure compared to the initial days of the first exposure period. Behavioral responses (e.g., stereotypy) and locomotion were elevated in response to heroin re-exposure at low doses. Rats conditioned for heroin place preference during the chronic re-exposure period expressed heroin preference during acute withdrawal; this preference was stronger than rats conditioned during chronic heroin exposure that followed chronic saline and injection-free periods. Extended withdrawal was associated with increased MOPr expression in the caudate-putamen and frontal and cingulate cortices. No changes in G-protein coupling were identified.

Conclusions

Aspects of tolerance/sensitization to heroin are present even after extended abstinence and may be associated with altered MOPr density.     

Phenolic fractions from Trifolium pallidum and Trifolium scabrum aerial parts in human plasma protect against changes induced by hyperhomocysteinemia in vitro

Elevated concentration of homocysteine (Hcy) in human plasma, defined as hyperhomocysteinemia has been correlated with some diseases, such as cardiovascular, neurodegenerative, and kidney disorders. Homocysteine occurs in human plasma in several forms, including the most reactive form of Hcy – its cyclic thioester – homocysteine thiolactone (HTL), which represents up to 0.29% of plasma total Hcy. It is suggested that Hcy and HTL may also act as oxidants, but various polyphenolic antioxidants are able to inhibit the oxidative damage induced by Hcy or HTL. The aim of our present study was to investigate in vitro oxidative changes in human plasma induced by the model of hyperhomocysteinemia in the presence of the phenolic fractions from selected clovers (Trifolium pallidum and Trifolium scabrum aerial parts). Hyperhomocysteinemia was stimulated by a reduced form of Hcy (final dose 100 μM) or HTL (final dose 1 μM). The aim of our study was also to explain the effect of the phenolic fractions on the coagulation activity of human plasma treated with Hcy and its thiolactone. Tested phenolic fractions significantly inhibited the oxidative stress (measured by the total antioxidant level – TAS) in plasma treated with Hcy or HTL. The phenolic fractions from T. pallidum and T. scabrum also caused a distinct reduction of plasma lipid peroxidation (measured by the level of thiobarbituric acid reactive substance) induced by the model of hyperhomocysteinemia. Moreover, tested fractions modulated the coagulation properties of plasma treated with homocysteine and its thiolactone. It seems that antioxidative activities of the phenolic fractions from T. pallidum and T. scabrum aerial parts may be responsible for their medicinal properties during hyperhomocysteinemia.     

Induction of oxidative stress in liver and kidney of rats exposed to Nigerian bonny light crude oil

The local population of Niger‐Delta in the Southern part of Nigeria have used bonny light crude oil (BLCO) as a remedy for various ailments and are exposed to some extent to this widespread environmental contaminant or its metabolites through the food chain. BLCO's hepatorenal toxicity was studied using oxidative stress indices to elucidate the precise nature and mechanism of action. BLCO was orally administered at concentrations of 0, 200, 400, and 800 mg kg^?1 to adult male rats for 7 days. After exposure, kidney weight was unaffected, but liver weight decreased significantly at 800 mg kg^?1 only compared with control. BLCO exposure resulted in dose‐dependent elevation of serum aminotransferases, total bilirubin, urea, and creatinine. Activities of superoxide dismutase and catalase decreased significantly, whereas γ‐glutamyltransferase activity and the level of glutathione increased significantly in BLCO‐treated animals compared with control in both liver and kidney of rat. Renal activities of glucose‐6‐phosphatase and 5′‐nucleotidase markedly decreased in a dose‐dependent manner in BLCO‐exposed rats. In addition, the levels of hydrogen peroxide and lipid peroxidation significantly increased, dose dependently, in liver and kidney of BLCO‐treated rats compared with control. BLCO‐treated rats showed marked degeneration of kidney evident in cortical hemorrhages, tubular necrosis, protein casts, and cellular infiltration. However, no treatment‐related liver histopathology was observed. The results suggested that BLCO elicits disruption of antioxidant status and concomitant elevation of hydrogen peroxide and lipid peroxidation differentially in liver and kidney of rats. The hepatorenal toxicity of BLCO could be due to induction of oxidative stress in liver and kidney. © 2011 Wiley Periodicals, Inc. Environ Toxicol, 2012.     

