Administration Of Α-tocopherol Research Articles

Ameliorative effect of α-tocopherol and tocotrienol-rich palm oil extract on menopause-associated mood disorder in ovariectomized mice

Menopause-associated mood disorder is characterized by emotional depression, anxiety, and stress, which accompany hypogonadism in women in the menopausal phase. The current treatment for menopause-associated mood disorder provides only symptomatic relief and is associated with many side effects. Supplementation with vitamin E has been shown to be effective in ameliorating anxiety and depression. However, the effects of vitamin E and its underlying mechanism in ameliorating menopause-associated mood disorders remain uncertain. This work evaluated the effects of α-tocopherol and tocotrienol-rich palm oil extract on depressive and anxiety-related phenotypes induced by estrogen deficiency through ovariectomy in mice. Our study revealed that ovariectomized mice exhibited alterations in behavior indicative of depressive- and anxiety-like behaviors. The serum corticosterone level, a glucocorticoid hormone associated with stress, was found to be elevated in ovariectomized mice as compared to the sham group. Oral administration of α-tocopherol (50 and 100 mg/kg) and tocotrienol-rich palm oil extract (100 and 200 mg/kg) for 14 days alleviated these behavioral changes, as observed in open field, social interaction, and tail suspension tests. However, treatment with tocotrienol-rich palm oil extract, but not α-tocopherol, modulated the depressive- and anxiety-like responses in ovariectomized mice subjected to chronic restraint stress. Both treatments suppressed the elevated serum corticosterone level. Our findings suggested that α-tocopherol and tocotrienol-rich palm oil extract alleviated menopause-associated mood disorder, at least in part, by modulating the hypothalamic-pituitary-adrenal (HPA) axis. The findings of this study can provide a new foundation for the treatment of menopause-associated depressive- and anxiety-like phenotypes, for the betterment of psychological wellbeing.

Evaluation of the effect of alpha-tocopherol on anxiety and the neuroinflammatory process during alcohol withdrawal in a model of forced and chronic self-administration of liquid diet containing ethanol: Behavioral and neurochemical evidence.

Alcoholism affects about 2 billion people worldwide. Withdrawal causes a neuroinflammatory response that increases anxiety. α-tocopherol is the most important antioxidant that has its invivo action currently known. Therefore, this study aimed to evaluate the effect of α-tocopherol on the neuroinflammatory process in brain regions involved in anxiety and its anxiolytic potential during alcohol withdrawal. For this, male Wistar rats were divided into four groups and submitted to a procedure of forced and chronic self-administration of liquid diet containing 6% and 8% ethanol for 15 days, followed by abrupt interruption of treatment. Animals in the control group received the liquid diet without ethanol. Twenty-four or 48h after ethanol discontinuation, and 30min after the last administration of α-tocopherol or saline, animals were evaluated in the elevated plus maze, light/dark box, and open field tests. At the end of the tests, each experimental group underwent brain tissue collection for analysis of cytokine levels. The results showed that: alcohol induces the neuroinflammatory process and anxiety; the stress generated by withdrawal can induce oxidative stress, which alters the production of inflammatory cytokines in the amygdaloid nuclei (AN) and medial hypothalamic nucleus (mHN); α-tocopherol exhibited anxiolytic and anti-inflammatory activity, attenuating the anxious behavior of abstinent animals and reducing neuroinflammation in AN and mHN; and the intensity of the anxiolytic and anti-inflammatory effect of α-tocopherol is dose-dependent. These results identify α-tocopherol as a potential therapeutic target supporting the fight against relapse during alcohol withdrawal.

The Ameliorative Effect of Fimasartan against Methotrexate-Induced Nephrotoxicity in Rats

Drug-induced acute kidney injury is a serious disorder. Oxidative stress has a key role in its initiation and progression. In this study, the possible ameliorative effect of fimasartan against methotrexate-induced nephrotoxicity was investigated in comparison with α-tocopherol in rats. Wistar rats were allocated into six groups and treated as follows: group Ӏ received water on a daily basis for 8 successive days; group ӀӀ received methotrexate (20 mg/kg) on day 1, followed by water for 7 successive days; group ӀӀӀ received fimasartan (3 mg/kg/day) for 7 successive days; group IV received α-tocopherol (1 g/kg/day) for 7 successive days; group V received methotrexate (20 mg/kg) on day 1, followed by fimasartan (3 mg/kg/day) for 7 successive days; and group VI received methotrexate (20 mg/kg) on day 1, followed by α-tocopherol (1 g/kg/day) for 7 successive days. Finally, after euthanization of each animal by diethyl ether, the samples were collected for analysis. Administration of fimasartan and α-tocopherol resulted in a significant decline in serum creatinine and urea, a significant reduction of renal malondialdehyde, and a significant elevation of renal superoxide dismutase-1 compared to the methotrexate-treated rats. In conclusion, fimasartan has ameliorative effects, comparable to those of α-tocopherol, on methotrexate-induced nephrotoxicity in rats.

