Stress In Brain Of Mice Research Articles

Protective effect of fruits of Morinda citrifolia L. on scopolamine induced memory impairment in mice: A behavioral, biochemical and cerebral blood flow study

Ethnopharmacological relsevanceNoni (Morinda citrifolia L.) is widely used for different illnesses including CNS disorders. Recently Noni has been reported to prevent amyloid beta induced memory impairment in mice. However, the influence of Noni on cholinergic system has not been explored so far. Therefore, present study was designed to investigate effect of Noni fruit on memory, cerebral blood flow (CBF), oxidative stress and acetylcholinesterase (AChE) activity in scopolamine induced amnesia model. Materials and methodsMice were orally treated with ethanolic extract of Noni fruit and chloroform, ethyl acetate and butanol fractions of ethanolic extract for three days. Scopolamine was administered 5min prior to acquisition trial and memory function was evaluated by passive avoidance test. CBF was measured by laser doppler flowmetry. AChE activity and oxidative stress parameters were estimated in mice brain at the end of behavioral studies. Further, effect of ethanolic extract and its fractions (5–400μg/ml) on AChE activity was measured in vitro. ResultsScopolamine caused memory impairment along with reduced CBF, increased AChE activity and oxidative stress in mice brain. Ethanolic extract of Noni fruits and its chloroform and ethyl acetate fractions significantly improved memory and CBF. However, butanol fraction had no effect. Further, increased oxidative stress and AChE activity following scopolamine was significantly attenuated by ethanolic extract of Noni and its fractions. Moreover ethanolic extract and its fractions showed dose dependent inhibition of AChE activity in vitro. ConclusionThese observations suggest that Noni may be useful in memory impairment due to its effect on CBF, AChE and oxidative stress.

Rotenone and Paraquat Linked to Parkinson’s Disease: Human Exposure Study Supports Years of Animal Studies

A growing body of evidence suggests pesticides may play a role in Parkinson’s disease (PD) in humans. Self-reported PD has been associated with lifetime use of pesticides, and animal studies have suggested that the pesticides paraquat and rotenone can cause oxidative stress and mitochondrial dysfunction, respectively—posited mechanisms of action in PD—as well as symptoms in rodents similar to human PD. Now, researchers have linked human exposure to paraquat and rotenone with PD [EHP 119(6):866–872; Tanner et al.]. Their study is the first analysis of pesticides classified by presumed mechanism of action rather than by intended use or chemical class. The researchers assessed lifetime use of pesticides as reported by participants in the Agricultural Health Study, a prospective study of private pesticide applicators (mostly farmers) and their spouses in Iowa and North Carolina. In the nested case–control study, neurologists specializing in movement disorders identified 110 people with PD and 358 controls without who were frequency matched by age, sex, and state. The researchers collected detailed information about use of 31 different pesticides as well as covariate information including lifelong smoking and family history of PD. Each pesticide was classified according to its mechanism of action as either an oxidative stressor or a mitochondrial complex I inhibitor. For participants with PD, the researchers considered pesticide use that occurred before their PD diagnosis. For controls, they considered pesticide use that occurred before the median age of PD diagnosis for cases in the corresponding age-, sex-, and state-specific groups. Among the mitochondrial complex I inhibitors studied, the researchers found the strongest association between PD and use of rotenone. Among oxidative stressors, they found the strongest association between PD and use of paraquat. Participants with PD were 2.5 times more likely than controls to have reported use of rotenone or paraquat. The results may have far-reaching implications, considering the widespread use of these pesticides. Paraquat remains one of the most widely used herbicides worldwide, and rotenone was used ubiquitously before most uses were voluntarily stopped in the United States in 2007. Other agents associated with mitochondrial complex I inhibition, such as permethrin, remain in common use. The authors point out several limitations of the study, including the fact that participants reported exposure to many pesticides, and effects of other agents can’t be excluded. However, the associations between PD and paraquat and rotenone remained after adjustment for overall pesticide use. It also was impossible to measure pesticide exposure, only estimate it retrospectively. Future investigations of combinations of pesticides and of other mechanistic groups will be important, as will mechanistic studies that model exposure conditions similar to those occurring in humans.

