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PubMed1984

Polycystic ovarian condition in estradiol valerate-treated rats: spontaneous changes in characteristic endocrine features.

A chronic anovulatory polycystic ovarian (PCO) condition can be induced in rats with estradiol valerate (EV). We have previously shown that the early stages (8-10 wk after EV treatment) of the condition are characterized by low basal plasma luteinizing hormone (LH) and estradiol concentrations, as well as poor LH responsiveness to LH-releasing hormone (LHRH). These observations suggested that alterations in pituitary LH secretory activity may be involved in induction and maintenance of the PCO condition. In order to examine this possibility we have measured basal plasma LH and follicle-stimulating hormone (FSH) concentrations at various times (6, 15, 20 and 22 wk) after treatment with EV. AT 22 wk animals were subjected to a double LHRH pulse or equivalent treatment with saline. Basal plasma LH concentrations in EV-treated animals doubled between 6 and 22 wk. Despite this sharp increase, basal plasma LH concentrations at 22 wk were still significantly lower in EV-treated animals compared to proestrous controls. Basal FSH in EV-treated animals, remained in the proestrous range throughout the 22-wk period. Pituitary FSH and LH secretions in response to the LHRH challenge were significantly greater in EV-treated animals compared to proestrous controls. Plasma estradiol was significantly greater at 22 wk post-EV treatment than at 9 wk and this difference was reflected in the histology of the endometrium. These results indicate that a PCO condition is compatible with radical alterations in basal LH, and responsiveness to LHRH. Thus, aberrations in the ability to secrete LH do not appear to be causal in maintaining the condition.

Animals↗
PubMed1986

Development of the polycystic ovarian condition (PCO) in the estradiol valerate-treated rat.

A wide range of experimental manipulations results in an anovulatory polycystic ovarian (PCO) condition in the rat. Although PCO has been studied in a number of these models, research has centered on the condition after it is well established rather than as it develops. Consequently, it is still not clear exactly what follicular cysts are or how and why they form. Therefore, we studied the development of PCO in rats treated with estradiol-valerate (EV). In this model, definitive cysts were present 8-9 wk after a single injection of EV. Animals were killed at 5, 11, 16, 21, 28 and 56 days after EV treatment. Serum was assayed for luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Ovaries were weighed and prepared for histologic examination. The ovaries were serially sectioned such that the number and size distribution of normal and atretic follicles could be assessed quantitatively. Oviducts were examined for the presence of ova. Immediately after EV treatment, ovulatory cycles ceased; by 16-20 days posttreatment, all animals exhibited persistent vaginal cornification. Basal concentrations of serum LH and FSH fell to a nadir at 11 days posttreatment, after which both gonadotropins exhibited a trend toward recovery. Within the first 28 days after treatment, ovarian weights declined significantly as did the total number of healthy follicles. Atretic follicles of all sizes were particularly numerous at 16 days. By 28 days, the decline in the number of healthy follicles reached a plateau. Numerous atretic, large secondary follicles were particularly prominent on the background of the decreasing number of normal follicles.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

An intractable, ovary-independent impairment in hypothalamo-pituitary function in the estradiol-valerate-induced polycystic ovarian condition in the rat.

A single injection of estradiol valerate (EV) produces anovulatory acyclicity and polycystic ovaries (PCO) in the rat. Basal serum luteinizing hormone (LH) concentrations are attenuated whereas serum follicle stimulating-hormone (FSH) concentrations are in the high normal range in these animals. Subsequent unilateral ovariectomy restores ovulatory cycles and normal histology in the remaining ovary without correcting the aberrant basal serum gonadotropin concentrations. This suggests that although the blocked surge mechanism is correctable, a second relatively intractable, ovary-independent impairment compromises basal gonadotropin production. To identify and characterize this second component, we have examined hypothalamic-pituitary function in PCO rats after bilateral ovariectomy. Adult (200-250 g), normal cyclic Wistar rats were injected with 2 mg EV or with vehicle (control). Nine weeks later all animals were ovariectomized and PCO was confirmed in the EV-treated animals. Animals were killed at 0, 2, 7, 14, and 28 days after ovariectomy, and hypothalamic content of luteinizing hormone-releasing hormone (LHRH) and pituitary and serum concentrations of LH and FSH were measured. LH and FSH responses to exogenous LHRH were assessed. Serum progesterone, testosterone, and estradiol concentrations were determined at 28 days. Hypothalamic LHRH decreased significantly in all animals over the 28-day period. Although LHRH values did not differ at Time 0, by 28 days there was significantly less LHRH in the hypothalami of control than in PCO rats. This pattern of depletion was mirrored by corresponding reciprocal patterns of increasing serum gonadotropin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Hypothalamic changes in norepinephrine release in rats with estradiol valerate-induced polycystic ovaries.

