Attenuation of the effect of progesterone and 4'-chlordiazepam on stress-induced immune responses by bicuculline

The present study investigates the effect of progesterone, a pregnane precursor of neurosteroids, and 4'-chlordiazepam (4'-CD), a specific ligand for mitochondrial diazepam binding inhibitor receptor (MDR) involved in neurosteroidogenesis, on restraint stress (RS)-induced modulation of humoral and cell-mediated immune responses. RS produced a significant reduction in anti-sheep red blood cells (SRBC) antibody titre, a measure of humoral immune response, and % leucocyte migration inhibition (LMI) and foot-pad thickness test, measures of cell-mediated immune responses. These effects of RS on immune responses were effectively blocked by pretreating the animals with progesterone (10 mg/kg, sc) or 4'-CD (0.5 mg/kg, sc) administered just before subjecting the animal to RS. The effect of both progesterone and 4'-CD on RS-induced immune modulation was significantly attenuated by bicuculline (2 mg/kg, ip) but not by flumazenil (10 mg/kg, ip). Unlike its effect on RS-induced immune responsiveness, progesterone (5, 10 mg/kg, sc) when administered to non-stressed animals produced a significant suppression of both humoral and cell-mediated immune responses which was not reversed by bicuculline. However, 4'-CD failed to modulate immune response in naive non-stressed animals. These results suggest that progesterone and 4'-CD affect stress-induced immune responses by modulating GABA-ergic mechanism. However, GABA-A receptor system does not appear to be involved in progesterone-induced immunosuppression in nonstressed animals.     

Protective effects of α-tocopherol against oxidative stress related to nephrotoxicity by monosodium glutamate in rats

Context: Chronic oral intake of high doses of monosodium glutamate (MSG) could be harmful to tissues and organs. Oxidative stress enhances membrane damage by lipid peroxidation and alterations of antioxidant enzymes, which affects the functional activity of organs. Antioxidant vitamins have the capacity to regulate the oxidative stress related functional and pathological processes. Objective: In this study, the protective role of α-tocopherol against MSG-induced nephrotoxicity was analyzed. Materials and methods: MSG (4?g/kg) was given orally to female wistar rats for a period of 180 days. Renal function parameters (urea, uric acid, and creatinine), lipid peroxidation markers (malondialdehyde and conjugated dienes), antioxidant system (superoxide dismutase, catalase, glutathione peroxidase, glutathione transferase, and reduced glutathione), and histopathology were investigated. All tests were done in rats treated with MSG and at two different doses of α-tocopherol (100 and 200?mg/kg). Results: Oral exposure of MSG significantly increased renal function markers, lipid peroxidation byproducts, and altered antioxidant system. Moreover, the kidney showed congested glomeruli, tubular swelling, capillary congestion and microhemorrhages in stromal areas of the tubules. Co-administration of MSG and α-tocopherol (200?mg/kg) significantly reduced the oxidative damage compared with MSG-treated group and also restored the normal renal function. Discussion: The results indicated that oxidative stress was involved in MSG-induced functional and pathological changes in the kidney. α-tocopherol modulates the functional disorder and maintains the normal architecture of renal tissue by reducing oxidative stress. Conclusion: The α-tocopherol may be a potent protective agent in combating MSG-induced renal toxicity.     

Protective effects of α-tocopherol against oxidative stress related to nephrotoxicity by monosodium glutamate in rats

Context: Chronic oral intake of high doses of monosodium glutamate (MSG) could be harmful to tissues and organs. Oxidative stress enhances membrane damage by lipid peroxidation and alterations of antioxidant enzymes, which affects the functional activity of organs. Antioxidant vitamins have the capacity to regulate the oxidative stress related functional and pathological processes.