Combined use of systemic quercetin, glutamine and alpha-tocopherol attenuates myocardial fibrosis in diabetic rats

This study aimed to analyze the effects of the quercetin (100 mg/kg), 1% glutamine and 1% α-tocopherol antioxidants in the myocardium of rats with streptozotocin-induced diabetes mellitus. Twenty male rats were subdivided into four groups (n = 5): N (normoglycemic); D (diabetic); NT (normoglycemic treated with antioxidants); and DT (diabetic treated with antioxidants) treated for 60 days. Clinical parameters, oxidative stress markers, inflammatory cytokines, myocardial collagen fibers and immunoexpression of superoxide dismutase 1 (SOD-1), glutathione peroxidase-1 (GPx-1), interleukin-1β (IL-1-β), transforming growth factor-beta (TGF-β), and fibroblast growth factor-2 (FGF-2) were evaluated. Results showed reduced body weight, hyperphagia, polydipsia and hyperglycemic state in groups D and DT. The levels of glutathione (GSH) were higher in NT and DT compared to N (p < 0.01) and D (p < 0.001) groups, respectively. Greater GSH levels were found in DT when compared to N animals (p < 0.001). In DT, there was an increase in IL-10 in relation to N, D and NT (p < 0.05), while GPx-1 expression was similar to N and lower compared to D (p < 0.001). TGF-β expression in DT was greater than N (p < 0.001) group, whereas FGF-2 in DT was higher than in the other groups (p < 0.001). A significant reduction in collagen fibers (type I) was found in DT compared to D (p < 0.05). The associated administration of quercetin, glutamine and α-tocopherol increased the levels of circulating interleukin-10 (IL-10) and GSH, and reduced the number of type I collagen fibers. Combined use of systemic quercetin, glutamine and alpha-tocopherol attenuates myocardial fibrosis in diabetic rats.

α-Tocopherol Prevents Sperm Apoptosis and Necrosis in Rats Exposed to 2,3,7,8-Tetrachlorodibenzo-p-dioxin.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent organic pollutant that induces overproduction of reactive oxygen species (ROS). Studies on avoiding the adverse effects of dioxin pollution exposure are needed in all aspects, including reproductive health. This study aimed to determine the effect of α-tocopherol on superoxide dismutase (SOD) and malondialdehyde (MDA) levels, live spermatozoa, apoptosis, and necrosis in male rats exposed to dioxin as a model. Thirty healthy 12-week-old male rats were randomly divided into five groups. Rats in the control group were given corn oil twice daily at 4-hour intervals. The remaining rats were given TCDD 700 mg/kg BW daily, followed by administration of corn oil and α-tocopherol at doses of 77, 140, and 259 mg/kg BW/d for T0, T1, T2, and T3 groups, respectively. The treatments were conducted for 45 days; all rats were euthanized to collect blood and testicular samples on day 46. The results showed that exposure of TCDD resulted in a decrease in SOD activity and live spermatozoa and increased MDA level and death, apoptosis, and necrosis of spermatozoa (T0) compared to the control (C) group (p < 0.05). The administration of α-tocopherol, starting from the doses of 77 (T1), 149 (T2), and 259 mg (T3) per kg BW, was sequentially followed by returning MDA levels, recovering SOD activities, and restoration in the percentage of living, dead, apoptotic, and necrotic spermatozoa, similar (p > 0.05) to those of the control group. It could be concluded that the administration of α-tocopherol resolves the harmful effects of TCDD on the viability of spermatozoa in rats as a model.

Assessment of Selected Morphological, Physical and Chemical Parameters of the Teeth of the Offspring of Female Rats Exposed to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), Taking into Account the Protective Role of Selected Antioxidants-Preliminary Study.