TRANSLATIONAL IMPACT

Ataxia telangiectasia (A-T) is a rare, recessive, neurodegenerative disease, with symptoms that normally appear in early childhood. Initial indications are usually ataxia (a lack of muscle control leading to loss of balance and coordination) and telangiectasia (tiny red veins, which are most noticeable on the whites of the eyes). The most serious clinical problem is loss of Purkinje cells, leading to degeneration of the cerebellum (the body’s motor control centre). About 70% of sufferers also have thymic hypoplasia and a compromised immune system. Patients are also highly sensitive to X-irradiation and are susceptible to malignant tumors. Currently, there is no cure, nor any treatment that halts the progression of the disease.A-T is caused by mutation of the ATM gene, which encodes a ubiquitous 370-kD serine-threonine kinase that is essential for normal repair of double-stranded DNA breaks; loss of ATM function results in DNA instability. However, there are atypical cases of A-T in which ATM is completely lacking: in these cases, DNA repair is defective, but symptoms are mild. These cases suggest that the severity of the neurological component of A-T might be due to a combination of defects, some of which are unknown.ATM phosphorylates several hundred substrates, including the transcription factor ZFHX3 (also known as ATBF1). In this study, the authors show that ZFHX3 is indirectly induced by ATM, and that ZFHX3 in turn induces the membrane tyrosine kinase PDGFRB, which is a survival factor in neurons. Neurons are highly susceptible to oxidative stress owing to their high rate of oxidative metabolism and low levels of antioxidant enzymes, and, in A-T mutant mice, oxidative stress is one of the major causes of Purkinje cell death. Inhibition of PDGFRB activity results in loss of ATM activity under conditions of oxidative stress, but not genotoxic stress, suggesting a means whereby ATM can rapidly autoregulate its activity.To induce oxidative stress, mice were treated with kainic acid, resulting in predominantly cytoplasmic activation of ATM in the cerebral cortex, hippocampus and deep cerebellar nuclei (DCN). The authors propose that activation of ATM in the cytoplasm might play a role in autophagic protection of neurons against oxidative stress.The signaling pathway from ATM to PDGFRB described here might be important in determining the response of neurons to oxidative stress, and be one of the hitherto unknown factors contributing to A-T. Therefore, targeting the action of PDGFRB might yield therapies that protect neurons against oxidative stress. The use of kainic acid to induce neuronal stress in mouse brains will also mean that Atm-deficient mice can be used to observe the early onset of neurodegeneration in the cerebellum; currently, the mice cannot be used as a model, because they die of cancer within 3–4 months, before manifestation of neurodegenerative disease. Kainic acid treatment will therefore be a good experimental tool to speed up screening of effective therapeutics.

Evaluation of lipofuscin-like pigments as an index of lead-induced oxidative damage in the brain

This study was carried out to investigate the role of lead in the development of oxidative stress in the brain. We examined the rate of lipid peroxidation and we determined lipid fluorescence products (lipofuscin-like pigments – LFP) as a marker of lipid peroxidation after short in vitro incubation of rat brain homogenates with lead acetate (10 −2, 10 −4, 10 −6 M lead acetate, 2 h). Simultaneously we examined by the same method in vivo indices of oxidative stress in brains of mice exposed for 12 weeks to 0.2% lead acetate in drinking water. The results show that the concentration of LFP in rat brain homogenates increased significantly after 2 h incubation with 10 −2 M lead acetate as compared to controls ( P < 0.0001). This effect was not observed in lower doses of lead acetate (10 −4 and 10 −6 M). After the long-term exposure of mice to 0.2% lead acetate, pronounced accumulation of lead and significantly increased concentration of LFP ( P < 0.004) in the brains of exposed animals as compared to controls were observed. The evidence for the formation of specific fluorophores originating from oxidative damage was shown also in qualitative changes in 3D spectral arrays and synchronous spectra. The presented results proved the influence of lead on the activation of radical reactions in the brain after short in vitro exposure of rat brain as well as within long-term in vivo exposure in mice using lipofuscin-like pigments as an indicator of oxidative stress.