Objective: In this study, the protective role of α-tocopherol against MSG-induced nephrotoxicity was analyzed. Materials and methods: MSG (4?g/kg) was given orally to female wistar rats for a period of 180 days. Renal function parameters (urea, uric acid, and creatinine), lipid peroxidation markers (malondialdehyde and conjugated dienes), antioxidant system (superoxide dismutase, catalase, glutathione peroxidase, glutathione transferase, and reduced glutathione), and histopathology were investigated. All tests were done in rats treated with MSG and at two different doses of α-tocopherol (100 and 200?mg/kg).

Results: Oral exposure of MSG significantly increased renal function markers, lipid peroxidation byproducts, and altered antioxidant system. Moreover, the kidney showed congested glomeruli, tubular swelling, capillary congestion and microhemorrhages in stromal areas of the tubules. Co-administration of MSG and α-tocopherol (200?mg/kg) significantly reduced the oxidative damage compared with MSG-treated group and also restored the normal renal function.

Discussion: The results indicated that oxidative stress was involved in MSG-induced functional and pathological changes in the kidney. α-tocopherol modulates the functional disorder and maintains the normal architecture of renal tissue by reducing oxidative stress.

Conclusion: The α-tocopherol may be a potent protective agent in combating MSG-induced renal toxicity.     

Role of Oxidative Stress in the Selective Toxicity of Dieldrin in the Mouse Liver

Dieldrin, an organochlorine insecticide, induces hepatic tumors in mice but not in rats. Although the mechanism(s) responsible for this species specificity is not fully understood, accumulating evidence indicates that oxidative stress may be involved. This study examined the association of dieldrin-induced hepatic DNA synthesis with the modulation of biomarkers of oxidative damage to lipids (malondialdehyde [MDA]) and DNA (8-hydroxy-2-deoxyguanosine [oh8dG]), in male B6C3F1 mice and F344 rats fed dieldrin (0.1, 1.0, or 10 mg/kg diet) for 7, 14, 28, and 90 days. The nonenzymatic components of the antioxidant defense system (ascorbic acid, glutathione, and α-tocopherol) were also examined. Increased urinary MDA was observed in mice fed 0.1, 1.0, or 10 mg dieldrin/kg diet for 7, 14, 28, and 90 days; while increased hepatic MDA was seen only after 7 days in mice fed 0.1, 1.0, or 10 mg dieldrin/kg diet and after 14 days in mice fed 10 mg/kg diet. In rats, dieldrin had no effect on either hepatic MDA or urine MDA levels after 7, 14, and 28 days of treatment. A dose-dependent increase in urinary MDA was observed in rats at the 90-day sampling time. The only significant elevation in urinary or hepatic oh8dG content was limited to urinary oh8dG in mice fed 10 mg/kg dieldrin diet for 14 days. Dietary dieldrin produced sustained decreases in hepatic and serum α-tocopherol and sustained elevations in hepatic ascorbic acid in both mice and rats. Rats, however, possessed a three- to four-fold higher content of endogenous or basal (control) hepatic α-tocopherol; and, even when fed 10 mg dieldrin/kg diet, the levels of hepatic α-tocopherol were maintained at higher levels than those of mice fed control diet. In both rats and mice fed dieldrin, transient (14 and 28 days on diet) elevations in hepatic glutathione were observed. These data support the hypothesis that the species specificity of dieldrin-induced hepatotoxicity may be related to dieldrin's ability to induce oxidative stress in the liver of mice, but not in rats. Only in mice fed dieldrin was a temporal association of increases in hepatic MDA content and hepatic DNA synthesis seen, suggesting that oxidative damage (shown by increased lipid peroxidation) may be involved in early events in dieldrin-induced hepatocarcinogenesis. Rats may be protected from dieldrin-induced oxidative stress by a more effective antioxidant defense system, characterized by higher basal levels of hepatic α-tocopherol and ascorbic acid than that seen in the mouse.     