Simple SummaryThe present study aimed to determine the possibility of limiting potential dioxin disorders of the structure of hard tissues in the offspring of intoxicated rat mothers by simultaneous administration of α-tocopherol (vitamin E) or acetylsalicylic acid (ASA). The levels of magnesium (Mg), calcium (Ca) and phosphorus (P) contained in bone tissue as indicators of the process of mineralization of hard tissues were also determined. The chaps were harvested from the offspring of eight female Buffalo rats for testing. Selected morphological, chemical and physical parameters of the teeth of the offspring of female rats from the experimental groups were analyzed. The analysis showed the effect of vitamin E and ASA for the content of Mg, Ca and P. In combination with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), vitamin E and ASA, they positively inhibit the inflammatory process, preventing the leaching of Ca and Mg from the bones. ASA counteracted this phenomenon much more effectively than vitamin E. An increase in the number of dentiform cells was observed, but a slightly lower Ca content, which means that the tooth walls in this group have a lower density. Despite the use of compounds protecting the teeth against the harmful effects of TCDD, disturbances in the structure of the tooth crown cusps were still observed.The studies conducted so far indicate a negative effect of dioxins on the structure of the alveolar bone and teeth, especially in the developmental period in rats. The research aimed to analyze the indirect effect of dioxins contained in the body of female rats on the structure of the dental organ in their offspring in the neonatal period and to determine the possibility of reducing potential dioxin disorders of the structure of hard tissues in the offspring of intoxicated mothers by simultaneous administration of vitamin E or acetylsalicylic acid (ASA). Another goal of the research was to determine the level of magnesium, calcium and phosphorus contained in bone tissue as indicators of the mineralization process of hard tissues in rats, in the case of using 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and acetylsalicylic acid or α-tocopherol. The experiment was carried out on eight female rats of the Buffalo strain divided into four groups. From the offspring of eight females, the mandibles were removed from the mandibular joints, and then, after the removal of soft tissues, they were prepared for individual tests. Selected morphological, chemical and physical parameters of the teeth of the offspring of female rats from the experimental groups were analyzed. The analysis showed the effect of vitamin E and ASA on the content of Mg, Ca and P. In combination with TCDD, vitamin E and ASA, they positively inhibit the inflammatory process, preventing the leaching of Ca and Mg from the bones. ASA counteracted this phenomenon much more effectively than vitamin E. Detailed analysis of the tooth morphology showed that the molars’ crowns exhibit shape disturbances under the influence of TCDD. Individual nodules in teeth T1, T2, T3 did not fuse, and the roots showed signs of hypertrophy. The study confirmed the negative effect of TCDD on tooth development. Teeth arising early in development are the most sensitive to the disorders, while the later ones are less exposed to the toxic effects of TCDD transmitted by the mother.

α-Tocopherol restores semen quality in rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Background and Aim:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent organic pollutant toxic to the human reproductive system. This study aimed to evaluate the effect of α-Tocopherol administration on the male fertility parameters of a rat model exposed to TCDD.Materials and Methods:Fifty healthy 12-week-old male rats were randomly divided into five groups. Rats in the control group were given corn oil twice daily in 4 h intervals. In the treatment groups, all rats were given TCDD at a dose of 700 ng/kg of body weight (BW)/day for 45 days. Four hours after receiving the TCDD, T0 rats were given corn oil, and T1, T2, and T3 rats were given α-Tocopherol at doses of 77, 140, and 259 mg/kg BW/day, respectively, for 45 days. On day 46, experimental animals were sacrificed to collect blood and testicular samples.Results:TCDD exposure decreased superoxide dismutase activity, plasma membrane integrity, Leydig cell count, sperm cell count, sperm viability and motility, and increased malondialdehyde levels, serum testosterone levels, and sperm morphological abnormalities. The administration of α-Tocopherol mitigated the effects of TCDD exposure, and the 140 and 259 mg/kg BW/day treatments returned those male fertility parameters to normal levels.Conclusion:The administration of 140 mg/kg BW/day α-Tocopherol restored male semen quality in rats exposed to TCDD. We found dynamics serum testosterone levels in rats exposed to TCDD that need to be further studied.