Microglial activation as a measure of stress in mouse brains exposed acutely (60 minutes) and long-term (2 years) to mobile telephone radiofrequency fields

To determine whether acute or long-term exposure of the brain to mobile telephone radiofrequency (RF) fields produces activation of microglia, which normally respond rapidly to any change in their microenvironment. Using a purpose designed exposure system at 900 MHz, mice were given a single, far-field whole body exposure at a specific absorption rate (SAR) of 4 W/kg for 60 min (acute) or on five successive days per week for 104 weeks (long-term). Control mice were sham-exposed or freely mobile in a cage to control for any stress caused by immobilisation in the exposure module. Positive control brains subjected to a stab wound were also included to confirm the ability of microglia to react to any neural stress. Brains were perfusion-fixed with 4% paraformaldehyde and representative regions of the cerebral cortex and hippocampus immunostained for ionised calcium binding adaptor molecule (Iba1), a specific microglial marker. There was no increase in microglial Iba1 expression in brains short or long-term exposed to mobile telephony microwaves compared to control (sham-exposed or freely moving caged mice) brains, while substantial microglial activation occurred in damaged positive control neural tissue. Acute (60 minutes) or longer duration (2 years) exposure of murine brains to mobile telephone RF fields did not produce any microglial activation detectable by Iba1 immunostaining.

Effects of peony glycosides on mice exposed to chronic unpredictable stress: Further evidence for antidepressant-like activity

Ethnopharmacology relevance Peony, the processed root of Paeonia lactiflora Pall. (Ranunculaceae), is a component herb of many traditional formulae for the treatment of depression-like disorders. Aim of the study The present study aimed to investigate whether the total glycosides of peony (TGP) could prevent depression induced by chronic stress. Materials and methods Mice were subjected to an experimental setting of chronic unpredictable stress (CUS). The effect of TGP treatment on CUS-induced depression was examined by measuring behavioral and neurochemical parameters of depression and the antioxidant status of brain tissue. Results CUS-induced depression, as indicated by a significant increase in immobility time in the tail suspension test, was associated with increases in the activities of monoamine oxidases, depletion of reduced glutathione, and an increase in malondialdehyde level, in mice brains. TGP treatment alleviated the extent of CUS-induced depression and the associated impairment of antioxidant status in the mouse brain. Conclusion The results suggest that TGP alleviates depression induced by chronic unpredictable stress. The antidepressant-like activity of TGP is probably mediated by inhibition of monoamine oxidases and the attenuation of oxidative stress in mouse brain.

Momordica charantia reduces high‐fat‐diet‐associated oxidative stress in mouse brain

Obesity‐associated increase in oxidative stress (OS) has been implicated in reduced cognition and brain function in rodents and humans. Ayurvedic medicine, Momordica charantia (bitter melon, BM) is traditionally used in the management of diabetes and its complications including neuropathies. We recently demonstrated that BM reduces weight gain, improves glucose and insulin tolerance and lowers plasma lipids in high‐fat‐diet (HFD) fed mice. The aim of this study was to investigate the effects of BM on brain antioxidant enzymes in HFD fed mice. Female C57BL/6 mice were randomized into three groups: 1) control, 2) HFD (58% kcal fat), and 3) HFD + 1.5% lyophilized BMJ (W/V). After 16 weeks, brains were excised and analyzed for catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), mitochondrial manganese superoxide dismutase (Mn‐SOD) and cytosolic copper/zinc‐superoxide dismutase (Cu/Zn‐SOD) activities using commercial kits. HFD‐fed mice demonstrated an initial stress response with increased brain cytosolic Cu/Zn‐SOD activity with a concomitant reduction in GSH, CAT and GPx activities. Feeding of BMJ normalized Cu/Zn‐SOD, CAT and GPx activities in brains of HFD‐fed mice. These data indicate a role for dietary therapies in reducing HFD‐associated OS in brain. [Grants: NCCAM (R21AT003719), and RCMI, NCRR (G12RR/AI03061), NIH].

Protective effect of arjunolic acid against arsenic‐induced oxidative stress in mouse brain