Preclinical study for the ameliorating effect of l-ascorbic acid for the oxidative stress of chronic administration of organic nitrates on myocardial tissue in high sucrose/fat rat model

BackgroundThe therapeutic activity of Glyceryl trinitrate (GTN) is mainly regulated by liberating nitric oxide (NO) and reactive nitrogen species (RNS). During this biotransformation, oxidative stress and lipid peroxidation inside the red blood cells (RBCs) occur. Hemoglobin tightly binds to NO forming methemoglobin altering the erythrocytic antioxidant defense system.AimThe principal objective of our research is to show the ameliorating effect of l-ascorbic acid for the deleterious effects of chronic administration of nitrovasodilator drugs used in cardiovascular diseases such as oxidative stresses and tolerance.MethodWe studied some biochemical parameters for the oxidative stress using groups of high sucrose/fat (HSF) diet Wistar male rats chronically orally administered different concentrations of Isosorbide-5-mononitrate (ISMN) 0.3 mg/kg, 0.6 mg/kg and 1.2 mg/kg. Afterwards, we evaluated the role of l-ascorbic acid against these biochemical changes in cardiac tissues.ResultsChronic treatment with organic nitrates caused elevated serum levels of lipid peroxidation, hemoglobin derivatives as methemoglobin and carboxyhemoglobin, rate of hemoglobin autoxidation, the cellular levels of the pro-inflammatory cytokines marker (NF-κB) and apoptosis markers (caspase-3) in the myocardium muscles in a dose-dependent manner. Meanwhile, such exposure caused a decline in the enzymatic effect of SOD, GSH and CAT accompanied by a decrease in the level of mitochondrial oxidative stress marker (nrf2) in the myocardium muscles and a decrease in the serum iron and total iron-binding capacity (TIBC) in a dose-dependent manner. Concomitant treatment with l-ascorbic acid significantly diminished these changes for all examined parameters.ConclusionChronic administration of organic nitrates leads to the alteration of the level of oxidative stress factors in the myocardium tissue due to the generation of reactive oxygen species. Using l-ascorbic acid can effectively ameliorate such intoxication to overcome nitrate tolerance.     

Effect of tocotrienols on iron-induced renal dysfunction and oxidative stress in rats

Ferric nitrilotriacetate (Fe-NTA) is a well-established nephrotoxic agent. This study was designed to investigate the modulatory effect of the subacute administration of tocotrienol-rich fraction (T3), a product from palm oil, and α-tocopherol (T) on Fe-NTA-induced renal injury and oxidative stress. Fe-NTA administration markedly increased blood urea nitrogen (BUN) and serum creatinine level, which was coupled with a marked lipid peroxidation, reduced activity of glutathione levels, and morphological alterations in rat kidney. Pretreatment with T3 (50?mg/kg/day) and T (50?mg/kg/day) for 7 days before Fe-NTA administration significantly reduced the serum creatinine and BUN levels, reduced lipid peroxidation in a significant manner, and restored levels of reduced glutathione and superoxide dismutase. T3 pretreatment also attenuated the serum tumor necrosis factor-alpha levels, as compared to pretreatment with T, and restored normal renal morphology. These findings suggest a strong correlation between iron-induced oxidative stress and renal dysfunction and point toward the protective effects of T3 in Fe-NTA-induced renal injury.     

Studies on comparative efficacy of α-linolenic acid and α-eleostearic acid on prevention of organic mercury-induced oxidative stress in kidney and liver of rat

The present study was undertaken to evaluate the effect of α-linolenic acid and α-eleostearic acid, two isomers of linolenic acid, against oxidative stress induced by organic mercury in kidney and liver cells of rat. Male albino rats were divided into six groups. Groups 1, 2 were normal control and methyl mercury chloride (MeHgCl) treated (5 mg/kg BW/day) control, respectively. Groups 3, 4, 5 and 6 were orally treated with different doses of two fatty acids (0.5% and 1.0% of total lipid given for each isomer) along with MeHgCl (5 mg/kg BW). Results showed that activity of antioxidant enzymes viz. catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), reduced glutathione (GSH) in liver and kidney decreased significantly due to oxidative stress generated by MeHg. Administration of the linolenic acid isomers almost restored all the altered parameters and also reduced lipid peroxidation and leakage of trans-aminase enzymes from liver to blood due to liver injury when administrated in higher doses. Histopathology of liver and kidney cells showed that administration of α-linolenic acid significantly reduced the damage generated by MeHg. Thus, α-linolenic acid and α-eleostearic acid could serve as cost-effective and natural phytochemical preparation to protect against the adverse effects caused by organic mercury in human.     