Chronic anovulation and polycystic ovaries (PCO) can be induced by a single i.m. injection of estradiol valerate (EV, 2 mg in oil) in the rat. Constant exposure to high plasma levels of estradiol provokes a neurotoxic effect on the hypothalamic neurons, including those from the arcuate nucleus. Because of the important participation of hypothalamic norepinephrine (NE) in the regulation of GnRH release and the possible noxious effect of prolonged exposure of these neurons to estradiol, our interest was to study the activity of the noradrenergic neurons innervating the hypothalamus. We analyzed the biosynthesis, content, and release of NE from the noradrenergic nerve terminals of the hypothalamus during the PCO condition. We found a decrease in tyrosine hydroxylase (TH) activity and in the content of dopamine (DA) in the anterior hypothalamus after 2 mo of EV injection, whereas dopamine-beta-hydroxylase (D beta H) was increased without changes in NE content. No variations in TH activity or in DA and NE contents in the medial hypothalamus were observed, but a decrease in D beta H activity was evident. After 2 mo of EV administration, an increase in the electrically induced release of NE from anterior hypothalamic blocks incubated in vitro was detected; this effect was not evidenced in the medial hypothalamus. After 5 mo of EV administration, release of NE increased in anterior hypothalamic blocks but decreased in medial hypothalamic tissue. The inhibitory effect of morphine on NE release found in control animals was increased in the hypothalamus from PCO rats, suggesting an increased number of mu-opioid binding sites in noradrenergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Endometrial development and adenogenesis in the neonatal pig: effects of estradiol valerate and the antiestrogen ICI 182,780.

In the pig, appearance of endometrial glands between birth (postnatal day [PND] 0) and PND 14 involves development of estrogen receptor-alpha-positive (ER+) phenotype by, and increased DNA synthesis in, nascent glandular epithelium (GE). To determine whether ER activation is required for this process, gilts were treated daily with either vehicle, the antiestrogen ICI 182,780 (ICI), estradiol-17beta valerate (EV), or both ICI and EV. Treatments began on PND 0, before onset of adenogenesis, or on PND 7, after onset of gland proliferation. Uteri obtained on PNDs 7 and 14 (study one) or on PND 14 (study two) were weighed; uterine histology was evaluated; DNA synthesis in luminal epithelium and GE was characterized by determining 5-bromo-2'-deoxyuridine (BrdU) labeling index; and patterns of ER mRNA expression were evaluated in situ (study one). Gland genesis was inhibited by ICI, which decreased gland penetration depth by PND 14 in study one, both endometrial thickness and BrdU-labeling index in GE in study two, and increased stromal cell compaction in both studies. Uterotropic effects of EV included increased gland development and epithelial BrdU labeling and decreased stromal compaction. These effects were inhibited by coadministration of ICI. Treatments did not alter ER mRNA expression, which remained limited to stroma and GE. Data indicate that endometrial maturation and adenogenesis in the neonatal pig require expression and activation of a functional ER system.

Aging↗
PubMed1994

P-glycoprotein overexpression in mouse cells does not correlate with resistance to N-benzyladriamycin-14-valerate (AD 198).