Quantitative measurement of oxidative damage in erythrocytes as indicator in benzene intoxications

The metabolism of aromatic hydrocarbons by the organism forms products that cause cell death depending on the type of exposure. Benzene exposure has been linked to oxidative stress, hepatic damage, aplastic anemia, and hematopoietic cancer as lymphoid and myeloid leukemia. However, there are not fast methods to evaluate chronic benzene exposure in human blood. The objective of this work was the evaluation of the correlation between oxidative damage with benzene exposure and the level of cellular plasma membrane stability (CPMS) in erythrocytes to use it as a future indicator to determine the grade of benzene intoxications. CPMS in vitro assays were used to evaluate damage for benzene, toluene, and xylene. Erythrocytes CPMS assays in vitro shows a progressive reduction with benzene, toluene, and xylene suggesting that aromatic hydrocarbons complexity favors CPMS damage. Eight groups of Wistar rats (n?=?5) were used to study the level of damage on CPMS by acute and chronic benzene administration. Enzymatic, metabolic, histological, and oxidative damage tests were performed. Acute administration (100?μL/100?g/single dose) showed a decrease of 66.7% in CPMS, while 63.6% for chronic administration (5?μL/100?g/every 2?days/3?months) showing a correlation with liver damage principally (transaminases activity increase, glycogen level decrease, and high oxidative damage). Tissue damage was observed in bone marrow, kidney, spleen, and lungs. Benzene produces damage on CPMS depending on the exposure time and dose. The CPMS technique could be used as an important aromatic hydrocarbons intoxication indicator.     

Influence of temperature on the subcritical water extraction of Actinidia arguta leaves: A screening of pro-healthy compounds

Actinidia arguta is a species disseminated in Europe and classified by the Chinese Herbal Medicine as a medicinal plant. The fruit (kiwiberry) has been extensively exploited for multiple purposes, while leaves where discarded. The objective of this study was to evaluate the optimal Subcritical Water Extraction (SWE) temperature (110 °C - 160 °C) of antioxidants and polyphenols from A. arguta leaves. The optimal temperature of extraction was 123 °C, revealing the highest phenolic and flavonoid contents and good scavenging efficiencies against HOCl (IC₅₀ = 17.06 μg/mL) and O₂^●- (IC₅₀ = 335.2 μg/mL), without toxicity on intestinal cells. The phenolic profile was characterized by high amounts of phenolic acids (e.g., gallic acids), flavanols (catechin) and flavonols (e.g., quercetin-3-O-galactoside). This work allows to conclude that SWE can be a useful extraction technique for the recovery of polyphenolics from A. arguta leaves.     

Comparison of the effect of chronic cadmium exposure on the antioxidant defense systems of kidney and brain in rat

Abstract

Cadmium (Cd²⁺) produces toxic effects on various tissues as kidney and liver, so several studies have focused to explore the effect produced by different doses and exposure times of this metal. However, little has been reported about the effect that Cd²⁺ shows in the brain in vivo. Hence, this study aimed at comparing the effect of chronic Cd²⁺ exposure on antioxidant defense systems of kidney and brain in rats. Six groups of male rats were employed; five were administered for 45 days with different doses of cadmium chloride (0.187, 0.375, 0.562, 0.937 and 1.125?mg/kg; i.p.) and the other was used as control. Free radicals (FRs) were directly quantified by electron paramagnetic resonance (EPR) spectroscopy; malondialdehyde (MDA), reduced glutathione (GSH) and the activity expression of superoxide dismutase (SOD2) and catalase (CAT) were also measured. The EPR results showed that there was no increase in FR content in kidney or brain. MDA and GSH levels increased in kidney but not in the brain. The SOD2 activity was not altered, but its expression decreased in both tissues. On the other hand, CAT activity and expression tended to increase at low doses and decrease at high doses in both tissues. Therefore, these results suggest that there exist compensatory mechanisms in both kidney and brain that are capable of avoiding the toxic effects exerted by Cd²⁺ at these doses and exposure time.     

Effects of ethanol withdrawal, stress and amphetamine on rat brain (Na+ + K+)-ATPase.

Rats were fed liquid diets containing ethanol (EtOH) or sucrose for 4 weeks, and killed at various times after removal of EtOH. In those having access to the diet up to the time of sacrifice, EtOH caused no increase in (Na⁺ + K⁺)-ATPase activity of whole brain homogenates. However, activity was increased during the period 12–48 hr after withdrawal of EtOH, and was greatest at 24 hr. Fractionation of the homogenate showed that the increase was confined to the lysed synaptosomal fraction. Activity was also increased at 16 hr after one acute dose of EtOH (5 g/kg). The increased ATPase activity during withdrawal could be blocked by administration of another dose of EtOH (3 g/kg) 1 hr before sacrifice, in both acutely and chronically EtOH-treated rats. This is consistent with enhanced sensitivity of noradrenaline-stimulated enzyme to inhibition by EtOH in vitro. ATPase activity was also increased by amphetamine in a dose-dependent manner, both in vivo and in vitro, and by forced swimming. The rise in (Na⁺ + K⁺)-ATPase activity during EtOH withdrawal is interpreted as an activation by conformational change, secondary to catecholamine release due to stress, rather than an adaptive response to chronic EtOH exposure.     