Propoxur-induced oxidative DNA damage in human peripheral blood mononuclear cells: protective effects of curcumin and α-tocopherol

The present study enumerates the attenuating effects of curcumin and α-tocopherol against propoxur induced oxidative DNA damage in human peripheral blood mononuclear cells (PBMC). Cultured cells were isolated from peripheral blood of healthy volunteers, and were exposed to varying concentrations of propoxur (0–21?μg/ml) for 6, 12, and 24?h, and in combination with curcumin (9.2?μg/ml) or α-tocopherol (4.3?μg/ml) or both. Cytotoxic effect of propoxur was examined by MTT assay. The role of oxidative stress beneath the cytotoxicity of propoxur was evaluated by the measurement of reduced glutathione (GSH), malondialdehyde (MDA) and 8-hydroxy-2′-deoxyguanosine (8-OH-dG) levels in cell lysate. A concentration-dependent cell death, depletion of GSH, an increase in the level of both MDA and 8-OH-dG were observed. Co-treatment with curcumin or α-tocopherol significantly attenuates depleted GSH, decrease in MDA and 8-OH-dG levels in propoxur exposed cells (p?相似文献   

OXIDATIVE EFFECTS OF NICKEL ON BONE MARROW AND BLOOD OF RATS

This study was undertaken to examine the oxidative effects of nickel (Ni) on rat blood and bone marrow. Treatment with either 100, 250, or 500 mumol/ kg Ni ip significantly enhanced lipid peroxidation in serum and bone marrow after 24 h. The concentrations of Ni and Fe in serum and bone marrow cells were also significantly increased after NiCl₂ administration. After treatment with NiCl₂, the activities of glutathione peroxidase (GPx) and levels of a -tocopherol in bone marrow cells were markedly reduced. There was an inverse association thiobarbituric acid elevated ( TBA)-chromogen product with decreased GPx activity and a -tocopherol levels in bone marrow cells of NiCl₂-treated rats. The concentrations of a -tocopherol in blood significant reduced with 100 and 250 mumol/ kg Ni but returned to control at the 500-mumol/kg dose. Data suggest that lipid peroxidation may be a contributing factor in Ni-induced tissue oxidative stress.     

Dietary α-tocopherol prevents dehydroepiandrosterone-induced lipid peroxidation in rat liver microsomes and mitochondria

Dehydroepiandrosterone (DHEA), an adrenal steroid, causes lipid peroxidation in rat liver microsomes and mitochondria and induces hepatocarcinogenesis. It was investigated whether α-tocopherol, a naturally occurring free radical chain terminator, could decrease lipid peroxidation. When DHEA-free diet supplemented with increasing concentrations of α-tocopherol (25, 50, 100, 200, 400 and 1000 mg/kg diet) was fed to rats for 7 days, a marked lipid peroxidation (measured as thiobarbituric acid reactive substances formation) was observed at concentrations 25 and 50 mg/kg in liver microsomes and mitochondria isolated from these animals. Lipid peroxidation was significantly reduced at concentrations ≥ 100 mg/kg. When DHEA (500 mg/kg diet) was fed to rats simultaneously with increasing concentrations of α-tocopherol, strong lipid peroxidation was observed at a-tocopherol concentrations ≤ 200 mg/kg diet. However, microsomes and mitochondria isolated from livers of rats fed a-tocopherol at doses of 400 and 1000 mg/kg diet produced only negligible amounts of thiobarbituric acid reactive substances. The data show that high concentrations of α-tocopherol in the diet decrease DHEA-induced microsomal and mitochondrial lipid peroxidation. Our results support the concept thatα-tocopherol can protect against DHEA-induced lipid peroxidation and consequently against steroid-induced liver cell damage and, perhaps, also tumour development.     