The novel anthracycline N-benzyladriamycin-14-valerate (AD 198) circumvents P-glycoprotein (P-gp)- and altered topoisomerase II-mediated drug resistance. Nevertheless, AD 198-resistant (AD 198R) murine J774.2 cells overexpressed P-gp, were cross-resistant to other drugs through reduced accumulation and were rendered sensitive by continuous exposure to verapamil. Intracellular AD 198 was, however, similar in sensitive and resistant cells. Consequently, the ability of P-gp to confer AD 198 resistance was examined. It was observed that (i) AD 198 resistance in AD 198R cells grown without drug for 15 months declined by 60% with only a 10-15% loss of vinblastine cross-resistance and P-gp expression; (ii) a cloned AD 198R P388 mouse leukemic cell line did not express P-gp; and (iii) verapamil did not attenuate resistance against high-dose, short-term exposure to AD 198. Therefore, AD 198 resistance appeared to be P-gp-independent despite P-gp overexpression. Antioxidant enzyme and topoisomerase II activities remained unchanged between sensitive and resistance cells. These results suggest that AD 198 resistance was conferred by a novel mechanism.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Activity of N-benzyl-adriamycin-14-valerate (AD198), a new anthracycline derivate, in multidrug resistant human ovarian and breast carcinoma cell lines.

The new lipophilic anthracycline N-benzyl-adriamycin-14-valerate (AD198) was evaluated for its activity in comparison to doxorubicin in P-glycoprotein (Pgp)-positive and -negative cell lines. AD198 and doxorubicin showed comparable antitumor activity in the Pgp-negative breast cancer cell line MCF-7 and the Pgp-negative ovarian carcinoma cell line A2780. By contrast, AD198 was significantly more active than doxorubicin in the Pgp-positive breast cancer cell line MCF7AD (IC50 values 2.5 and 0.15 microM for 96 h continuous exposure) and the Pgp-positive ovarian carcinoma cell line A2780 DX5 (IC50 values 0.6 and 0.07 microM, respectively). Unlike doxorubicin, the activity of AD198 was not increased by concommittant application of cyclosporin A in cell line MCF7AD. Flow cytometry studies showed that, in contrast to doxorubicin, AD198 was not transported by Pgp and that verapamil did not change the intracellular pharmacokinetics of this new anthracycline. These data provide evidence that AD198 possesses high activity in human solid tumor cell lines expressing the classical multidrug resistant phenotype. Its further clinical development appears to be warranted.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

N-benzyladriamycin-14-valerate (AD 198) activates protein kinase C-delta holoenzyme to trigger mitochondrial depolarization and cytochrome c release independently of permeability transition pore opening and Ca2+ influx.

Unlike nuclear-targeted anthracyclines, the extranuclear-targeted doxorubicin congener, N-benzyladriamycin-14-valerate (AD 198), does not interfere with normal topoisomerase II activity, but binds to the C1b regulatory domain of conventional and novel isoforms of protein kinase C (PKC). The resulting interaction leads to enzyme activation and rapid apoptosis in a variety of mammalian cell lines through a pathway involving mitochondrial events such as membrane depolarization (Deltapsim) and cytochrome c release. Unlike other triggers of apoptosis, AD 198-mediated apoptosis is unimpeded by the expression of Bcl-2 and Bcl-XL. We have further examined AD 198-induced apoptosis in 32D.3 mouse myeloid cells to determine how the anti-apoptotic effects of Bcl-2 are circumvented. The PKC-delta inhibitor, rottlerin, and transfection with a transdominant-negative PKC-delta expression vector both inhibit AD 198 cytotoxicity through inhibition of Deltapsim and cytochrome c release. While the pan-caspase inhibitor Z-VAD-FMK blocks AD 198-induced PKC-delta cleavage, however, it does not inhibit Deltapsim and cytochrome c release, indicating that AD 198 induces PKC-delta holoenzyme activation to achieve apoptotic mitochondrial effects. AD 198-mediated Deltapsim and cytochrome c release are also unaffected by cellular treatment with either the mitochondrial permeability transition pore complex (PTPC) inhibitor cyclosporin A or the Ca chelators EGTA and BAPTA-AM. These results suggest that AD 198 activates PKC-delta holoenzyme, resulting in Deltapsim and cytochrome c release through a mechanism that is independent of both PTPC activation and Ca flux across the mitochondria. PTPC-independent mitochondrial activation by AD 198 is consistent with the inability of Bcl-2 and Bcl-XL expression to block AD 198-induced apoptosis.

Amino Acid Chloromethyl Ketones↗
PubMed2004

A comparative pharmacokinetic study of micronized estradiol valerate administered alone and in combination with medroxyprogesterone acetate in postmenopausal women.