Caffeic acid protects tissue antioxidants and DNA content in methamphetamine induced tissue toxicity in Sprague Dawley rats

Caffeic acid (CA) (3,4-dihydroxycinnamic acid) is among the major hydroxycinnamic acids. Hydroxycinnamic acid is the major subgroup of phenolic compounds. Methamphetamine (METH) is a potent addictive psychostimulant. Chronic use and acute METH intoxication can cause substantial medical consequences, including spleen, kidney, liver and heart. The objective of the present study was to evaluate the antioxidant activity of CA to protect against oxidative stress and DNA damage to various organs in METH toxicity. Thirty-two male Sprague Dawley (SD) rats were divided into four equal groups: group 1 was injected (i.p) with saline (1 mL/kg) while groups 2,3 and 4 were injected (i.p) with METH (10 mg/kg) twice a day over five days period. Where 100 & 200 mg/kg of CA were injected (i.p) into groups 3 and 4, respectively one day before exposure to METH injections. Tissue antioxidants and DNA content were evaluated in different tissues. METH decreased glutathione (GSH) and glutathione peroxidase (GPx) levels while increased malondialdehyde (MDA), catalase (CAT) and protein carbonyl levels in brain (hypothalamus), liver, and kidney tissues of rats. METH increased hyperdiploidy in these tissues and DNA damage results. Prior treatment of CA to animals exposed to METH restores the above parameters to the normal levels and preserves the DNA content of these tissues. These results were supported by histopathological investigations. In conclusion, METH induced oxidative stress and DNA damage and pretreatment of CA before METH injections prevented tissue oxidative stress and DNA damage in METH-treated animals.     

Pomegranate peel attenuates aluminum-induced hepatorenal toxicity

Abstract

The present study was undertaken to determine the potential role of methanolic extract of pomegranate peel (MEPP) in modulating aluminum chloride (AlCl₃) induced hepatorenal toxicity in female rats. The effect of MEPP (200?mg/kg?bwt) on AlCl₃ (34?mg/kg?bwt) induced hepatorenal toxicity, accumulation of aluminum (Al), hepatorenal functions and oxidant/antioxidant status of liver and kidney were determined. The changes of liver and kidney structures were investigated with hematoxyline and eosin, in addition, the anti-apoptotic effect of MEPP was analyzed by immunohistochemistry. The present study showed an indication of carcinogenicity in the AlCl₃ treated group represented by an increase in tumor necrosis factor-α and angiogenin and inflammation by inducing an increase in prostaglandin E2 and F2α. MEPP protected liver and kidney through reduce the Al accumulation, stimulated antioxidant activities and elevated the anti-apoptotic protein namely Bcl-2. Therefore, these results indicated that the methanolic extract of pomegranate peel has beneficial influences and could be able to inhibit Al-induced oxidative stress and histopathological alternations in liver and kidney of female rats, and these effects may be related to anti-apoptotic and antioxidant activities.     

Prolonged Peripheral Immunosuppressive Responses as Consequences of Random Amphetamine Treatment,Amphetamine Withdrawal and Subsequent Amphetamine Challenges in Rats

Drug-induced immunosuppression may underline increased hypothalamic–pituitary–adrenal axis response to stress observed following chronic psychostimulant treatment. However, the consequences of random amphetamine (AMPH) treatment, withdrawal and AMPH challenge after withdrawal on the peripheral immunity and systemic corticosterone response are unknown. In this study, the total blood and spleen leukocyte, lymphocyte, T, B, NK, TCD4⁺/TCD8⁺ cell numbers and ratio, pro-inflammatory interferon gamma (IFN-γ), and anti-inflammatory interleukin-4 (IL-4) production, and plasma corticosterone concentration in Wistar rats were investigated after: chronic, random AMPH/SAL treatment alone (20 injections in 60 days, 1 mg/kg b.w., i.p.), AMPH/SAL withdrawal (for 20 consecutive days after random AMPH/SAL exposure) or AMPH/SAL challenge after withdrawal (single injection after the AMPH/SAL withdrawal phase). The results showed blood and spleen leukopenia, lymphopenia, lower blood production of IFN-ɤ, and increased plasma corticosterone concentration after the AMPH treatment, which were more pronounced in the AMPH after withdrawal group. In contrast, an increased number of blood NK cells and production of IL-4 after chronic, random AMPH treatment alone, were found. Blood AMPH-induced leukopenia and lymphopenia were due to decreased total number of T, B lymphocytes and, at least in part, of granulocytes and monocytes. Moreover, decreases in the number of blood TCD4⁺ and TCD8⁺ lymphocytes both in the AMPH chronic alone and withdrawal phases, were found.