Arsenic, a notoriously poisonous metalloid, is ubiquitous in the environment, and it affects nearly all organ systems of animals including humans. The present study was designed to investigate the preventive role of a triterpenoid saponin, arjunolic acid against arsenic-induced oxidative damage in murine brain. Sodium arsenite was selected as a source of arsenic for this study. The free-radical-scavenging activity and the in vivo antioxidant power of arjunolic acid were determined from its 2,2-diphenyl-1-picryl hydrazyl radical scavenging ability and ferric reducing/antioxidant power assay, respectively. Oral administration of sodium arsenite at a dose of 10 mg/kg body weight for 2 days significantly decreased the activities of antioxidant enzymes, superoxide dismutase, catalase, glutathione-S-transferase, glutathione reductase and glutathione peroxidase, the level of cellular metabolites, reduced glutathione, total thiols and increased the level of oxidized glutathione. In addition, it enhanced the levels of lipid peroxidation end products and protein carbonyl content. Treatment with arjunolic acid at a dose of 20 mg/kg body weight for 4 days prior to arsenic administration almost normalized above indices. Histological findings due to arsenic intoxication and arjunolic acid treatment supported the other biochemical changes in murine brains. Results of 2,2-diphenyl-1-picryl hydrazyl radical scavenging and ferric reducing/antioxidant power assays clearly showed the in vitro radical scavenging as well as the in vivo antioxidant power of arjunolic acid, respectively. The effect of a well-established antioxidant, vitamin C, has been included in the study as a positive control. Combining all, results suggest that arjunolic acid possessed the ability to ameliorate arsenic-induced oxidative insult in murine brain and is probably due to its antioxidant activity.

Protective action of honokiol, administered orally, against oxidative stress in brain of mice challenged with NMDA

Neuroprotective effect of honokiol (HK), orally administered, on oxidative damage in the brain of mice challenged with N-methyl-d-aspartic acid (NMDA) was examined. HK (1-100 mg/kg) was administered to Institute of Cancer Research (ICR) male mice through a gavage for 3 days consecutively, and on the third day, NMDA (150 mg/kg) was intraperitoneally (i.p.) administered. Administration of NMDA, causing a lethality of approximately 60%, resulted in a significant decrease of total glutathione (GSH) level and increase of thiobarbituric acid-reactive substances (TBARS) value in brain tissue. Meanwhile, oral administration of HK (> or = 3 mg/kg) for 3 days reduced the lethality (60%) in NMDA-treated group to 10% level, and alleviated the behavioral signs of NMDA neurotoxicity. Moreover, HK pretreatment restored the levels of total GSH and TBARS in the brain tissue to control levels (p<0.01). Additionally, GSH peroxidase activity in cytosolic portion of brain homogenate was also restored significantly (p<0.01), whereas GSH reductase activity was not. Separately, compared to vehicle-treated control, no significant changes in body and brain weight were observed in mice administered with HK. Based on these results, oral intake of HK is suggested to prevent oxidative stress in the brain of mice.

Genetic vitamin E deficiency does not affect MPTP susceptibility in the mouse brain

Oxidative stress is involved in the degeneration of the nigrostriatal dopaminergic system in Parkinson's disease (PD). Vitamin E (alpha-tocopherol) is a potent antioxidant in the cell membrane that can trap free radicals and prohibit lipid peroxidation. The retention and secretion of vitamin E are regulated by alpha-tocopherol transfer protein (TTP) in the brain and liver. Dysfunction of TTP results in systemic deficiency of vitamin E in humans and mice, and increased oxidative stress in mouse brain. In this study, we investigated the effect of vitamin E deficiency in PD development by generating an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD using TTP knockout (TTP-/-) mice. Vitamin E concentration in the brains of TTP+/- mice was half that in TTP+/+ mice, and in TTP-/- mice, was undetectable. MPTP treatment tended to decrease striatal dopamine, but the effect was comparable and not significant in any of the three genotypes. Furthermore, the extent of loss of dopaminergic cell bodies in the substantia nigra did not differ among the groups. One the other hand, oral administration of vitamin E resulted in the partial protection of striatal dopaminergic terminals against MPTP toxicity. Our results suggest that vitamin E does not play a major protective role in MPTP-induced nigrostriatal dopaminergic neurodegeneration in the brain.