The objective of this study was to evaluate a possible pharmacokinetic interaction between 17beta-estradiol (E2) and medroxyprogesterone (MP) when administered together in a combined tablet because both hormones have common metabolic routes of biotransformation. The study assessed the mean pharmacokinetics parameters of E2 found after 1-dose administration of 2 different tablets containing E2, 1 containing 2 mg of micronized 17beta-estradiol valerate (E2V) and the other, administered after 2 weeks, 2 mg of E2V in combination with 5 mg of medroxyprogesterone acetate (MPA). The subjects were 15 healthy postmenopausal women with normal laboratory and clinic tests. The study was randomized, double blind, crossover, with 2 periods and 2 sequences. The blood samples were obtained at 0, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after each administration. The E2 serum concentrations were determined by electrochemoluminiscence assay. From these data, the following pharmacokinetic parameters were calculated for E2 alone and E2 in combination with MPA (E2V/MPA): Cmax = 104.89 +/- 26.96, 103.27 +/- 44.40; AUC0-24 =1900.30 +/- 392.23, 1783.70 +/- 756.39; AUC0-infinity = 5576.06 +/- 4065.87, 5317.89 +/- 3702.54; ka = 1.06 +/- 0.31, 1.09 +/- 0.13; t1/2 = 35.65 +/- 20.62, 36.12 +/- 18.04; MRT = 16.29 +/- 8.77, 16.27 +/- 4.88; V/F = 16.29 +/- 8.76, 16.27 +/- 4.88. No significant differences between the pharmacokinetic parameters of E2 and E2/MPA were found, which led us to conclude that there is no pharmacokinetic interaction.

Area Under Curve↗
PubMed2000

Combined oral oestradiol valerate-norethisterone treatment over three years in postmenopausal women: correlation between oestrogen levels and bone mineral density sites.

OBJECTIVE: To compare trabecular and compact bone response and relationship to oestrogen status using continuous oestradiol valerate 2 mg and norethisterone 0.7 mg daily as hormone replacement and to determine the therapeutic range of 17 beta-oestradiol. DESIGN: Open label trial. SETTING: Independent endocrine clinic SAMPLE: One hundred and thirty-one patients were compared at point of entry and at 36 months. METHODS: Postmenopausal women were assessed using a Lunar dual photon and single photon bone scanner, and bone mineral density of the lumbar spine, right hip and left forearm were annually correlated with 17 beta-oestradiol and oestrone levels over three years. Total alkaline phosphatase was compared between improvers and decliners of bone mineral density. RESULTS: Significant improvement in bone mineral density (P < 0.0001) occurred at all sites except the left forearm, where bone loss was prevented. There was no correlation between oestrogen levels and bone mineral density improvements at hip sites. However, in the lumbar spine larger improvements in bone mineral density occurred in women with 17 beta-oestradiol levels > 185 pmol/L compared with those below, which were statistically significant for those with 17 beta-oestradiol levels > 248 pmol/L. Bone turnover, as quanitifed by total alkaline phosphatase measurements, was suppressed in most patients, but there were no differences in the mean alkaline phosphatase levels between the best improvers and worst decliners for lumbar spine bone mineral density. Improvers had an age mean of 5.21 years greater than decliners (P = 0.01) and a mean duration difference since the menopause of 5 1 years compared with decliners (P = 0.007). CONCLUSION: This combined continuous preparation of hormone replacement therapy improves not only trabecular bone but prevents compact bone loss, and the data suggest that the therapeutic range of 17 beta-oestradiol is between 200 pmol/L and 350 pmol/L.

Administration, Oral↗
PubMed1978

The effect of oestradiol valerate therapy on coagulation factors and lipid and oestrogen levels in oöphorectomised women.

The effect of oestradiol valerate on levels of blood cholesterol, triglycerides, free oestradiol and coagulation factors, as well as on urinary oestrogens and free cortisol was measured in 10 oöphorectomised women. Despite the very high urinary oestrogen levles obtained, there was no significant change found in the other parameters during and after treatment. These findings are discussed, as is the significance of the metabolism of both endogenously produced and orally administered oestrogens in the menopausal woman.

Adult↗
PubMed1989

Pharmacokinetic interpretation of toxicity tests in rats treated with oestradiol valerate in the diet.

