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PubMed1997

Bile ductular damage induced by methylene dianiline inhibits oval cell activation.

Administration of 2-acetylaminofluorene (2-AAF) given before a two-thirds partial hepatectomy (PHx), results in suppression of hepatocyte proliferation and stimulation of oval cell proliferation. Our objective in this study was to examine the oval cell response and associated alpha-fetoprotein (AFP) gene expression by combining 2-AAF with selective hepatic damage caused by either carbon tetrachloride (CCl4) exposure or by PHx. We also examined oval cell response with the above two protocols (2-AAF/CCl4 and 2-AAF/PHx) as affected by previous bile ductular damage caused by 4,4'-methylene dianiline (4,4'-diaminodiphenylmethane, DAPM) exposure. DAPM is an aromatic diamine, known to cause bile ductular damage in both humans and animals. Using the protocols of 2-AAF/ CCl4 and 2-AAF/PHx, when DAPM was given 24 hours before the hepatic injury, no oval cell proliferation was seen (histological) and AFP expression was not detected by Northern blot analysis. These results provide direct evidence that oval cells are closely associated with the biliary epithelial cells and supports the theory that hepatic oval cells may originate from cells derived from either intraportal or periportal ductules.

2-Acetylaminofluorene↗

PubMed2005

Short-term effects of endocrine-disrupting chemicals on the expression of estrogen-responsive genes in male medaka (Oryzias latipes).

To evaluate the estrogenic activities of selected estrogenic compounds such as estradiol-17beta (E2), nonylphenol (NP), 4-(1-adamantyl)phenol (AdP), bisphenol A (BPA), BPA metabolite 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) and 4,4'-dihydroxy-alpha-methylstilbene (DHMS) in the shortest possible time, we investigated the expression of estrogen-responsive genes such as vitellogenin I, vitellogenin II and alpha-type estrogen receptor genes in the liver of male medaka (Oryzias latipes) using reverse transcription-polymerase chain reaction (RT-PCR) techniques. These estrogen-responsive genes responded rapidly to selected estrogenic compounds after 8 h exposure, and the expression of hepatic vitellogenin II and estrogen receptor alpha mRNA was found to be more responsive than that of vitellogenin I mRNA. As a result, the relative estrogenic potencies of tested chemicals descended in the order of E2 (100)>MBP (0.38)>AdP (0.25)>DHMS (0.05)>NP (0.02)>BPA (0.001). Moreover, this preliminary study indicates that AdP and DHMS should be considered as candidate estrogenic compounds with the potential to induce hepatic estrogen-responsive genes in male medaka. These results suggest that vitellogenin I, vitellogenin II and estrogen receptor alpha gene expression patterns alter in male medaka treated with selected estrogenic compounds, and that these genes may be useful molecular biomarkers for screening estrogenic endocrine-disrupting chemicals in the shortest possible time.

Adamantane↗

PubMed2002

Determination of the xenoestrogens 4-nonylphenol and bisphenol A by high-performance liquid chromatography and fluorescence detection after derivatisation with dansyl chloride.

An easily performable and highly selective method for the determination of the xenoestrogens bisphenol A (BPA) and technical 4-nonylphenol (mixture of isomers) from environmental samples was developed. The method consists of fluorigenic labelling of the substances by dansylation followed by HPLC separation of the derivatives. Specific wavelengths (lembda(ex)=354 nm, lambda(em)=545 nm) for detection of the dansylated phenols were determined in order to reduce the signals of interfering compounds. The applicablility of the method for environmental samples was demonstrated by using sewage sludge spiked with BPA and 4-n-nonylphenol (as internal standard).

Benzhydryl Compounds↗

PubMed2002

Chlorination of bisphenol A in aqueous media: formation of chlorinated bisphenol A congeners and degradation to chlorinated phenolic compounds.