Alpha-tocopherol-loaded polycaprolactone nanoparticles improve the inflammation and systemic oxidative stress of arthritic rats

Background and aimThe present study investigated the effects of orally administered α-tocopherol-loaded polycaprolactone nanoparticles on the articular inflammation and systemic oxidative status of middle-aged Holtzman rats with Freund's adjuvant-induced polyarthritis, a model for rheumatoid arthritis. Intraperitoneally administered free α-tocopherol provided the reference for comparison. Experimental procedureTwo protocols of treatment were followed: intraperitoneal administration of free α-tocopherol (100 mg/kg i.p.) or oral administration of free and nanoencapsulated α-tocopherol (100 mg/kg p.o.). Animals were treated during 18 days after arthritis induction. ResultsFree (i.p.) and encapsulated α-tocopherol decreased the hind paws edema, the leukocytes infiltration into femorotibial joints and the mRNA expression of pro-inflammatory cytokines in the tibial anterior muscle of arthritic rats, but the encapsulated compound was more effective. Free (i.p.) and encapsulated α-tocopherol decreased the high levels of reactive oxygen species in the brain and liver, but only the encapsulated compound decreased the levels of protein carbonyl groups in these organs. Both free (i.p.) and encapsulated α-tocopherol increased the α-tocopherol levels and the ratio of reduced to oxidized glutathione in these organs. ConclusionBoth intraperitoneally administered free α-tocopherol and orally administered encapsulated α-tocopherol effectively improved inflammation and systemic oxidative stress in middle-aged arthritic rats. However, the encapsulated form should be preferred because the oral administration route does not be linked to the evident discomfort that is caused in general by injectable medicaments. Consequently, α-tocopherol-loaded polycaprolactone nanoparticles may be a promising adjuvant to the most current approaches aiming at rheumatoid arthritis therapy.

Efek pemberian α-tokoferol terhadap jumlah sel spermatogenik dan sel Leydig pada tikus putih (Rattus norvegicus) yang dipapar 2,3,7,8 Tetrachlorodibenzo-p-dioxin

This research aimed to determine the effect of α-tocopherol on the count of spermatogenic and Leydig cells in rats (Rattus norvegicus) exposed to 2,3,7,8 tetrachlorodibenzo-p-dioxin (dioxin). Dioxin is an endocrine-disrupting agent that adversely affects reproductive health, while α-tocopherol maintains fertility. This research used 25 rats aged 10-12 weeks weighing 150-200 grams. Rats were divided into five groups (K, P0, P1, P2 and P3). The K (control group) was administered with corn oil 1 ml/day. P0 was exposed to 700 ng/kg/day dioxin. P1, P2 and P3 was exposed to dioxin at a dose of 700 ng/kg/day and administered with α-tocopherol at a dose of 77, 140 and 259 mg/kg/day respectively. Dioxin exposure, corn oil and α-tocopherol administration were conducted orally for 20 days. On day-21, all rats were sacrificed for histological slides preparation of testicles with hematoxylin-eosin staining. Data were analyzed with analysis of variance and continued with the Duncan test. The results indicated that exposure to dioxin caused a decrease in the number of spermatogenic and Leydig cells. The administration of α-tocopherol at a dose of 140 mg/kg/day eliminated the effect of reducing the number of spermatogenic and Leydig cells caused by exposure to dioxin. The conclusion was the administration of α-tocopherol at 140 mg/kg/day was effective in maintaining the number of spermatogenic and Leydig cells in rats (Rattus norvegicus) exposed to 2,3,7,8 tetrachlorodibenzo-p-dioxin.

Isolation Purification and Partial Characterization of Antisnake Venom Plant Peptide (BRS-P19) from Bauhinia rufescens (LAM FAM) Seed as Potential Alternative to Serum-Based Antivenin