Oestrogen concentrations (oestradiol = E2 and oestriol = E3) were determined in plasma and liver tissue of female rats before, during and after treatment with two different doses (1.2 and 12.0 mg/kg/d) of oestradiol valerate (E2-val) given in the feed over 27 days. The oral bioavailability of E2 was determined in a pharmacokinetic study in which rats received a single intramuscular administration of E2-val. The aim of the present investigation was to support the evaluation of the results of a previous 90 weeks chronic toxicity and tumorigenicity study in rats where the same dosages were administered. The bioavailability was approximately 0.5%; the systemic body burden of exogenous E2 was 1.6 fold, the endogenous E2 burden at the low, and 9 fold at the high dose. Despite these low values, distinct systemic effects were noted. At 1.2 mg/kg/d a marked decrease in food consumption and body weight gain occurred in the 27 day study as well as in the chronic study. In addition, in the latter study mortality increased from the low dose onwards and was complete at the high dose after 72 weeks. The incidence of pituitary adenoma increased. The results indicate that theoretically rats are far more sensitive towards exogenous oestradiol treatment than humans.

Animals↗
PubMed1992

Transport of the anti-varicella-zoster virus agent 6-methoxypurine arabinoside and its 2'-O-valerate prodrug into human erythrocytes.

The transport of the anti-varicella-zoster virus agent 6-methoxypurine arabinoside and its 2'-O-valerate prodrug, 170U88, was investigated by using the human erythrocyte model. The influx of 6-methoxypurine arabinoside was found to occur primarily by means of the nucleoside transporter. (i) Influx was nonconcentrative and saturable (Km = 106 +/- 2 microM). (ii) The inhibitors of nucleoside transport, nitrobenzylthionosine, dipyridamole, and dilazep, inhibited the influx of 10 microM 6-methoxypurine arabinoside by greater than 94%. (iii) Influx was inhibited by nucleosides but not by nucleobases. (iv) 6-Methoxypurine arabinoside was a competitive inhibitor (Ki = 129 +/- 10 microM) of adenosine influx, and adenosine (Km = 160 +/- 9 microM) was found to be a competitive inhibitor (Ki = 134 +/- 9 microM) of 6-methoxypurine arabinoside influx. By contrast, the influx of 170U88 occurred by means of nonfacilitated diffusion. (i) Influx was linearly dependent on the 170U88 concentration. (ii) Influx was not inhibited by nucleobases, nucleosides, or inhibitors of nucleoside transport.

Antiviral Agents↗
PubMed1980

N-trifluoroacetyladriamycin-14-valerate and adriamycin induced DNA damage in the RPMI-6410 human lymphoblastoid cell line.

The adriamycin- and N-trifluoroacetyladriamycin-14-valerate (AD-32) induced DNA cross-linking and breakage in human RPMI-6410 cells was compared using the alkaline elution technique of Kohn and co-workers. At comparable growth-inhibitory concentrations both adriamycin and AD-32 caused DNA cross-linking. Treatment with proteinase-K showed this cross-linking to be mainly DNA-protein in character. Proteinase-K treatment also revealed that both drugs caused either single-strand DNA breaks or increased alkaline sensitivity. With adriamycin the degree of cross-linking and breakage was dose related over the range studied (0.05 - 0.4 micron/mL), whereas with AD-32 there appeared to be a saturation of both effects at concentrations in excess of 3 micron/mL. With both drugs the extent of cross-linking and breakage was maximal at the end of the drug exposure. This work suggests that AD-32 or some metabolite of its binds to DNA and this binding leads to DNA damage that is similar to that caused by adriamycin. These AD-32 results are somewhat surprising in light of earlier model studies showing that AD-32 does not bind to isolated DNA.

Cell Division↗
PubMed1990

Plasma gonadotropin patterns characterizing the development of polycystic ovaries in the estradiol valerate treated rat.

Polycystic ovaries (PCO) develop in female rats within 4 weeks of an injection of estradiol valerate (EV). The final morphological transition from a noncystic to a cystic state occurs in the presence of estrous (control) mean serum gonadotropin concentrations, suggesting that gonadotropin patterns rather than mean concentrations are causal to PCO. We have examined plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) patterns in female rats at estrus and on days 5, 11, 16, and 21 following EV treatment. Estrous animals displayed large amplitude LH pulses of short duration, interspersed among frequent, low amplitude pulses of similar duration, and infrequent, broad-based LH episodes. Following EV treatment, there was a progressive decline in the frequency and magnitude of the large amplitude LH pulses, such that by day 16, they ceased altogether. Conversely, the frequency of the low amplitude pulses increased such that the total pulse frequency remained constant. The onset of this pattern coincides with the wave of atresia that precedes the emergence of cystic follicles. The pulsatile plasma pattern of FSH seen at estrus remained unaltered at all time intervals examined after EV treatment. We conclude that there is a specific LH pattern responsible for the generation and maintenance of the PCO condition.