The chlorination of bisphenol A (BPA) in aqueous media was investigated in order to describe the degradation profile of this compound and the formation of chlorinated products. Aqueous solutions of BPA (approx. 1 mg/l) were chlorinated by sodium hypochlorite solution at room temperature and under weakly alkaline conditions. Chlorinated compounds were extracted with dichloromethane and determined by gas chromatography/mass spectrometry (GC/MS). BPA was consumed completely within 5 min of chlorination, when the initial chlorine concentration was 10.24 mg/l (molar ratio to BPA, 58.7). On the other hand, when the initial chlorine concentration was 1.03 mg/l (molar ratio, 6.56), 9.3% of BPA still remained after 60 min chlorination. Five chlorinated BPA congeners, 2-chlorobisphenol A (MCBPA), 2,6-dichlorobisphenol A (2,6-D2CBPA), 2,2'-dichlorobisphenol A (2,2'-D2CBPA), 2,2',6-trichlorobisphenol A (T3CBPA) and 2,2', 6,6'-tetrachlorobisphenol A (T4CBPA) were formed in the earlier stages of chlorination. Several chlorinated phenolic compounds, 2,4,6-trichlorophenol (T3CP), 2,6-dichloro-1,4-benzoquinone (D2CBQ), 2,6-dichloro-1,4-hydroquinone (D2CHQ), C9H10Cl2O2, C9H8Cl2O and C10H12Cl2O2, were also formed by further chlorination.

Benzhydryl Compounds↗

PubMed2001

Toxicology of environmental estrogens.

It has been hypothesized that environmental contaminants that modulate endocrine signaling pathways may be causally linked to adverse health effects in humans. There has been particular concern regarding synthetic estrogens and their role in disrupting normal development of the male reproductive tract. Most estrogenic industrial compounds, such as bisphenol A (BPA) and nonylphenol, typically bind estrogen receptors alpha (ERalpha) and beta (ERbeta) and induce transactivation of estrogen-responsive genes/reporter genes, but their potencies are usually > or = 1,000-fold lower than observed for 17beta-estradiol (E2). Selective estrogen receptor modulators (SERMs) represent another class of synthetic estrogens that are being developed for treatment of hormone-dependent problems. The SERMs differentially activate wild-type ERalpha and variant forms expressing activation function 1 (ER-AF1) and AF2 (ER-AF2) in human HepG2 hepatoma cells transfected with a pC3-luciferase construct, and these in vitro differences reflect their unique in vivo biologies. The HepG2 cell assay has also been used in our laboratories to investigate the estrogenic activities of the following structurally diverse synthetic and phytoestrogens: 4'-hydroxytamoxifen; BPA; 2',4',6'-trichloro-4-biphenylol; 2',3',4',5'-tetrachloro-4-biphenylol; p-t-octylphenol; p-nonylphenol; naringenin; kepone; resveratrol; and 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE). The results show that synthetic and phytoestrogens induce distinct patterns of gene activation in HepG2 and U2 osteogenic sarcoma cells, suggesting that these compounds will induce tissue-specific in vivo ER agonist or antagonist activities. The predicted differences between these compounds, based on results of the in vitro bioassay, have been confirmed. For example, BPA inhibits E2-induced responses in the rodent uterus, and HPTE and structurally related compounds are ERalpha agonists and ERbeta antagonists in assays carried out in HepG2 and other cancer cell lines.

Animals↗

PubMed2005

4,4'-methylenedianiline-induced hepatotoxicity is modified by N-acetyltransferase 2 (NAT2) acetylator polymorphism in the rat.

4,4'-Methylenedianiline (MDA) is widely used in the manufacturing of polyurethane foam, epoxy resins, and polymers. Exposure to MDA induces liver damage in humans and rats. MDA undergoes N-acetylation catalyzed by N-acetyltransferase 1 (NAT1) and 2 (NAT2) in the liver. Both human and rat NAT2 are polymorphic, and human NAT2 genetic polymorphism modifies the frequency and/or severity of drug and xenobiotic toxicity in human populations. Recombinant expression of rat Nats in Escherichia coli showed that MDA was acetylated by both recombinant rat Nat1 and Nat2 and was catalyzed at substantially higher rates by rapid acetylator Nat2 compared with slow acetylator Nat2. Rapid acetylator F344 rat liver cytosols catalyzed the N-acetylation of MDA at significantly higher rates than those from slow acetylator Wistar-Kyoto (WKY) inbred rats. To test the effect of NAT2 genetic polymorphism on hepatotoxicity from acute MDA exposure, we compared hepatotoxicity in rapid (F344) and slow (WKY) Nat2 acetylator inbred rats that were administered MDA. Based on the results of dose-response studies ranging up to 150 mg/kg MDA administered by intragastric gavage, the effect of a moderately hepatotoxic dose (37.5 mg/kg) was compared in rapid versus slow acetylator rats. Plasma alanine transaminase enzyme activities were approximately 5-fold higher (p < 0.05) in rapid versus slow acetylator rats after MDA treatment, and necrotizing hepatitis with portal damage consisting of bile ductular necrosis, portal expansion, and inflammation was clearly more prominent. These results suggest that acetylator phenotype is an important factor for susceptibility toward MDA hepatotoxicity.