Montelukast abrogates rhabdomyolysis-induced acute renal failure via rectifying detrimental changes in antioxidant profile and systemic cytokines and apoptotic factors production

In addition to antiasthmatic effect, the cysteinyl leukotriene receptor 1 (CysLT?) antagonist montelukast shows renoprotective effect during ischemia/reperfusion and cyclosporine-induced renal damage. Here, we proposed that montelukast protects against rhabdomyolysis-induced acute renal failure. Compared with saline-treated rats, at 48 h following the induction of rhabdomyolysis using intramuscular glycerol (10 ml 50% glycerol/kg), significant elevations in serum levels of urea, creatinine, phosphate and acute renal tubular necrosis were observed. This was associated with elevations in serum Fas, interleukin-10, tumor necrotic factor-alpha, and transforming growth factor-beta1 and renal malondialdehyde and nitrite and detrimental reductions in renal catalase and superoxide dismutase activities. The effects of rhabdomyolysis on renal functional, biochemical and structural integrity and the associated changes in cytokines and Fas levels were abolished upon concurrent administration of montelukast (10 mg/kg i.p.) for 3 days (1 day before and 2 days after induction of rhabdomyolysis). Alternatively, administration of the anti-oxidant, α-tocopherol (400 mg/kg i.m.) for 3 days, succeeded in alleviating renal oxidative stress, but had no significant effect on the circulating levels of most cytokines and partially restored kidney functional and structural damage. Serum level of interleukin-6 was not altered by rhabdomyolysis but showed significant elevations in rats treated with montelukast or α-tocopherol. Collectively, motelukast abrogated functional and structural renal damage induced by rhabdomyolysis via ameliorating renal oxidative stress and modulation of systemic cytokines and apoptotic factors production. The results of this work are expected to open new avenues for early prevention of rhabdomyolysis-induced acute renal failure using selective CysLT? antagonists such as montelukast.     

Molecular effects of chemotherapeutic drugs and their modulation by antioxidants in the testis

Cisplatin-based chemotherapy regimens are preferred in the treatment of a variety of cancers. The present study investigated early cumulative molecular effects of therapeutic dose-levels of bleomycin, etoposide and cisplatin (BEP) in the testis and their modulation by an antioxidant cocktail (AO). Adult male Sprague-Dawley rats (N=7/group [G]) were treated with BEP as follows: G1 - control; G2 - AO (α-tocopherol [100 mg/kg], l-ascorbic acid [50 mg/kg], Zn [40 mg/l] and Se [100 μg/l]); G3 - B, 1.5 mg/kg on day 2; E, 15 mg/kg and P, 3 mg/kg for 4 days, and G4 - similar to G3 but also treated with AO for 4 days. In G3, the testis weight, sperm count and motility, and activities of enzymatic antioxidants decreased and lipid peroxidation increased compared to that in G1 (P<0.05). Seminiferous epithelial sloughing and degeneration were observed. In G3, mRNA levels of p53, Bcl-2 and Bax were unaltered but protein expression of p53 and Bax was up-regulated and that of Bcl-2 was down-regulated (P<0.05). These changes led to an increase in terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) positive germ cells indicating cell death (P<0.05). The AO recovered the BEP-induced molecular alterations to control levels. The mechanism of BEP-induced early testicular damage involves the initiation of oxidative stress, up-regulation of pro-apoptotic proteins and induction of cell death. Further, the induced testicular structural changes are negligible and less than those observed in single drug exposure studies reported in literature. The AO significantly ameliorates the BEP-induced pathogenesis of testicular damage suggesting its potential therapeutic uses.     