Animals↗
PubMed2005

N-benzyladriamycin-14-valerate (AD198) induces apoptosis through protein kinase C-delta-induced phosphorylation of phospholipid scramblase 3.

Phospholipid scramblase 3 (PLS3) is an enzyme that plays a critical role in mitochondrial morphology, functions, and apoptotic response. During apoptosis, activated protein kinase C-delta (PKC-delta) translocates to mitochondria and phosphorylates PLS3. Here, we utilize an extranuclear-targeted anthracycline N-benzyladriamycin-14-valerate (AD198), a PKC-delta activator, to investigate the mechanism of PLS3 phosphorylation by PKC-delta. Overexpression of PLS3 enhanced, whereas down-regulation of PLS3 by small interfering RNA decreased, the sensitivity of AD198-induced apoptosis. Overexpression of PKC-delta, but not the kinase-defective PKC-delta, and AD198 treatment enhanced threonine phosphorylation of PLS3. The phosphorylated threonine was mapped to Thr21 of PLS3. Mutation of Thr21 to alanine did not affect mitochondrial localization of PLS3 but abolished threonine phosphorylation by PKC-delta in vitro and AD198-induced PLS3 phosphorylation in vivo. Expression of PLS3(T21A) in cells could not enhance AD198-induced apoptosis compared with expression of the wild-type PLS3. Using benzyloxycarbonyl-Val-Ala-Asp-(OMe) fluoromethyl ketone and cyclosporine A, we also showed that AD198-induced PLS3 phosphorylation occurs upstream of caspase activation and independent of mitochondrial permeability transition. These studies establish that AD198-activated PKC-delta induces phosphorylation of mitochondrial PLS3 at Thr21 and that PLS3 is a critical downstream effector of PKC-delta in AD198-induced apoptosis.

Antibiotics, Antineoplastic↗
PubMed1993

Does salicylic acid increase the percutaneous absorption of diflucortolone-21-valerate?

The percutaneous absorption of diflucortolone-21-valerate (DFV) and its effect on the pituitary adrenal system were investigated during large skin area treatment (20 g ointment twice a day for 8 days) of two groups of healthy volunteers with Nerisona and Nerisalic ointment, respectively. Plasma levels of diflucortolone, cortisol and dehydroepiandrosterone (DHEA) were measured in both groups whereas plasma levels of salicylic acid were measured additionally in volunteers treated with Nerisalic. No differences, neither in percutaneous absorption of DFV nor in effects on cortisol and DHEA were found between the two treatment groups. There was a slight reduction in cortisol levels under both treatments, but the circadian rhythm was not disturbed. Mean salicylic acid plasma levels under high-dose topical Nerisalic treatment were about 50-fold below levels where toxicity may be expected.

Adult↗
PubMed2005

Protective effect of alpha-keto-beta-methyl-n-valeric acid on BV-2 microglia under hypoxia or oxidative stress.

The alpha-ketoglutarate dehydrogenase complex (KGDHC) is a mitochondrial enzyme in the TCA cycle. Inhibition of KGDHC activity by alpha-keto-beta-methyl-n-valeric acid (KMV) is associated with neuron death. However, the effect of KMV in microglia is unclear. Therefore, we investigated the effect of KMV on BV-2 microglial cells exposed to hypoxia or oxidative stress. The results showed that KMV (1-20 mM) enhanced the cell viability under hypoxia. KMV dose-dependently reduced ROS and LDH releases from hypoxic BV-2 cells. KMV also reduced ROS production and enhanced the cell viability under H2O2 but failed to reduce the SIN-1 and sodium nitroprusside (SNP) toxicity. KMV also reduced caspase-3 and -9 activation under stress. These results suggest that KMV protects BV-2 cells from stress and acts by reducing ROS production through inhibition of KDGHC.

Apoptosis↗