Acetylation↗

PubMed2006

Nonylphenol modulates expression of androgen receptor and estrogen receptor genes differently in gender types of the hermaphroditic fish Rivulus marmoratus.

To uncover the effect of estrogenic chemicals [4-nonylphenol (NP) and bisphenol A (BisA)] on the expression of androgen receptor (AR) and estrogen receptors (ERalpha and ERbeta) in the hermaphroditic fish Rivulus marmoratus, we cloned the full length of the cDNAs encoding AR, ERalpha, and ERbeta from gonadal tissue of R. marmoratus and analyzed the modulation of expression of these genes following exposure to estrogenic chemicals using real-time RT-PCR. R. marmoratus AR, ERalpha, and ERbeta genes showed a high similarity to the relevant fish species on amino acid residues, respectively. Rm-ERalpha and Rm-ERbeta cDNAs included a serine-rich region when compared to other teleost fish ER genes. Tissue-specific expression of Rm-AR and Rm-ERbeta mRNAs in adult hermaphrodite R. marmoratus was high in the gonad, while Rm-ERalpha mRNA was high in the liver based on real-time RT-PCR. In addition, Rm-AR and Rm-ERalpha mRNAs increased along with developmental stage from stage 3 (5 dpf) to hatching, while Rm-ERbeta mRNA increased from stage 2 (2 dpf). To uncover the effect of estrogenic chemicals on R. marmoratus, we exposed the fish to NP (300 microg/l) and BisA (600 microg/l) for 96 h. Significant down-regulation of Rm-AR, Rm-ERalpha, and Rm-ERbeta mRNA was observed in gonadal tissue after exposure to NP but not BisA. In the liver, there were gender differences in gene expression after EDC exposure. These results demonstrate that expression patterns of the Rm-AR, Rm-ERalpha, and Rm-ERbeta genes in the hermaphroditic fish, R. marmoratus, vary according to tissue and developmental stage as well as the specificity of environmental estrogenic chemicals. These genes can be useful as molecular biomarkers in assessing the potential impact of estrogenic compounds using this species as a model system.

Amino Acid Sequence↗

PubMed2005

Partition of endocrine-disrupting chemicals between colloids and dissolved phase as determined by cross-flow ultrafiltration.

Cross-flow ultrafiltration (CFUF) was developed first for the isolation of natural colloids and subsequently for determining the partition of selected endocrine-disrupting chemicals (EDCs) between river colloids and dissolved phase. In this study, a 1-kDa Millipore Pellicon 2 cartridge type CFUF system was validated using a range of molecular probes spiked in natural waters. Results show that good retention (>80%) of high molecular weight (HMW, >1 kDa) molecules and low retention of low molecular weight (LMW, <1 kDa) molecules can be achieved at high concentration factor (cf) values in sampling mode or over long time scales in recirculation mode. The interactions between aquatic colloids and EDCs were studied by mixing EDCs, water, and colloids previously isolated by CFUF for a certain duration, followed by the separation of the target compounds between the truly dissolved and colloid-bound phases by CFUF and analysis by gas chromatography-mass spectrometry (GC-MS). The kinetics of EDCs binding to colloids were relatively rapid, reaching equilibrium within 5 min. The mass balance of chosen EDCs through CFUF system was fully investigated, with good recovery for the relatively polar EDCs such as estrone and 17beta-estradiol. On the basis of EDC sorption by colloids, the partition coefficient normalized to colloidal organic carbon content (Kcoc) was 8.85 x 10(3), 1.50 x 10(4), 8.85 x 10(3), 4.87 x 10(4), and 1.59 x 10(4) mL/g for bisphenol A, estrone, 17beta-estradiol, 17alpha-ethynylestradiol, and 16alpha-hydroxyestrone, respectively, which are comparable with the values reported in the literature. In addition, it has been shown that the Kcoc values of EDCs were relatively independent of their octanol-water partition coefficient (Kow) values, suggesting the important role of different binding mechanisms other than nonspecific hydrophobic interaction between EDCs and natural colloids. As the CFUF-GC-MS method can be used to quantify very low concentration of pollutants and is not limited to fluorescent compounds, it has the potential to be a widely applicable separation/analytical tool for determining the partition of organic pollutants between colloidal materials and dissolved phase.