Oxidative Stress in Mouse Brain Exposed to Lead

This study was carried out to investigate effects of developmental Pb-exposure on antioxidant enzyme activities of mice brain. BALB dams were exposed to 600 p.p.m. of Pb-acetate in drinking water during pregnancy and lactation. Pb-exposure presented significant increase of plasma and brain Pb and 5-aminolevulinic acid (ALA) concentrations of weaned pups. In Pb-exposed 21-day-old pups, activities of superoxide dismutase, glutathione peroxidase (GSH-Px) and glutathione reductase (GSH-Re) decreased significantly in hypothalamus, corpora quadrigemina and corpus striatum compared with Na-exposed pups. Regarding 70-day-old pups, Pb-exposure had different effects on antioxidant enzymes of the three brain regions. The activities of GSH-Px and GSH-Re in corpora quadrigemina and GSH-Re in hypothalamus of Pb-exposure group did not decrease significantly. That meant that the lead employed might make occurrence of long-term effect on the antioxidant enzymes possible. The result also implied a correlation between ALA and oxidative stress in mice brain. Based on these results, it seemed that oxidative stress because of decreased antioxidant function, induced by significant accumulation of ALA, might be the main mechanism involved in mice brain neurotoxicity induced by developmental Pb-exposure.

Neuroprotection by extract of Petasites japonicus leaves, a traditional vegetable, against oxidative stress in brain of mice challenged with kainic acid

Reactive oxygen radicals have been implicated in the pathophysiology of many neurologic disorders and brain dysfunctions. Kainic acid has been used as a model agent for the study of neurotoxicity of various excitatory amino acids, since it induces neuronal damage through excessive production of reactive oxygen species. Petasites japonicus MAX (butterbur), cultivated as culinary vegetables in Eastern Asia, contains various kinds of phenolic compounds as well as sesquiterpenes, such as petasin. In European countries, the extracts from roots of Petasites species have been used in the therapy of headache or asthma. The objective of our study is to examine the neuroprotective action of the Petasites japonicus MAX (butterbur) extract against oxidative damage in the brain of mice treated with kainic acid. Male ICR mice, 6-8 weeks of age, were administered orally the butanol fraction from methanol extract of Petasites japonicus (BMP) or its subfraction (BMP-I or BMP-II) for 5 consecutive days. Thirty min after the final administration, the animals were challenged s. c. with kainic acid (45 mg/kg), and neurobehavioral activities were monitored. In addition, biomarkers of oxidative stress and neuronal loss in the hippocampus for the biochemical, neurobehavioral,morphological evaluations were analyzed 2 days after the kainic acid challenge. During 5-day treatment with BMP or BMP-1, the body weight gain was not significantly different from that of vehicle- treated control animals. Administration of kainic acid alone induced severe epileptiform seizures, causing a lethality of approximately 50%, and injuries of pyramidal cells in the hippocampus of mice which survived the challenge. Kainic acid exposure also resulted in a remarkable decrease in total glutathione level and glutathione peroxidase activity, and an increase in the thiobarbituric acid-reactive substance (TBARS) value in brain tissues. In comparison, coadministration with BMP (400 mg/kg) reduced the 54% lethality of mice, administered with kainic acid alone, to 25 % (P <0.05). Moreover, BMP at the same dose restored the levels of reduced glutathione and TBARS to control values (P <0.05). In further studies, BMP-I (200 mg/kg) ameliorated significantly (P <0.05) the kainic acid-induced behavioral signs, such as seizure activity, and all mice administered with BMP-I (200 mg/kg) survived the kainic acid toxicity. Consistent with the above, the administration with BMP-1 remarkably attenuated the neurobehavioral signs and neuronal loss in hippocampal CA1 and CA3 regions. On the basis of these results, the butanol fraction, especially BMP-I, of Petasites japonicus MAX extract is possibly suggested to be a functional agent to prevent oxidative damage in the brain of mice.

Protective effects of thiazolo[3,2-b]-1,2,4-triazoles on ethanol-induced oxidative stress in mouse brain and liver

A series of 3-[1-(4-(2-methylpropyl) phenyl) ethyl]-1 ,2,4-triazole-5-thione (I) and its bicyclic condensed derivatives 6-benzylidenethiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones (IIa-IIf) were investigated for the prevention of ethanol-induced oxidative stress in liver and brain of mice. Administration of ethanol (0.1 mL/mice, p.o.) resulted in a drop of total thiol groups (T-SH) and non-protein thiol groups (NP-SH), and an increase in thiobarbituric acid reactive substances (TBARS) in both liver and brain tissue of mice (p < 0.001). Among the compounds investigated (at a dose of 200 mg/kg, p.o.), I and IId ameliorated the peroxidative injury in these tissues effectively. Compounds IIa, IIc and IIe improved the peroxidative tissue injury only in brain. These findings suggest that certain condensed thiazolo-triazole compounds may contribute to the control of ethanol-induced oxidative stress in an organ selective manner.

