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Epilepsia 2004Development and sex hormones are important determinants of seizure susceptibility. Seizures develop in the immature brain more readily than in the mature brain. Male... (Comparative Study)
Comparative Study
PURPOSE
Development and sex hormones are important determinants of seizure susceptibility. Seizures develop in the immature brain more readily than in the mature brain. Male children experience a higher incidence of epilepsy or unprovoked seizures than do female children. Sex-specific differences in the development of seizure-suppressing neuronal networks may account, at least in part, for this increased age- and sex-related susceptibility to seizures. The control of seizures can be influenced by the substantia nigra pars reticulata (SNR) in an age- and sex-specific manner. In the adult male rat SNR, two topographically discrete regions (SNRanterior and SNRposterior) mediate distinct effects on seizures, by using divergent output networks in response to localized infusions of gamma-aminobutyric acid (GABA)A agents, such as muscimol. The GABAA-sensitive "anticonvulsant" region is located in the SNRanterior, whereas the GABAA-sensitive "proconvulsant region is in the SNRposterior. In immature postnatal day (PN)15-21 male rats, the SNR is not topographically segregated, and GABAAergic drug infusions produce similar effects when applied in the SNRanterior or SNRposterior. Only a GABAA-sensitive proconvulsant network is evident. By contrast, female SNR does not contain any region that mediates muscimol-related proconvulsant effects. As with the adult, immature female rats do not develop a proconvulsant SNR region at any age.
METHODS
We measured the effects of SNR muscimol infusions on seizures in male rats castrated at birth to better understand the effects of testosterone on the formation of age- and sex-specific features of the SNR.
RESULTS
Neonatal castration permanently alters the maturation of the muscimol-sensitive SNR effect on seizures. The SNR of neonatally castrated rats develops functionally like the "female" SNR. The "proconvulsant" SNR region does not develop in the absence of testosterone in the immediate postnatal period. The "male" type of SNR effects can be induced in neonatally castrated rats by restoration of testosterone levels or in female rats by artificially increasing testosterone levels. Dihydrotestosterone and estrogen, produced by the reduction and aromatization of testosterone, respectively, are the direct mediators of testosterone actions. At PN0, only beta estrogen receptors are equally expressed in the SNRs of males and females and may be responsible for testosterone-mediated effects in both sexes.
CONCLUSIONS
The phenotype of SNR GABAergic neurons, as characterized by GABAA-receptor subunit composition, by muscimol-induced electrophysiologic responses, and by connectivity of output networks each may be altered by the presence of testosterone. Higher KCC2 messenger RNA (mRNA) expression in female PN15 SNR neurons compared with males may be responsible for sex-related differences in muscimol-induced electrophysiologic responses. In summary, a growing body of compelling evidence identifying sex-related differences in the SNR implicates postnatal testosterone as a critical factor in the development of pro- or anticonvulsant circuits. The recognition of sex- and age-related features in the SNR holds the promise that these findings can be translated into the development of specific and effective treatments for seizure disorders.
Topics: Age Factors; Anethole Trithione; Animals; Animals, Newborn; Anticonvulsants; Brain; Convulsants; Female; Gonadal Steroid Hormones; Humans; Male; Rats; Receptors, GABA-A; Seizures; Sex Factors; Substantia Nigra; Testosterone
PubMed: 15610187
DOI: 10.1111/j.0013-9580.2004.458002.x -
Nitric Oxide : Biology and Chemistry Apr 2015H2S donor molecules have the potential to be viable therapeutic agents. The aim of this current study was (i) to investigate the effects of a novel triphenylphosphonium...
Effects of AP39, a novel triphenylphosphonium derivatised anethole dithiolethione hydrogen sulfide donor, on rat haemodynamic parameters and chloride and calcium Cav3 and RyR2 channels.
H2S donor molecules have the potential to be viable therapeutic agents. The aim of this current study was (i) to investigate the effects of a novel triphenylphosphonium derivatised dithiolethione (AP39), in the presence and absence of reduced nitric oxide bioavailability and (ii) to determine the effects of AP39 on myocardial membrane channels; CaV3, RyR2 and Cl(-). Normotensive, L-NAME- or phenylephrine-treated rats were administered Na2S, AP39 or control compounds (AP219 and ADT-OH) (0.25-1 µmol kg(-1)i.v.) and haemodynamic parameters measured. The involvement of membrane channels T-type Ca(2+) channels CaV3.1, CaV3.2 and CaV3.3 as well as Ca(2+) ryanodine (RyR2) and Cl(-) single channels derived from rat heart sarcoplasmic reticulum were also investigated. In anaesthetised Wistar rats, AP39 (0.25-1 µmol kg(-1) i.v) transiently decreased blood pressure, heart rate and pulse wave velocity, whereas AP219 and ADT-OH and Na2S had no significant effect. In L-NAME treated rats, AP39 significantly lowered systolic blood pressure for a prolonged period, decreased heart rate and arterial stiffness. In electrophysiological studies, AP39 significantly inhibited Ca(2+) current through all three CaV3 channels. AP39 decreased RyR2 channels activity and increased conductance and mean open time of Cl(-) channels. This study suggests that AP39 may offer a novel therapeutic opportunity in conditions whereby (•)NO and H2S bioavailability are deficient such as hypertension, and that CaV3, RyR2 and Cl(-) cardiac membrane channels might be involved in its biological actions.