Adsorption↗

PubMed1998

Food contamination from epoxy resins and organosols used as can coatings: analysis by gradient NPLC.

Normal phase LC with gradient elution enabled the analysis of a broadened range of oligomers of BADGE (Bisphenol-A diglycidyl ether) and Novolak compounds in canned foods, such as sea foods in oil, meat products and soups. A major component released from Bisphenol-A resins was identified as the cyclo-(Bisphenol-A monoglycidyl ether) dimer and was commonly present in foods at concentrations of around 1 mg/kg. For the epoxy Novolaks, concentrations of the three- to six-ring compounds often far exceeded those of BFDGE (Bisphenol-F diglycidyl ether) and reached 20 mg/kg in foods. A two-step acylation is proposed for the detection of epoxy components.

Benzhydryl Compounds↗

PubMed1991

Drugs affecting triglycerides.

Nicotinic acid and clofibrate derivatives are the main triglyceride-metabolism-affecting drugs. Nicotinic acid and its derivatives block adipose tissue lipolysis thus reducing the FFA flux of free fatty acids to the liver and the synthesis of very-low-density lipoproteins (VLDL). VLDL removal rate is also enhanced. Disturbing side effects (mostly flushing) limit the use of this compound. Clofibrate and its derivatives decrease the synthesis of VLDL and increase their catabolism. Lipoprotein lipase activity as well as VLDL fractional catabolic rate are increased by fibrates. Triglyceride synthesis is also reduced.

Benzhydryl Compounds↗

PubMed1978

Dose-related effects of non-steroidal antioestrogens nad oestrogens on the measurement of cytoplasmic oestrogen receptors in the rat and mouse uterus.

The dose-related effects of non-steroidal antioestrogens and oestrogens on the measurement of cytoplasmic oestrogen receptors in the rat uterus have been determined. The simultaneous administration of tamoxifen or monohydroxytamoxifen and oestradiol on three consecutive days resulted in dose-dependent decreases in both the wet weight of the uterus and the number of available cytoplasmic oestrogen receptors. The oestrogenic triphenylethylenes ICI 47 699 and ICI 3188 both produced dose-dependent decreases in the number of available cytoplasmic oestrogen receptors. Increasing doses of ICI 47 699 resulted in increasing concentrations of oestrogen receptors within the nucleus. The effects of tamoxifen and oestradiol-17 beta were compared in the ovariectomized mouse; replenishment of uterine oestrogen receptors was less evident in tamoxifen-treated animals than in animals receiving oestradiol, although increases in uterine weight were similar. A single large dose of tamoxifen (50 microgram) produced a prolonged depletion of cytoplasmic oestrogen receptors whilst stimulating rises in uterine weight and DNA and protein content. The results demonstrate that the depletion of the uterine cytoplasmic oestrogen receptor pool is a function of the dose administered for any compound with the ability to translocate oestrogen receptors to the nucleus and as such is not an exclusive characteristic of non-steroidal antioestrogens.

Animals↗

PubMed1987

Mechanical properties and biocompatibility of two polyepoxy matrices: DGEBA-DDM and DGEBA-IPD.

The aim of this paper was to study the biocompatibility and mechanical properties of materials for orthopaedic and odontologic surgical use. The products used were obtained by polycondensation of a diepoxy resin (DGEBA) with two curing agents (DDM or IPD). The materials present a slight swelling in liquid medium and their thermomechanical properties are hardly affected after 12 month implantation. The absence of molecular desorption in isotonic liquid and human serum confirms their hydrolytic stability and thus their inertia. These materials do not give rise to an intolerance reaction by neighbouring tissues during implantation time (1 d to 12 month).

Aniline Compounds↗

PubMed2001

Mechanisms of blockade by the novel migraine prophylactic agent, dotarizine, of various brain and peripheral vessel contractility.