Several studies have been reported on active peptides isolated from some medicinal plants, which were effective inhibitors against snake venom induced toxicities. Hence, the aim of this research work was to isolate, purify and characterize an antisnake venom plant peptide from Bauhinia rufescens seed that can serve as potential alternative to serum-based antivenins. B. rufescens seed was collected, duly identified, authenticated and processed. The peptide was isolated from the seed and purified using gel filtration chromatography and SDS-PAGE and then named as BRS-P19. Venom Phospholipase A2 (VPLA2) was used for the study and was isolated from Naja nigricollis venom. Albino mice of both sexes were used for in vivo experiments. They were divided into seven (7) groups of three (3) mice each. Group 1 served as normal control, group 2 were injected with VPLA2 only, group 3 and 4 were injected with VPLA2 then treated with BRS-P19 at doses of 0.2 and 0.4 mg/kg b.w. respectively, while mice in group 5 were injected with VPLA2 then treated with standard antivenin, group 6 and 7 were injected with VPLA2 followed by administration of ascorbic acid and α-tocopherol respectively. In all the groups, hepatic and renal levels of reactive oxygen species (ROS), lipid peroxidation (MDA) and activities of antioxidant enzymes were determined. The results showed that, the BRS-P19 has molecular weight of ~19kD. Its percentage in vitro inhibitory effect against VPLA2 was 91.85 ± 0.32%. For the in vivo study, the animals treated with 0.4 mg/kg b.w. of the BRS-P19 showed a significant (P&lt;0.05) decrease in the hepatic and renal ROS and MDA levels when compared with the VPLA2 untreated group. But, the activities of the antioxidant enzymes in all the treated groups were significantly (P&lt;0.05) increased by the BRS-P19 at 0.4 mg/kg b.w. when compared to the VPLA2 untreated group. Based on these findings, it has been established that, BRS-P19 has antisnake venom effect through inhibition of VPLA2 and antioxidant activity as the possible mechanisms of action.

Effects of Vitamins C and E on Free Radical Processes in the Blood of Rats in Acute Moderate Hypothermia

We assessed the effect of intraperitoneal administration of ascorbic acid (vitamin C, 100 mg/kg/day) and α-tocopherol (vitamin E–selenium, 40 mg/kg/day), given alone or in combination for seven days, on the intensity of free-radical processes in the blood of rats in acute short-term hypothermia of 30○С. Hypothermia contributes to the development of oxidative stress in erythrocytes, stimulating the lipid peroxidation and oxidative modification of proteins (OMP), decreasing the content of glutathione (GSH) and increasing the activity of superoxide dismutase (SOD) in erythrocytes. A separate administration of vitamins prevents a decrease in the level of GSH and an increase in the activity of SOD in erythrocytes in hypothermia, but vitamin C stimulates lipid peroxidation and OMP and vitamin E stimulates OMP of the erythrocyte membranes. Coadministration of vitamins C and E completely prevents the development of oxidative stress in erythrocytes during hypothermia.

Multi-faceted therapeutic strategy for treatment of Alzheimer's disease by concurrent administration of etodolac and α-tocopherol

Alzheimer's disease (AD) is a complex neurodegenerative disorder with multiple dysfunctional pathways. Therefore, a sophisticated treatment strategy that simultaneously targets multiple brain cell types and disease pathways could be advantageous for effective intervention. To elucidate an effective treatment, we developed an in vitro high-throughput screening (HTS) assay to evaluate candidate drugs for their ability to enhance the integrity of the blood-brain barrier (BBB) and improve clearance of amyloid-β (Aβ) using a cell-based BBB model. Results from HTS identified etodolac and α-tocopherol as promising drugs for further investigation. Both drugs were tested separately and in combination for the purpose of targeting multiple pathways including neuroinflammation and oxidative stress. In vitro studies assessed the effects of etodolac and α-tocopherol individually and collectively for BBB integrity and Aβ transport, synaptic markers and Aβ production in APP-transfected neuronal cells, as well as effects on inflammation and oxidative stress in astrocytes. Transgenic 5XFAD mice were used to translate in vitro results of etodolac and α-tocopherol independently and with concurrent administration. Compared to either drug alone, the combination significantly enhanced the BBB function, decreased total Aβ load correlated with increased expression of major transport proteins, promoted APP processing towards the neuroprotective and non-amyloidogenic pathway, induced synaptic markers expression, and significantly reduced neuroinflammation and oxidative stress both in vitro and in vivo. Collective findings demonstrated the combination produced mixed interaction showing additive, less than additive or synergistic effects on the evaluated markers. In conclusion, this study highlights the significance of combination therapy to simultaneously target multiple disease pathways, and suggest the repurposing and combination of etodolac and α-tocopherol as a novel therapeutic strategy against AD.

Interaperitoneal Administration of Αlpha-Tocopherol Loaded Nanoparticles Improves Ischemia-Reperfusion Injury in Rat Ovaries Torsion and Detorsion Model.