Topics: Anethole Trithione; Animals; Blood Pressure; Caveolin 3; Hydrogen Sulfide; NG-Nitroarginine Methyl Ester; Organophosphorus Compounds; Phenylephrine; Pulse Wave Analysis; Rats; Rats, Wistar; Ryanodine Receptor Calcium Release Channel
PubMed: 25555533
DOI: 10.1016/j.niox.2014.12.012 -
Biochemical Pharmacology Jul 1998The protective effects of anethole dithiolethione (ADT) against H2O2- or 4-hydroxynonenal (HNE)-induced cytotoxicity in human Jurkat T cells were investigated. Jurkat T...
The protective effects of anethole dithiolethione (ADT) against H2O2- or 4-hydroxynonenal (HNE)-induced cytotoxicity in human Jurkat T cells were investigated. Jurkat T cells were pretreated with ADT (10-50 microM) for 18 hr and then challenged with H202 or HNE for up to 4 hr. Cytotoxicity was assessed by measuring: 1) leakage of lactate dehydrogenase from cells to medium; and 2) exclusion of the DNA intercalating fluorescent probe propidium iodide by viable cells. Pretreatment of cells with ADT (10 or 25 microM) for 18 hr significantly protected cells against H202- or HNE-induced cytotoxicity. Treatment of cells with ADT (10-50 microM) for 72 hr significantly increased the activities of catalase and glutathione reductase. The maximum effect of ADT treatment on the activity of these enzymes was observed when cells were treated with 25 microM of ADT for 72 hr. A significant increase in cellular GSH was observed in cells that were treated with ADT for 72 hr. Using monobromobimane as a thiol probe, we consistently observed that cells pretreated for 18 hr with ADT (25 or 50 microM) had also increased total thiol content. Exposure of Jurkat T cells to H202 or HNE resulted in a time-dependent decrease in cellular GSH. ADT (10-50 microM, 18 hr) pretreatment circumvented H202-dependent lowering of cellular GSH. In conclusion, ADT proved to be a potent cytoprotective thiol antioxidant with multifaceted mechanisms of action, suggesting that the drug has a remarkable therapeutic potential.
Topics: Anethole Trithione; Cell Survival; Chromatography, High Pressure Liquid; Culture Media; Electrochemistry; Glutathione; Humans; Hydrogen Peroxide; Jurkat Cells; Kinetics; Leukocyte Elastase; Oxidative Stress; Sulfhydryl Compounds
PubMed: 9698089
DOI: 10.1016/s0006-2952(98)00113-0 -
Journal of the National Cancer Institute Jul 2002Results from preclinical studies have suggested that the organosulfur compound anethole dithiolethione (ADT) may be an effective chemopreventive agent for lung cancer.... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
Results from preclinical studies have suggested that the organosulfur compound anethole dithiolethione (ADT) may be an effective chemopreventive agent for lung cancer. We conducted a phase IIb study to determine the effects of ADT in smokers with bronchial dysplasia.
METHODS
One hundred twelve current and former smokers with a smoking history of at least 30 pack-years and at least one site of bronchial dysplasia identified by an autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive placebo or ADT at 25 mg orally thrice daily for 6 months. Each subject then underwent a follow-up bronchoscopy-directed biopsy. We used changes in histopathologic grade and nuclear morphometry index (MI) as the primary and secondary end point biomarkers, respectively. Chi-square tests with continuity correction were used to compare response rates on a lesion- and person-specific basis between the two study groups. All statistical tests were two-sided.
RESULTS
One hundred one subjects had a follow-up bronchoscopy. In the lesion-specific analysis, progression rate of pre-existing dysplastic lesions by two or more grades and/or the appearance of new lesions was statistically significantly lower in the ADT group (8%) than in the placebo group (17%) (P<.001; difference = 9%, 95% confidence interval [CI] = 4% to 15%). In the person-specific analysis, the disease progression rate was statistically significantly lower in the ADT group (32%) than in the placebo group (59%) (P =.013; difference = 27%, 95% CI = 6% to 48%). The two treatment groups did not differ statistically significantly in terms of nuclear MI. Among individuals with an abnormal nuclear MI before treatment (29 in the ADT group and 25 in the placebo group), the progression rate in the ADT group (41%) was substantially lower than that in the placebo group (60%), although the difference was not statistically significant (P =.28; difference = 19%, 95% CI = -11% to 49%). Adverse events were mostly minor gastrointestinal symptoms that resolved with dose reduction or discontinuation of the medication.