The major findings of this study are that AMPH treatment after the long-term withdrawal from previous random AMPH exposure, accelerates the drug-induced immunosuppressive and systemic corticosterone responses, suggesting prolonged immunosuppressive effects and an increase in incidence of infectious diseases.

Graphical Abstract

Prolonged peripheral immunosuppressive responses as consequences of random amphetamine…The results indicate that the chronic and random AMPH exposure alone and the acute (single injection) challenge of the drug after the withdrawal phase induced long-term immunosuppressive effects, which were similar to those occurring during the stress response, and sensitized the peripheral immunosuppressive and corticosterone responses of the rat to the disinhibitory effects of this stressor.

     

Cadmium and nickel co‐exposure exacerbates genotoxicity and not oxido‐inflammatory stress in liver and kidney of rats: Protective role of omega‐3 fatty acid

The present study examined the influence of co‐exposure to cadmium (Cd) and nickel (Ni) on hepatorenal function as well as the protective role of omega‐3 polyunsaturated fatty acids (ω‐3FA) in rats. The animals were exposed to Cd (5 mg/kg) and Ni (150 μg/L in drinking water) singly or co‐exposed to both metals and ω‐3FA at 20 mg/kg for 14 consecutive days. Results showed that hepatorenal injury resulting from individual exposure to Cd or Ni was not aggravated in the co‐exposure group. Moreover, ω‐3FA markedly abrogated the reduction in the antioxidant enzyme activities, the increase in reactive oxygen and nitrogen species, and lipid peroxidation induced by Cd and Ni co‐exposure. Additionally, ω‐3FA administration markedly suppressed the increase in hepatic and renal myeloperoxidase activity, nitric oxide, tumor necrosis factor alpha, and interleukin‐1 β levels in the co‐exposure group. Genotoxicity resulting from individual exposure to Cd or Ni was intensified in the co‐exposure group. However, ω‐3FA administration markedly ameliorated the genotoxicity and histological lesions in the co‐exposure group. Taken together, co‐exposure to Cd and Ni aggravated genotoxicity and not oxido‐inflammatory stress in the liver and kidney of rats. ω‐3FA abated hepatorenal injury and genotoxicity induced by Cd and Ni co‐exposure in rats.     

Effects of Methyl Mercury and Triethyllead on Na+K+ATPase and Pyruvate Dehydrogenase Activities in Glioma C6 Cells

Abstract: The effect of methyl mercury (MeHg) and triethyllead (Et₃Pb) on the membrane bound SH-enzymes Na⁺K⁺ATPase and pyruvate dehydrogenase (PDH) was studied in relation to the effect on the galactosyl ceramide sulfotransferase (CST) and to morphological changes in glioma C₆ cells. Two-day-old cultures were incubated for 1 or 20 hrs with 5–30 μg MeHgCl and 2–8 μg Et₃PbCl/mg cell protein. The results show that both compounds induced morphological changes and a reduction of CST activity at growth inhibitory concentrations. A less marked reduction of Na⁺K⁺ATPase was induced with increasing exposure time only in MeHgCl treated cultures, and PDH activity was not affected by either of the compounds under the experimental conditions. Thus, an interference with Na⁺K⁺ATPase and PDH activities do not appear to be a primary effect of MeHg and Et₃Pb intoxication.     