Objective:To investigate effects of intraperitoneally administration of α-tocopherol loaded nanoparticles (TNP) on ischemia-reperfusion injury in ovaries.Methods:Thirty-five healthy female Wistar rats ~250g were randomized into seven experimental groups (n = 5): Group SHAM: The rats underwent only laparotomy. Group Ischemia: A 3- hour ischemia only. Group I/R: A 3-hour ischemia and a 3-hour reperfusion. Group I/T: A 3-hour ischemia only and 100 mg/kg intraperitoneal administration (IP) of α-tocopherol 2.5 hours after induction of ischemia. Group I/R/T: A 3-hour ischemia, a 3-hour reperfusion and 100 mg/kg IP of α-tocopherol 2.5 hours after induction of ischemia. Group I/TNP: A 3-hour ischemia only and 1 mg/kg IP of TNP 2.5 hours after induction of ischemia. Group I/R/TNP: A 3-hour ischemia, a 3-hour reperfusion and 1 mg/kg IP of TNP 2.5 hours after induction of ischemia. Results:Animals treated with αTNP showed significantly ameliorated development of ischemia and reperfusion tissue injury compared to those of other groups (p=0.001). The significant higher values of SOD, tGSH, GPO, GSHRd and GST were observed in I/R/NC animals compared to those of other groups (p=0.001). Damage indicators (NOS, MDA, MPO and DNA damage level) were significantly lower in I/R/NC animal compared to those of other groups (p=0.001). Conclusion: Intraperitoneal administration of TNP could be helpful in minimizing ischemia-reperfusion injury in ovarian tissue exposed to ischemia.

α-tocopherol attenuates acetaminophen-induced testicular dysfunction in adult male rats

BACKGROUND: Acetaminophen (Paracetamol) is a widely used over-the-counter analgesic and an antipyretic drug known to inhibit cyclooxygenase II enzyme paramount in the prostaglandin synthesis and essential for normal male reproductive function. α-tocopherol (Vitamin E), an antioxidant has been used in the management of a number of conditions including infertility. However, there is a dearth of information on the role of α-tocopherol in the management of testicular dysfunction. This study was designed to investigate the ameliorative effect of α-tocopherol in acetaminophen-induced testicular dysfunction. MATERIALS AND METHODS: Adult male Wistar rats were randomly allotted into groups; Control 1 (vehicle 1; received 0.2 ml of olive oil), Control 2 (vehicle 2; received 0.2 ml of distilled water), acetaminophen- treated (ACE-treated; received 500 mg/kg b. w), α-tocopherol-treated (AT-treated; received 100 mg/kg b. w), and α-tocopherol + acetaminophen-treated (AT + ACE-treated). The treatment lasted for 14 days, and the administration was given orally. The body weight change was monitored using animal weighing balance (Olympia SCL66110 model, Kent Scientific Corporation, Torrington, CT06790, USA), semen analysis and biochemical assay were performed. RESULTS: The results showed a significant increase in body weight gain and significant alteration of spermatozoa integrity in the acetaminophen-treated group when compared to the vehicle-treated groups. These alterations were associated with decreased hypophyseal-gonadotropic hormones, testosterone, and increased testicular tissue oxidative redox status. Concomitant administration of α-tocopherol during treatment with acetaminophen ameliorated the alterations. CONCLUSION: The present study demonstrates that administration of α-tocopherol during treatment with acetaminophen preserves testicular function. This might be due to its antioxidative effect and enhancement of hypophyseal-gonadotropic hormone secretion.

Alpha-tocopherol attenuates the anti-tumor activity of crizotinib against cells transformed by NPM-ALK.

Anaplastic large cell lymphomas (ALCL) are mainly characterized by harboring the fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The ALK inhibitor, crizotinib specifically induced apoptosis in Ba/F3 cells expressing NPM-ALK by inhibiting the activation of NPM-ALK and its downstream molecule, signal transducer and activator of transcription factor 3 (STAT3). We found that α-tocopherol, a major component of vitamin E, attenuated the effects of crizotinib independently of its anti-oxidant properties. Although α-tocopherol suppressed the inhibitory effects of crizotinib on the signaling axis including NPM-ALK and STAT3, it had no influence on the intake of crizotinib into cells. Crizotinib also directly inhibited the kinase activity of NPM-ALK; however, this inhibitory effect was not altered by the co-treatment with α-tocopherol. Whereas the nuclear localization of NPM-ALK was disappeared by the treatment with crizotinib, the co-treatment with α-tocopherol swept the effect of crizotinib and caused the localization of NPM-ALK in nucleus. The administration of α-tocopherol attenuated the anti-tumor activity of crizotinib against NPM-ALK-provoked tumorigenesis in vivo. Furthermore, the α-tocopherol-induced inhibition of crizotinib-caused apoptosis was also observed in NPM-ALK-positive cells derived from ALCL patients, namely, SUDHL-1 and Ki-JK. Collectively, these results not only revealed the novel mechanism underlying crizotinib-induced apoptosis in NPM-ALK-positive cells, but also suggest that the anti-tumor effects of crizotinib are attenuated when it is taken in combination with vitamin E.