Protective effect of eugenol against restraint stress-induced gastrointestinal dysfunction: Potential use in irritable bowel syndrome

Abstract

Context: Eugenol, an essential constituent found in plants such as Eugenia caryophyllata Thunb. (Myrtaceae) is reported to possess neuroprotective and anti-stress activities. These activities can potentially be useful in the treatment of stress-induced irritable bowel syndrome (IBS).

Objective: The protective effect of eugenol was assessed against restraint stress (RS)-induced IBS-like gastrointestinal dysfunction in rats. Further, its centrally mediated effect was evaluated in this model.

Materials and methods: Eugenol (12.5, 25, and 50?mg/kg), ondansetron (4.0?mg/kg, p.o.), and vehicle were administered to rats for 7 consecutive days before exposure to 1?h RS. One control group was not exposed to RS-induction. The effect of eugenol (50?mg/kg) with and without RS exposure was evaluated for mechanism of action and per se effect, respectively. The hypothalamic–pituitary–adrenal cortex (HPA)-axis function was evaluated by estimating the plasma corticosterone level. The levels of brain monoamines, namely serotonin, norepinephrine, dopamine, and their metabolites were estimated in stress-responsive regions such as hippocampus, hypothalamus, pre-frontal cortex (PFC), and amygdala. Oxidative damage and antioxidant defenses were also assessed in brain regions.

Results: Eugenol (50?mg/kg) reduced 80% of RS-induced increase in fecal pellets similar to that of ondansetron. Eugenol attenuated 80% of stress-induced increase in plasma corticosterone and modulated the serotonergic system in the PFC and amygdala. Eugenol attenuated stress-induced changes in norepinephrine and potentiated the antioxidant defense system in all brain regions.

Conclusion: Eugenol protected against RS-induced development of IBS-like gastrointestinal dysfunction through modulation of HPA-axis and brain monoaminergic pathways apart from its antioxidant effect.     

Cold-pressed raspberry seeds oil ameliorates high-fat diet triggered non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is considered one of the most serious public health problems affecting liver. The reported beneficial impact of raspberries on obesity and associated metabolic disorder makes it a suitable candidate against NAFLD. In the current study, the chemical profile of raspberry seed oil (RO) was characterized by analysis of fatty acid and tocopherol contents using high-performance liquid chromatography (HPLC) in addition to the determination of total phenolic and flavonoids. High levels of unsaturated fatty acids, linoleic acid (49.9%), α-linolenic acid (25.98%), and oleic acid (17.6%), along with high total tocopherol content (184 mg/100 gm) were detected in oil. The total phenolic and flavonoid contents in RO were estimated to be 22.40 ± 0.25 mg gallic acid equivalent (GAE)/100 mg oil and 1.34 ± 0.15 mg quercetin (QU)/100 mg, respectively. Anti-NAFLD efficacy of RO at different doses (0.4 and 0.8 mL) in a model of a high-fat diet (HFD) fed rats was assessed by estimating lipid profile, liver enzyme activity, glucose and insulin levels as well as adipokines and inflammatory marker. Peroxisome proliferator-activated receptor γ (PPARγ), which is a molecular target for NAFLD was also tested. Liver histopathology was carried out and its homogenate was used to estimate oxidative stress markers. Consumption of RO significantly improved lipid parameters and hepatic enzyme activities, reduced insulin resistance and glucose levels, significantly ameliorated inflammatory and oxidative stress markers. Furthermore, RO treatment significantly modulated adipokines activities and elevated PPARγ levels. Raspberry seed oil administration significantly improved these HFD induced histopathological alterations. Moreover, a molecular docking study was performed on the identified fatty acids and tocopherols. Among the identified compounds, oleic acid, α-linolenic acid and γ-tocopherol exhibited the highest docking score as PPARγ activator posing them as a potential anti-NAFLD drug leads. Study findings suggest RO as an effective therapeutic candidate for ameliorating NAFLD.     

