Progress on physiological activities and synthetic methods of ebselen / 药学实践杂志

Organoselenium compounds are bioactive substances with extensive physiological activities .As a representa-tive compound ,ebselen could be used as mimics of glutathione peroxidase ,and in the treatment of many diseases ,such as car-diovascular and cerebrovascular diseases ,inflammation and noise-induced hearing loss .the research progress in physiological activities and synthetic methods of ebselen were reviewed in this paper .

Protective effects of organoselenium compounds against methylmercury-induced oxidative stress in mouse brain mitochondrial-enriched fractions

We evaluated the potential neuroprotective effect of 1-100 µM of four organoselenium compounds: diphenyl diselenide, 3’3-ditri-fluoromethyldiphenyl diselenide, p-methoxy-diphenyl diselenide, and p-chloro-diphenyl diselenide, against methylmercury-induced mitochondrial dysfunction and oxidative stress in mitochondrial-enriched fractions from adult Swiss mouse brain. Methylmercury (10-100 µM) significantly decreased mitochondrial activity, assessed by MTT reduction assay, in a dose-dependent manner, which occurred in parallel with increased glutathione oxidation, hydroperoxide formation (xylenol orange assay) and lipid peroxidation end-products (thiobarbituric acid reactive substances, TBARS). The co-incubation with diphenyl diselenide (100 µM) completely prevented the disruption of mitochondrial activity as well as the increase in TBARS levels caused by methylmercury. The compound 3’3-ditrifluoromethyldiphenyl diselenide provided a partial but significant protection against methylmercury-induced mitochondrial dysfunction (45.4 ± 5.8 percent inhibition of the methylmercury effect). Diphenyl diselenide showed a higher thiol peroxidase activity compared to the other three compounds. Catalase blocked methylmercury-induced TBARS, pointing to hydrogen peroxide as a vector during methylmercury toxicity in this model. This result also suggests that thiol peroxidase activity of organoselenium compounds accounts for their protective actions against methylmercury-induced oxidative stress. Our results show that diphenyl diselenide and potentially other organoselenium compounds may represent important molecules in the search for an improved therapy against the deleterious effects of methylmercury as well as other mercury compounds.

The effects of synthetic organoselenium compounds on nitric oxide in DMBA - induced rat liver.

DMBA (7,12-dimethylbenz[a]anthracene) is known to generate DNA-reactive species during their metabolism, which may enhance oxidative stress in cells. Since selenium is known as a non-enzymic antioxidant, health problems induced by many environmental pollutants, have stimulated the evaluation of relative antioxidant potential of selenium and synthetic organoselenium compounds. Therefore, we aimed to evaluate chemopreventive potential of synthetic organoselenium compounds by monitoring level of liver nitric oxide. In this study, adult female Wistar rats were treated with DMBA and the novel organoselenium compounds (Se I) and (Se II) in the determined doses. DMBA-induced in rats, the effects of organoselenium compounds on nitric oxide levels in rat liver was studied. In this study, it has been observed a statistically significant increase in (Nitric Oxide) levels for the liver of rat exposed to DMBA (p<0.05). However with administration of Se I and Se II there was a statistically significant decrease in NO levels (p<0.05). The ability of the organoselenium compounds to prevent oxidative damage induced by DMBA in rat livers was rationalized. Protection against nitric oxide measured in Se I and Se II treated groups were provided by synthesized organoselenium compounds. Se I and Se II both provided chemoprevention against DMBA-induced oxidative stress in rat liver.

Pharmacology and toxicology of diphenyl diselenide in several biological models

The pharmacology of synthetic organoselenium compounds indicates that they can be used as antioxidants, enzyme inhibitors, neuroprotectors, anti-tumor and anti-infectious agents, and immunomodulators. In this review, we focus on the effects of diphenyl diselenide (DPDS) in various biological model organisms. DPDS possesses antioxidant activity, confirmed in several in vitro and in vivo systems, and thus has a protective effect against hepatic, renal and gastric injuries, in addition to its neuroprotective activity. The activity of the compound on the central nervous system has been studied since DPDS has lipophilic characteristics, increasing adenylyl cyclase activity and inhibiting glutamate and MK-801 binding to rat synaptic membranes. Systemic administration facilitates the formation of long-term object recognition memory in mice and has a protective effect against brain ischemia and on reserpine-induced orofacial dyskinesia in rats. On the other hand, DPDS may be toxic, mainly because of its interaction with thiol groups. In the yeast Saccharomyces cerevisiae, the molecule acts as a pro-oxidant by depleting free glutathione. Administration to mice during cadmium intoxication has the opposite effect, reducing oxidative stress in various tissues. DPDS is a potent inhibitor of d-aminolevulinate dehydratase and chronic exposure to high doses of this compound has central effects on mouse brain, as well as liver and renal toxicity. Genotoxicity of this compound has been assessed in bacteria, haploid and diploid yeast and in a tumor cell line.