Comparison of chemopreventive effects of Vitamin E plus selenium versus melatonin in 7,12-dimethylbenz( a)anthracene-induced mouse brain damage

In this work, the protective effect of Vitamin E plus selenium (Vit E + Se) and melatonin against 7,12-dimethylbenz( a)anthracene (7,12-DMBA)-induced changes in superoxide dismutase (SOD), glutathione peroxidase (GSHPx), catalase (CAT) and carbonic anhydrase (CA) activities and malonedialdehyde (MDA) levels of mouse brain were compared. 12-month old mice were divided into four groups each including 10 animals. The first group served as control group. The second group was treated with 7,12-DMBA (20 mg/(kg day)). The third group was treated with 7,12-DMBA and Vitamin E (90 μg/(individual day)) and selenium (1.8 μg/(individual day)) simultaneously. The fourth group was treated with 7,12-DMBA and melatonin (4.2 mg/(kg day)) simultaneously. Treatment continued for 21 days after which the mice were sacrificed and brain homogenates were prepared. 7,12-DMBA treated group exhibited significantly decreased levels of brain SOD, GSHPx, CAT and CA activities and increased MDA levels as compared to control. Vitamin E + Se fully or partially restored enzyme inhibition except for SOD. Lipid peroxidation was also reduced in Vitamin E + Se treated group. Melatonin provided a better protection for SOD, GSHPx and CAT, and a plausible protection for CA activity. Protection against lipid peroxidation measured as MDA in melatonin treated group was appreciable although slightly lesser than the protection provided by Vitamin E + Se. The results imply that Vitamin E + Se and melatonin both provide chemoprevention against 7,12-DMBA-induced oxidative stress in mouse brain.

Met-enkephalin modulates resistance to oxidative stress in mouse brain.

The purpose of this study was to investigate the effect of opioide peptide Met-enkephalin (MENK) on resistance to oxidative stress in the brain of 4, 10 and 18 months old CBA mice of both sexes. This was done by determination of oxidant status via lipid peroxidation (LPO) and antioxidant status by determination of total superoxide dismutase (tSOD), catalase (CAT) and glutathione peroxidase (Gpx). Results showed that brain of adult male mice is less resistant to oxidative stress than brain of adult females. The difference is mainly due to higher CAT activity and lower LPO activity in female brain. MENK decreased resistance to stress in the brain of both sexes but the effect appeared earlier in males (10 months of age) than in females (18 months of age). Also, MENK could pronounce its effect on resistance to oxidative stress in a gender-related manner: in female mice via regulation of antioxidant enzyme activities and in male mice via regulation of oxidant processes respectively.

Impairment of cell and plasma redox state in subjects professionally exposed to chromium.

Chromium (Cr) is widely used in chemical, tannery, building, and metal industries. More recently, it has been demonstrated that Cr induces oxidative stress in mouse brain. Nevertheless very few data exist on in vivo oxidative damage in humans exposed to Cr. Changes in antioxidant parameters both in plasma (acid ascorbic redox state and total antioxidant capacity) and in red blood cells (glutathione (GSH) redox state) of 40 subjects (age 37.65 +/- 7.46; M/F 20/20) professionally exposed to Cr who were recruited from metal, chemistry, and building industries were evaluated. We also evaluated the levels of lipoperoxidation (thiobarbituric acid-reactive material, TBA-RM) and thiol levels in plasma to assess the extent of oxidative stress state. To evaluate Cr exposure rate, we measured urinary-chromium (U-Cr) by an electrothermic atomization-atomic absorption spectrometry (ETA-AAS) method. In this study, we found that Cr exposure induced a decrease both in GSH (P < 0.0005) and GSH/oxidized glutathione (GSSG) ratio (P < 0.0001) in red blood cells from workers with respect to control subjects. Furthermore, we also demonstrated a significant decrease of plasma acid ascorbic levels (45.7 +/- 14.9 vs. 53.5 +/- 16.5 micromol/L; P < 0.05) and in total plasma antioxidant capacity (1,126.3 +/- 212.2 vs. 1,266.9 +/- 207.8 micromol/L; P < 0.05) in subjects exposed to Cr. No difference was found with regard to TBA-RM and thiol levels. This study demonstrated that in humans, an oxidative stress occurs for Cr exposures as low as those considered safe. This oxidative stress appears to be able to affect intracellular and plasmatic antioxidant defense.