Tannic acid mitigates cisplatin-induced nephrotoxicity in mice

Cisplatin (CP) is a well-known chemotherapeutic drug that displays dose-limiting nephrotoxicity. In this study, tannic acid (TA), a naturally occurring plant polyphenol, was evaluated for its antioxidant and antigenotoxicity potential against the CP-induced renal oxidative stress and genotoxicity in Swiss albino mice. The mice were given a prophylactic treatment of TA orally at a dose of 40 and 80 mg/kg body weight (b wt) for 7 consecutive days before the administration of a single intraperitoneal (i.p.) injection of CP at 7 mg/kg b wt. The modulatory effects of TA on CP-induced nephrotoxicity and genotoxicity were investigated by assaying oxidative stress biomarkers, serum kidney toxicity markers, DNA fragmentation, alkaline unwinding, micronuclei assay, and by histopathological examination of kidney architecture. CP administration altered the antioxidant levels, enhanced lipid peroxidation, induced DNA strand breaks, and altered the levels of micronuclei among polychromatic erythrocytes (PCEs) significantly (p < 0.001). Pretreatment of TA in mice showed significant (p < 0.001) recovery in antioxidant status, viz., reduced glutathione content and its dependent enzymes, quinone reductase and γ-glutamyl transpeptidase. TA significantly (p < 0.001) reinstated the normal serum levels of blood urea nitrogen (BUN) and creatinine. TA showed strongly inhibited (p < 0.001) micronuclei induction, DNA strand breaks, and DNA fragmentation. Thus, TA as a phytochemical protects kidneys through its antigenotoxic activity and antioxidant potential.     

Vasopressor nerve responses in the pithed rat, previously identified as α2-adrenoceptor mediated, may be α1D-adrenoceptor mediated

Responses to pressor nerve stimulation in the pithed rat have been variously described as mediated, at least in part, by α(2)-adrenoceptors and by α(1A) and α(1D)-adrenoceptors. We have examined the subtypes of α-adrenoceptor involved in rises in diastolic blood pressure in the pithed rat preparation produced by vasopressor nerve stimulation with 10 pulses at 1 Hz or 20 pulses at 5 Hz. Vasopressor nerve responses to 1 Hz stimulation were markedly inhibited by the α(1A)-adrenoceptor antagonist RS 100329 (0.1mg/kg) and by the α(1D-)adrenoceptor antagonist BMY 7378 (0.1mg/kg). The α(2)-adrenoceptor antagonist yohimbine (0.1mg/kg) significantly increased pressor nerve responses to 1 Hz stimulation, but yohimbine (1mg/kg) significantly reduced pressor nerve responses. However, following BMY 7378 (0.1mg/kg), yohimbine (1mg/kg) did not produce any further inhibition of pressor nerve responses to 1 Hz stimulation. The α(2A)-adrenoceptor antagonist BRL 44408 (1mg/kg) did not reduce pressor responses to 1 Hz stimulation. BMY 7378 produced much less inhibition of pressor nerve responses to 5 Hz stimulation, whereas RS 100329 produced similar inhibition of 1 Hz and 5 Hz responses. Yohimbine (0.1 and 1mg/kg) did not significantly affect pressor nerve responses to 5 Hz stimulation. In conclusion, pressor nerve responses in the pithed rat involve both α(1A) and α(1D)-adrenoceptor, but there is no clear evidence for the involvement of α(2)-adrenoceptors.     