Supplementation of α-Tocopherol Attenuates Minerals Disturbance, Oxidative Stress and Apoptosis Occurring in Favism

The favism is a metabolic disease that characterized with an acute hemolytic anemia where α-tocopherol is a type of tocopherol accumulated inside the human body. The objective of such a study was established to evaluate the effect of α-tocopherol in favism disorders. A total of 75 human cases were divided into 5 groups as follow; group 1 normal cases without any treatment and group 2 normal cases orally administrated α-tocopherol (200mg/kg) once a day over 30days period. Group 3 favism patients without any treatment. Groups 4 and 5 favism patients orally administrated 100 and 200mg α-tocopherol/kg, respectively once a day over 30days period. The results obtained revealed that oral administration of α-tocopherol into normal cases over 30days period did not induce any biological change. In favism, hemoglobin, hematocrit, red and white blood cells, serum glucose, glucose-6-phosphate dehydrogenase, total protein, albumin, globulin, aspartate and alanine aminotransferases, blood glutathione, superoxide dismutase, glutathione peroxidase and serum calcium, phosphorous, sodium, potassium and chloride levels were significantly decreased. On the other hand, serum alkaline phosphatase, bilirubin, selenium, zinc, manganese, copper and iron, malondialdehyde levels showed significant increase in favism. Supplementation with α-tocopherol into favism restores all the above mentioned parameters to approach the normal levels. Also, α-tocopherol has anti-apoptotic effect in favism. In conclusion, α-tocopherol attenuates minerals disturbance, oxidative stress and apoptosis occurring in favism.

Antidepressant-like effect of α-tocopherol in a mouse model of depressive-like behavior induced by TNF-α

Taking into account that pro-inflammatory cytokines and oxidative and nitrosative stress are implicated in the pathogenesis of depression and that α-tocopherol has antidepressant, anti-inflammatory and antioxidant properties, this study investigated the ability of α-tocopherol to abolish the depressive-like behavior induced by i.c.v. administration of TNF-α in the mouse TST. Additionally, we investigated the occurrence of changes in the levels of Bcl2 and Bax and phosphorylation of GSK-3β (Ser9) in the hippocampus of mice. The administration of TNF-α (0.001fg/site, i.c.v.) increased the immobility time in the TST, which was prevented by the administration of α-tocopherol at the doses of 10, 30 and 100mg/kg (p.o.). Subeffective doses of α-tocopherol (10mg/kg, p.o.) and/or the antidepressants fluoxetine (5mg/kg, p.o.), imipramine (0.1mg/kg, p.o.) and bupropion (1mg/kg, p.o.), the NMDA receptor antagonist MK-801 (0.001mg/kg, p.o.) or the neuronal nitric oxide synthase inhibitor 7-nitroindazole (25mg/kg, i.p.) prevented the depressive-like effect induced by TNF-α. None of the treatments altered the locomotor activity of mice. Treatment with TNF-α and/or α-tocopherol did not alter the levels of Bax and Bcl2 or the phosphorylation of GSK-3β in the hippocampus of mice. Together, our results show a synergistic antidepressant-like effect of α-tocopherol with antidepressants against the depressive-like behavior induced by an inflammatory insult, suggesting that this vitamin may be useful to optimize conventional pharmacotherapy of depression, including depressive states associated with inflammatory conditions.