The novel antimigraineur, dotarizine, inhibited 5-HT (5 hydroxytryptamine)-evoked contractions of rabbit vertebral, aorta, femoral and mesenteric arteries, with IC(50)s of 1.35, 1.40, 0.52 and 1.09 microM, respectively. Flunarizine had little effect on these contractions, while ketanserin was more potent (IC(50)s of 0.17 microM for vertebral, 0.22 microM for aorta, 0.05 microM for femoral and 0.03 microM for mesenteric arteries). At 10 microM, dotarizine caused 40% blockade of K(+)-evoked contractions of rabbit aorta, and 70% inhibition of 5-HT-evoked responses; these values were 30% and 20% for 10 microM flunarizine. Contractions of rabbit aorta elicited by noradrenaline, angiotensin II or prostaglandin F(2alpha) were not affected by 10 microM dotarizine or flunarizine. Ketanserin shifted to the right, in parallel, the concentration-response curves for 5-HT in rabbit aorta; however, dotarizine caused a non-competitive type of blockade, increasing the maximum 5-HT contraction at 30 nM and decreasing it at 3 and 30 microM. K(+)-evoked contractions of rabbit aorta were halved by 3 microM dotarizine in a voltage-independent manner; flunarizine caused a delayed-type, non-reversible post-drug blockade, and exhibited some voltage-dependence. Blockade by nifedipine was voltage-dependent and fully reversible. Ca(2+)-evoked contractions of depolarised bovine middle cerebral arteries were blocked by 1--3 microM dotarizine in a non-surmountable manner. Contraction of these vessels evoked by electrical stimulation was blocked 50% and 70% by 1 and 3 microM dotarizine, respectively. Dotarizine (1--3 microM) also inhibited to a similar extent the K(+)-evoked [(3)H]noradrenaline release from cultured rat sympathetic neurones. These data suggest that the mechanism of blockade by dotarizine of cerebral vessels contractility has three components: (i) presynaptic inhibition of noradrenaline release; (ii) blockade of postsynaptic vascular 5-HT receptors; (iii) blockade of Ca(2+)entry into the vascular smooth muscle cell cytosol. The compound does not affect the vascular receptors for noradrenaline, angiotensin II or prostaglandin F(2alpha).

Animals↗

PubMed2000

Genotoxicity of the coating lacquer on food cans, bisphenol A diglycidyl ether (BADGE), its hydrolysis products and a chlorohydrin of BADGE.

The epoxy resin bisphenol A diglycidyl ether (BADGE), its hydrolysis products and a chlorohydrin of BADGE (BADGE.2HCl), were examined for their genotoxicity in the micronucleus test (MNT) with human peripheral blood lymphocytes in vitro, in presence and in absence of an exogenous metabolizing system S9 rat liver. The treatment was done using different compound concentrations up to cytotoxic doses. The concentrations tested ranged between 12.5 to 62.5microg/ml of BADGE, 12.5 to 62.5microg/ml of first BADGE hydrolysis product (BADGE.H(2)O), 25.0 to 100.0microg/ml of second BADGE hydrolysis product (BADGE.2H(2)O) and 6.25 to 50.0microg/ml of BADGE.2HCl. These compounds are able to induce both cytotoxic and genotoxic effects, as revealed by the increases observed in cytokinesis block proliferation index (CBPI) and in micronuclei (MN) frequencies, respectively.

Animals↗

PubMed2003

Glutathione depletion exacerbates methylenedianiline toxicity to biliary epithelial cells and hepatocytes in rats.

Methylenedianiline (DAPM) initially injures epithelial cells of major bile ducts, which is followed by cholestasis, cholangitis, and hepatocellular damage. This pattern of biliary injury resembles that produced by alpha-naphthylisothiocyanate (ANIT), a classic bile duct toxicant. Our goal was to determine whether prior depletion of hepatic total glutathione (GSx), a condition reported to protect against biliary tract injury by ANIT, would also protect against DAPM-induced bile duct injury. A new protocol for extensive, sustained depletion of GSx was established. We found that administration of 1-bromoheptane followed 1 h later by buthionine sulfoximine resulted in an approximately 96% depletion of hepatic GSx that persisted through 6 h without biochemical or morphological signs of hepatic injury. Treatment of rats with a minimally hepatotoxic dose of DAPM (without GSx depletion) produced at 6 h injury similar to previous studies: moderate oncosis of biliary epithelial cells (BEC), mild edema of portal triads, and increases in glutathione S-transferase (GST) activities without alterations in hepatic GSx/glutathione disulfide (GSSG), coenzyme A (CoASH)/coenzyme A-glutathione disulfide (CoASSG), or thiobarbituric acid-reactive substances (TBARS). In contrast, DAPM treatment of GSx-depleted rats produced severe oncosis of BEC, marked inflammatory and edematous alterations to portal tracts, and oncosis/apoptosis in scattered hepatocytes. The observed acceleration and enhancement of DAPM-induced liver injury by GSx depletion was associated with a concurrent sevenfold increase in hepatic CoASSG and a fourfold decrease in the ratio of CoASH to CoASSG, compounds presumably localized to mitochondria and a purported index of mitochondrial thiol/disulfide status. These results indicate that: (1) GSx depletion exacerbates BEC and hepatocellular injury induced by DAPM, and (2) the mechanism by which DAPM causes liver injury is likely different from that of the classic bile duct toxicant, ANIT.