Chronic treatment with tocotrienol, an isoform of vitamin E, prevents intracerebroventricular streptozotocin-induced cognitive impairment and oxidative-nitrosative stress in rats

Intracerebroventricular (ICV) streptozotocin (STZ) has been shown to cause cognitive impairment, which is associated with increased oxidative stress in the brain of rats. In the present study, we investigated the effect of both the isoforms of vitamin E, α-tocopherol and tocotrienol against ICV STZ-induced cognitive impairment and oxidative-nitrosative stress in rats. Adult male Wistar rats were injected with ICV STZ (3 mg/kg) bilaterally. The learning and memory behavior was assessed using Morris water maze and elevated plus maze. The rats were sacrificed on day 21 and parameters of oxidative stress, nitrite levels and acetylcholinesterase activity were measured in brain homogenate. α-Tocopherol as well as tocotrienol treated groups showed significantly less cognitive impairment in both the behavioral paradigms but the effect was more potent with tocotrienol. Both isoforms of vitamin E effectively attenuated the reduction in glutathione and catalase and reduced the malonaldehyde, nitrite as well as cholinesterase activity in the brains of ICV STZ rats in a dose dependent manner. The study demonstrates the effectiveness of vitamin E isoforms, of which tocotrienol being more potent in preventing the cognitive deficits caused by ICV STZ in rats and suggests its potential in the treatment of neurodegenerative diseases such as Alzheimer's disease.     

Alpha-lipoic acid protects oxidative stress,changes in cholinergic system and tissue histopathology during co-exposure to arsenic-dichlorvos in rats

We investigated protective efficacy of α-lipoic acid (LA), an antioxidant against arsenic and DDVP co-exposed rats. Biochemical variables suggestive of oxidative stress, neurological dysfunction, and tissue histopathological alterations were determined. Male rats were exposed either to 50 ppm sodium arsenite in drinking water or in combination with DDVP (4 mg/kg, subcutaneously) for 10 weeks. α-Lipoic acid (50 mg/kg, pos) was also co-administered in above groups. Arsenic exposure led to significant oxidative stress along, hepatotoxicity, hematotoxicity and altered brain biogenic amines levels accompanied by increased arsenic accumulation in blood and tissues. These altered biochemical variables were supported by histopathological examinations leading to oxidative stress and cell death. These biochemical alterations were significantly restored by co-administration of α-lipoic acid with arsenic and DDVP alone and concomitantly. The results indicate that arsenic and DDVP induced oxidative stress and cholinergic dysfunction can be significantly protected by the supplementation of α-lipoic acid.     

Protective role of exogenous α-lipoic acid (ALA) on hippocampal antioxidant status and memory function in rat pups exposed to sodium arsenite during the early post-natal period

The present work focussed on the effect of exogenous α-lipoic acid (ALA) administration on retention memory and oxidative stress markers in the hippocampus subsequent to early post-natal exposure of rat pups to sodium arsenite (NaAsO(2)). Wistar rat pups were divided into the control groups receiving either no treatment (Ia) or distilled water by intraperitoneal route (i.p.) (Ib) and the experimental groups receiving either NaAsO(2) alone (1.5 and 2.0?mg/kg body wt.) (IIa, IIb) or NaAsO(2) (1.5 and 2.0?mg/kg body wt.) followed by ALA (70?mg/kg body wt.) (IIIa, IIIb) (i.p.) from post-natal day (PND) 4-15. The initial and retention transfer latency (ITL and RTL) was determined on PND 14 and 15 using elevated plus maze. The animals were sacrificed by cervical decapitation (PND 16) and the brains were obtained. The dissected out hippocampus was processed for estimation of oxidative stress markers, glutathione (GSH), and superoxide dismutase (SOD). NaAsO(2) exposure resulted in longer RTL in animal groups IIa and IIb, thereby suggestive of arsenic-induced impairment in retention memory. RTL was significantly shorter in animal groups (IIIa, IIIb) receiving ALA following NaAsO(2), thereby suggestive of improvement in retention memory. GSH and SOD levels were significantly decreased in animals receiving NaAsO(2) alone as against group Ib and administration of ALA following NaAsO(2) increased the levels of hippocampal GSH and SOD. These observations are suggestive of the role of exogenous ALA in ameliorating the adverse effects induced by NaAsO(2) exposure of rat pups on retention memory and oxidative stress markers.