Alpha-tocopherol ameliorates oxidative renal insult associated with spinal cord reperfusion injury

Ischemic-reperfusion procedures targeting a specific organ often results in remote multiple organ injuries mediated possibly by heightened oxidative stress levels. As the kidney is one of the most vulnerable organs for ischemic oxidative stress, the aim of the present study was to confirm the occurrence of renal complication secondary to spinal cord ischemic-reperfusion injury (SC-IRI) induced by aortic clamping. The study also investigated the possible prophylactic effect of long-term administration of α-tocopherol (α-TOL) against high level of renal oxidative stress and inflammatory processes induced by SC-IRI. In this study, a total of 60 male Sprague-Dawley rats were randomly divided into five equal groups: C group underwent no surgery; CE group received α-TOL 600 mg/kg intramuscular twice weekly for 6 weeks; S group were subjected to laparotomy without clamping of the aorta; SE group were handled as S group and treated with α-TOL as group CE; SC-IRI group were subjected to laparotomy with clamping of the aorta just above the bifurcation of the aorta for 45 min, then the clamp was released for 48 h for reperfusion. SC-IRIE group was subjected to IRI as in group SC-IRI and was injected with α-TOL in the same dose and route as α-TOL-treated control group. SC-IRI resulted in increases in serum creatinine, blood urea nitrogen, plasma nitrite/nitrate level, serum tumor necrosis factor alpha, renal tissue homogenate level for malondialdehyde, superoxide dismutase and prostaglandin E2. Long-term prophylactic treatment with α-TOL resulted in amelioration of the renal functional disturbances and all measured parameters of oxidative stress and inflammation. Ischemic reperfusion injury of the spinal cord induced some remote renal functional disturbances although some of the observed changes may have resulted from decreased renal blood flow due to the hypotension induced during the procedure. Prophylactic long-term α-TOL administration guards against the renal function disturbances an effect that can be attributed, at least partially, to improvement of the renal pro-oxidant/antioxidant balance and inhibition of the inflammatory processes.

Ameliorative Effect of &amp;alpha;-Tocopherol and Selenium on Effects of Malathion on Plasmatic Biochemical Indices and Lesions in the Liver of Rats

The aim of the present study was to evaluate the potential hepatoprotective effect of α-tocopherol and/or selenium on some plasmatic biochemical indices of liver profile and hepatic damage induced in adult male rats exposed to subchronic dose of malathion (MTN) equivalent to 1/50 LD50. Oral administration of MTN for 45 days significantly induced severe hepatic injury as revealed by increased activity of plasmatic biochemical indices, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and gamma-glutamyl transferase (GGT) enzymes. Oral administration of α-tocopherol (α-T) and selenium (Se) concomitant with MTN resulted in a significant ameliorative effect by lowering the elevated plasma levels of the previous enzymes. Light microscopic investigation revealed that MTN exposure was associated with necrosis of hepatocytes and marked degenerative changes of liver tissues. Coadministration of (α-T) and Se concomitant with MTN to rats improved the histopathological severity score from severe to normal. However the individual treatment of (α-T) or Se correlated with a relative protection as reflected in the change of the histopathological severity score from severe to mild and moderate, respectively. Thus, it appears that the treatment with (α-T) and/or Se improves MTN hepatotoxicity but is not completely protective.

Ameliorative effect of α‐tocopherol on monosodium glutamate‐induced cardiac histological alterations and oxidative stress

Chronic oral intake of high doses of monosodium glutamate (MSG) causes oxidative stress. Oxidative stress plays an important role in the development of cardiac dysfunction and injury. Supplementation with α-tocopherol protects the body against oxidative stress and its related complications. This study was proposed to examine the protective effect of α-tocopherol against MSG-induced biochemical and histological alterations in blood and cardiac tissue of rats for a period of 180 days. Chronic oral administration of MSG (4 g kg(-1)) caused oxidative stress that was manifested by significant increase (P < 0.05) in malondialdehyde, conjugated dienes and by the decrease in the activities of superoxide dismutase, catalase, reduced glutathione, glutathione peroxidase and glutathione S-transferase in cardiac tissue. The significantly increased (P < 0.05) activities of aspartate transaminase, creatine phosphokinase and lactate dehydrogenase in serum suggested a cardiac functional disorder. Moreover, heart muscle fibers showed cloudy swelling, fiber separation and vascular congestion. Administration of α-tocopherol (200 mg kg(-1)) significantly (P < 0.05) attenuated the MSG-induced biochemical alterations in serum and cardiac tissue. α-Tocopherol also prevented the pathological changes in cardiac tissue when compared with the MSG-treated group. Our findings suggest that α-tocopherol may have a protective effect against MSG-induced cardiotoxicity, possibly through its antioxidant activity.