Low concentration of arsenic could induce caspase-3 mediated head kidney macrophage apoptosis with JNK-p38 activation in Clarias batrachus

We had earlier demonstrated that chronic exposure (30 days) to micro-molar concentration (0.50 μM) of arsenic induced head kidney macrophage (HKM) death in Clarias batrachus. The purpose of the present study is to characterize the nature of HKM death induced by arsenic and elucidate the signal transduction pathways involved in the process. Arsenic-induced HKM death was apoptotic in nature as evident from DNA gel, Annexin V-propidium iodide, Hoechst 33342 staining and TdT-mediated dUTP nick end labeling (TUNEL) assays. Inhibitor studies and immunoblot analyses further demonstrated that arsenic-induced HKM apoptosis involved activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase, a well-characterized caspase-3 substrate. Preincubation with antioxidants N-acetyl-cysteine or dimethyl sulfoxide significantly lowered reactive oxygen species (ROS) levels in arsenic-treated HKM and prevented caspase activation, malondialdehyde formation and HKM apoptosis. Arsenic induced membrane translocation of the NADPH oxidase subunit p47^phox. Preincubation with apocynin and diphenyleneiodonium chloride, both selective inhibitors of NADPH oxidases, prevented p47^phox translocation, ROS production and HKM death. Exposure of HKM to arsenic induced the activation of mitogen-activated protein kinase family (MAPK) proteins including c-Jun NH₂-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (p38). Preincubation of HKM with p38 inhibitor SB203580 and JNK inhibitor SP600125 protected the HKM against arsenic-induced apoptosis. We conclude that exposure to micro-molar concentration of arsenic induces ROS generation through the activation of NADPH oxidases, which in turn causes caspase-3 mediated HKM apoptosis. In addition, the study also indicates a role of p38-JNK pathway in arsenic-induced HKM apoptosis in C. batrachus.     

Serotonin1A receptor autoradiography during alcohol-withdrawal kindling

A series of autoradiography experiments were conducted in order to test the theory that the serotonin (5-HT) receptor subtype 5-HT_1a is involved in alcohol-withdrawal kindled convulsive behaviour. Alcohol-withdrawal kindling was performed by subjecting male Wistar rats to multiple episodes consisting of 2 days of alcohol intoxication and 5 days of alcohol withdrawal. In the first episode alcohol intoxication led to focal downregulation of [³H]-8-hydroxy-2-(di-n-propylamino)tetralin ([³H]-8-OH-DPAT) binding sites in septum and subregions of frontal cortex, hippocampus, and entorhinal cortex. This alcohol-induced response was blunted in both alcohol-withdrawal kindled animals and in animals exposed to repeated alcohol dependence in which the previous withdrawal reactions were blocked by diazepam administration. A paradoxical upregulation of [³H]-8-OH-DPAT binding sites was found in septum and subregions of frontal cortex, hippocampus, and entorhinal cortex in control animals which were fed isocalorically with the alcohol-withdrawal kindled animals and subsequently exposed to 2 days of alcohol intoxication. It was concluded that the alterations in the alcohol induced 5-HT_1a receptor regulation after multiple episodes of alcohol dependence were not caused by alcohol-withdrawal kindling processes per se, but were due to both alcohol specific and alcohol non-specific effects. Received: 24 April 1996/Final version: 15 January 1997     

Detoxification and antioxidant effects of curcumin in rats experimentally exposed to mercury

Curcumin, a safe nutritional component and a highly promising natural antioxidant with a wide spectrum of biological functions, has been examined in several metal toxicity studies, but its role in protection against mercury toxicity has not been investigated. Therefore, the detoxification and antioxidant effects of curcumin were examined to determine its prophylactic/therapeutic role in rats experimentally exposed to mercury (in the from of mercuric chloride‐HgCl₂, 12 µmol kg^?1 b.w. single intraperitoneal injection). Curcumin treatment (80 mg kg^?1 b.w. daily for 3 days, orally) was found to have a protective effect on mercury‐induced oxidative stress parameters, namely, lipid peroxidation and glutathione levels and superoxide dismutase, glutathione peroxidase and catalase activities in the liver, kidney and brain. Curcumin treatment was also effective for reversing mercury‐induced serum biochemical changes, which are the markers of liver and kidney injury. Mercury concentration in the tissues was also decreased by the pre/post‐treatment with curcumin. However, histopathological alterations in the liver and kidney were not reversed by curcumin treatment. Mercury exposure resulted in the induction of metallothionein (MT) mRNA expressions in the liver and kidney. Metallothionein mRNA expression levels were found to decrease after the pre‐treatment with curcumin, whereas post‐treatment with curcumin further increased MT mRNA expression levels. Our findings suggest that curcumin pretreatment has a protective effect and that curcumin can be used as a therapeutic agent in mercury intoxication. The study indicates that curcumin, an effective antioxidant, may have a protective effect through its routine dietary intake against mercury exposure.