Immune regulating activity of a novel organoselenium compound ethaselen-1 in C57/BL mice / 北京大学学报(医学版)

Objective: To detect the Immune regulating activity of ethaselen-1(Eb1),a novel organoselenium compound,in C57/BL mice transplanted with Lewis lung cancer(LLC).Methods: The LLC transplanted C57/BL mice models were established,and the mice was randomly divided into four groups,including high dose Eb1 group(25.0 mg/kg),low dose Eb1 group(12.5 mg/kg),positive control group(levamisole,LMS,2.0 mg/kg) and negative control group(solvent).Intraperitoneal injections(ip.) of the four pharmaceuticals were performed once a day through the abdominal wall separately,from the second to the eighth day after cancer was transplanted.On the eleventh day,six mice of each group were killed and relative weight of spleen,transforming activity of spleen lymphocytes,NK cell activity,LAK cell activity and percentage of CD_4~+CD_8~+T lymphocyte were detect.Results: Compared with the control group,high dose Eb1 could obviously increase the relative weight of spleen(150.59% and 122.55%),transforming activity of spleen lymphocytes(162.25% and 561.98%),NK cell activity(78.60% and 219.42%) and percentage of CD_4~-/CD_8~+ T lymphocyte(104.72% and 105.87%) in normal mice and LLC mice.Compared with the control group,high dose Eb1 could also increase LAK cell activity of LLC mice by 195.11%.Conclusion: The novel organoselenium compound Eb1 has immune regulating activity in vivo.

The antitumor activity of Shuang-Xi-Zuo-Wan-1 in C57/BL mice / 北京大学学报(医学版)

Objective: To detect the antitumor activity of Shuang-Xi-Zuo-Wan-1(Eb), a novel organoselenium compound, in C57/BL mice transplanted with Lewis lung cancer(LLC). Methods: The LLC transplanted C57/BL mice model was established,and the mice were randomly divided into four groups, including high dose Eb group (25.0 mg/kg),low dose Eb group (12.5 mg/kg), positive control group (DDP,2.0 mg/kg) and negative control group(solvent).Each group had twelve mice. Intraperitoneal injections (ip.) of four pharmaceuticals were performed once a day through the abdominal wall separately, from the second to the eighth days after cancer was transplanted. On the eleventh day,six mice of each group were killed and the influences of Eb on growth speed ,size, weight, invasion, inhibitory rate, proliferation index and apoptosis rate of LLC were observed and calculated.The remaining mice were fed till all of them died naturely and the average survival time of each group was calculated. Results:Eb could inhibit the growth and infiltration of LLC(the cancer inhibitory rate of high does Eb was 80.31%) obviously and prolong the average survival time of these with mice cancer. After being given Eb,the nuclear of the cancer cell concentrated and the fission phase cells reduced.In addition,the number of apoptosis cancer cells increased.Conclusion:The novel organoselenium compound Eb has antitumo activity in vivo .It can inhibit the growth and infiltration of LLC in mice, and induce the apoptosis of cancer cells.

STUDY ON THE PROTECTIVE EFFECT OF ORGANOSELENIUM FROM SE-ENRLED LACTOBACILLUS ON CHEMICAL LIVER INJURY AND ITS MECHANISM / 营养学报

Objective: To study the protective effect in CCl4-induced liver injury by organoselenium from Se-enriched lactobacillus. Methods: (1) In the first series, forty-five animals were randomly divided into control (C) group, CCl4 group, CCl4 plus organoselenium group (CCl4-Se group). The liver injury was induced by abdominal injection of CCl4 every other day for 4 w. Changes of GSH-Px, CAT and SOD activities as well as MDA content in liver were estimated in the 2nd and 4th week after CCl4 injection respectively. (2) In the second series, forty-eight mice were randomly divided into C group, CCl4 group, CCl4 plus low dose organoselenium group (CCl4-LSe group) and CCl4 plus high dose organoselenium group (CCl4-HSe group). Changes of hepatocyte [Ca2+]i in animals in every group were investigated by means of confocal laser microscope on the 4th and 8th day after CCl4 injection respectively. Results: During the entire experimental period, liver MDA of CCl4 group was markedly superior to that of C and CCl4-Se groups, and the level of latter two groups was very close. The GSH-Px and CAT activities were higher in CCl4-Se group than in CCl4 group,but lower than that of C group. There were higher SOD activities in C and CCl4-Se groups compared to that in CCl4 group though without obvious difference. Average fluorescence pixels of hepatocyte [Ca2+]i in CCl4 group was 2.8 and 5.5 times higher than that of group C in the 4th and 8th day respectively,while those in CCl4-Se groups were significantly lower than those of CCl4 group, and close to C group. Conclusions: Organoselenium from Se-enriched lactobacillus, can protect hepatocyte [Ca2+]i homeostasis by reducing lipid peroxidation after CCl4 exposure.