Allergens↗

PubMed2004

Synthetic small-molecule complement inhibitors.

During the past few years, several large molecular-weight compounds with complement-inhibitory activities have entered clinical trials for a wide variety of acute and chronic inflammatory conditions. Various small synthetic compounds that offer several advantages over the larger complement inhibitors are also being discovered at a rapid pace. In this review, the focus will be on three of these small molecules, a C3-binding peptide, compstatin; a synthetic peptidic antagonist of the C5a anaphylatoxin receptor, 3D53; and a non-peptidergic antagonist of the C3a anaphylatoxin receptor, SB-290157. In recent years, compstatin has undergone a series of optimizations that have led to more active and stable analogs, while 3D53 and SB-290157 have been more extensively tested in animal models of various human inflammatory diseases. These compounds have been shown to be effective and display little or no toxicity, and as such may be promising new candidates for further therapeutic development.

Animals↗

PubMed1994

Simultaneous determination of modafinil and its acid metabolite by high-performance liquid chromatography in human plasma.

A sensitive and selective high-performance liquid chromatographic (HPLC) method for the simultaneous quantitation of modafinil and its acid metabolite in human plasma has been developed. The method is based on a liquid-liquid extraction followed by isocratic reversed-phase HPLC with ultraviolet absorbance detection at 236 nm. The eluent used was acetonitrile-water-acetic acid (150:420:12, v/v/v). The run time was 45 in. The method provided a detection limit of 0.04 mg/l for modafinil and the acid metabolite, a quantitation limit of 0.13 mg/l for modafinil and 0.14 mg/l for the acid metabolite. A good linear relationship was obtained in the concentration range studied (0.1-20 mg/l) for both compounds and the method was sufficiently accurate and precise to support clinical pharmacokinetic studies. To our knowledge this is the first described method for determination of modafinil and its acid metabolite in plasma.

Benzhydryl Compounds↗

PubMed2005

Albumin prevents mitochondrial depolarization and apoptosis elicited by endoplasmic reticulum calcium depletion of neuroblastoma cells.

Serum albumin protects against cell death elicited by various cytotoxic agents; however, conflicting views on the protective mechanism still remain. Hence, we have studied the ability of serum albumin to prevent apoptosis of human neuroblastoma SH-SY 5 Y cells elicited by four compounds known to release Ca(2+) from the endoplasmic reticulum, i.e. dotarizine, flunarizine, thapsigargin and cyclopiazonic acid. Spontaneous basal apoptosis, after 24 h incubation in Dulbecco's Modified Eagle Medium (DMEM) containing 10% serum, was 5%. Dotarizine (30--50 microM) enhanced basal apoptosis to 18--43%, flunarizine (30--50 microM) to 15%, thapsigargin (1--10 microM) to 21--35%, and cyclopiazonic acid (100 microM) to 10%. Serum deprivation augmented basal apoptosis to 20%. Under serum-free medium, 30 microM dotarizine or flunarizine drastically enhanced apoptosis to 63% and 68%, respectively; the increase was milder with 1 microM thapsigargin (37%) and 30 microM cyclopiazonic acid (27%). In serum-free medium, albumin (29 or 49 mg/ml) fully prevented the apoptotic effects of dotarizine, flunarizine and cyclopiazonic acid. The four compounds increased the cytosolic Ca(2+) concentration ([Ca(2+)](c)) in fluo-4 loaded cells; such increase developed slowly to reach a plateau after several minutes, followed by a slow decline. Albumin did not modify the kinetic parameters of such increase. In the absence of serum, dotarizine, flunarizine, thapsigargin, and cyclopiazonic acid caused mitochondrial depolarization in tetramethylrhodamine ethyl ester (TMRE)-loaded cells; depolarization was inhibited by cytoprotective concentrations of albumin. These results suggest that albumin protects cells from entering into apoptosis by preventing mitochondrial depolarization. They also suggest that inhibition of mitochondrial depolarization might become a target to develop new anti-apoptotic compounds with therapeutic neuroprotective potential in stroke, Alzheimer's disease, and other neurodegenerative diseases.

Apoptosis↗