Neuroprotective Effect of Maltol Against Oxidative Stress in Brain of Mice Challenged with Kainic Acid

The neuroprotective effect of maltol on oxidative damage in the brain of mice challenged with kainic acid was examined. Male ICR mice, 6-8 weeks of age, were administered orally with maltol (50 or 100 mg/kg) for 5 consecutive days. Thirty minutes after the final administration, the animals were challenged s.c. with kainic acid (50 mg/kg), and neurobehavioral activities were monitored. In addition, biomarkers of oxidative stress and neuronal loss in hippocampus for the biochemical and morphological evaluations were analyzed 2 days after the kainic acid challenge. During 5-day treatment with maltol, the body weight gain was not significantly different from that of vehicle-treated control animals. Administration of kainic acid alone induced severe epileptiform seizures, causing a lethality of approximately 50%, and injuries of pyramidals cells in hippocampus of mice survived the challenge. Kainic acid exposure also resulted in marked decreases in total glutathione level and glutathione peroxidase activity, and an increase in thiobarbituric acid-reactive substances (TBARS) value in brain tissues. In comparison, coadministration with maltol (100 mg/kg) remarkably attenuated the neurobehavioral signs and neuronal loss in hippocampus, leading to a decrease in mortality of animals to 12.5% (p<0.05), although maltol at a dose of 50 mg/kg failed to show any remarkable protection. In addition, the changes in glutathione and TBARS values and glutathione peroxidase activity induced by kainic acid were restored to control levels by pretreatment with maltol (100 mg/kg). On the basis of these results, maltol is suggested to be a functional agent to prevent the oxidative damage in the brain of mice.

Protective effect of vegetable extracts on oxidative stress in brain of mice administered with NMDA

To find natural products showing a protective action against oxidative stress in the brain, extracts of various vegetables were administered i.p. with NMDA via gavage to ICR female mice. Changes in total glutathione, lipid peroxidation and protein oxidation in the brain tissue were examined. When compared to the vehicle-treated control, no significant ( P<0.05) changes in body and brain weight were observed in mice groups administered with either NMDA or vegetable extracts. Administration of NMDA at 80 mg/kg decreased the level of total glutathione. When 20 vegetable extracts were examined for their neuroprotective action, three vegetables, rough aster, sedum and red cabbage, showed the most marked action in restoring glutathione level. In addition, rough aster and red cabbage exhibited a significant ( P<0.05) prevention against the NMDA-induced increase of thiobarbituric acid-reactive substances (TBARS) value in the cytosolic portion of brain homogenate, while their effect on protein oxidation and glutathione-related enzymes was not marked. Based on these results, some vegetable extracts were suggested as functional agents to prevent against oxidative stress in the brain of mice.

Effects of oxidative stress on the expression of limbic-specific protease neuropsin and avoidance learning in mice

We evaluated the effects of oxidative stress in mouse brain induced by the intraperitoneal injection of diethyldithiocarbamate (DDC) on gene expression of the novel serine protease, neuropsin, and on shock-avoidance learning. The level of neuropsin mRNA in the hippocampal pyramidal neurons increased at 2 h after DDC treatment and decreased thereafter. At 7 days neuropsin mRNA significantly decreased to 60% of the pretreated control level and then returned to the control level at 30 days. Genes for tissue plasminogen activator, manganese superoxide dismutase, and heat shock protein did not differ in DDC-treated mice vs. the control group at 7 and 30 days. The shuttle-box avoidance learning was retarded at 7 days after DDC administration. However, it recovered to the control level at 30 days after DDC administration. The results suggest that generation of reactive oxygen species has an important role in neuropsin transcript in the limbic areas which might be related to the disturbance in avoidance learning.

C-fos mRNA expression following electrical-induced seizure and acute nociceptive stress in mouse brain

A single electroconvulsive shock (ECS) induced a rapid and transient expression of c-fos mRNA in mouse brain. In earclipped sham controls, low but significant expression of c-fos mRNA was also observed. These data suggest that c-fos mRNA may be transiently induced by seizure activity as well as much more subtle and qualitative different stimuli, such as the acute nociceptive stress associated with earclipping.