CONCLUSION
Our results suggest that, in smokers, ADT is a potentially efficacious chemoprevention agent for lung cancer.
Topics: Adult; Aged; Anethole Trithione; Antineoplastic Agents; Bronchi; Case-Control Studies; Cell Nucleus; Double-Blind Method; Female; Humans; Lung Neoplasms; Male; Metaplasia; Middle Aged; Odds Ratio; Precancerous Conditions; Smoking
PubMed: 12096085
DOI: 10.1093/jnci/94.13.1001 -
Parasite Immunology Nov 1985Administration of the antioxidants 2(3)-tert-butyl-4-hydroxyanisole (BHA) or 5-(P-methoxyphenyl)-3H-1,2-dithiol-3-thione (ADT) to female CD-1 mice starting 4 weeks after...
Administration of the antioxidants 2(3)-tert-butyl-4-hydroxyanisole (BHA) or 5-(P-methoxyphenyl)-3H-1,2-dithiol-3-thione (ADT) to female CD-1 mice starting 4 weeks after infection with 70 cercariae of Schistosoma mansoni resulted in a decrease in the size of the inner fibrotic region of the hepatic granuloma. The cellular composition of the granuloma was not altered by treatment with these two compounds. The administration of the specific superoxide scavenger copper diisopropylsalicylate (CuDIPS) resulted in a similar decrease in granuloma size, suggesting a role of superoxide radicals in the granulomatous response.
Topics: Anethole Trithione; Animals; Anisoles; Antioxidants; Butylated Hydroxytoluene; Chemotaxis, Leukocyte; Female; Free Radicals; Granuloma; Inflammation; Liver Diseases, Parasitic; Mice; Ovum; Oxygen; Salicylates; Schistosoma mansoni; Schistosomiasis mansoni; Superoxides; Triglycerides
PubMed: 3005948
DOI: 10.1111/j.1365-3024.1985.tb00100.x -
Naunyn-Schmiedeberg's Archives of... Dec 1998Astroglial cells protect neurons against oxidative damage. The antioxidant glutathione plays a pivotal role in the neuroprotective action of astroglial cells which is...
Astroglial cells protect neurons against oxidative damage. The antioxidant glutathione plays a pivotal role in the neuroprotective action of astroglial cells which is impaired following loss of glutathione. Anethole dithiolethione (ADT), a sulfur-containing compound which is used in humans as a secretagogue, increases glutathione levels in cultured astroglial cells under "physiological" conditions and is thought thereby to protect against oxidative damage. Presently, we report the effect of ADT (3-100 microM) on glutathione content of and efflux from rat primary astroglia-rich cultures under "pathological" conditions, i.e., extended deprivation of glucose and amino acids. Although cellular viability was not affected significantly, starvation of these cultures for 24 h in a bicarbonate buffer lacking glucose and amino acids led to a decrease in glutathione and protein content of approximately 43% and 40%, respectively. Although no effect on the protein loss occurred, the presence of ADT during starvation counteracted the starvation-induced loss of intracellular glutathione in a concentration-dependent way. At a concentration of 100 microM ADT even a significant increase in astroglial glutathione content was noted after 24 h of starvation. Alike intracellular glutathione levels, the amount of glutathione found in the buffer was elevated substantially if ADT was present during starvation. This ADT-mediated, apparent increase in glutathione efflux was additive to the stimulatory effect on extracellular glutathione levels of acivicin (100 microM), an inhibitor of extracellular enzymatic glutathione breakdown. However, the ADT-induced elevation of both intra- and extracellular glutathione content during starvation was prevented completely by coincubation with buthionine sulfoximine (10 microM), an inhibitor of glutathione synthesis. These results demonstrate that, most likely through stimulation of glutathione synthesis, ADT enables astroglial cells to maintain higher intra- and extracellular levels of glutathione under adverse conditions. Considering the lowered glutathione levels in neurodegenerative syndromes, we conclude that further evaluation of the therapeutic potential of the compound is warranted.
Topics: Amino Acids; Anethole Trithione; Animals; Animals, Newborn; Astrocytes; Buthionine Sulfoximine; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glucose; Glutathione; Isoxazoles; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Wistar; Starvation
PubMed: 9879719
DOI: 10.1007/pl00005302 -
Methods in Enzymology 1999
Topics: Anethole Trithione; Antioxidants; Chromatography, High Pressure Liquid; Electrochemistry; Humans; Jurkat Cells; Reproducibility of Results; Sensitivity and Specificity; T-Lymphocytes
PubMed: 9916209
DOI: 10.1016/s0076-6879(99)99030-4 -
ACS Nano Feb 2017Nanosized drug delivery systems have offered promising approaches for cancer theranostics. However, few are effective to simultaneously maximize tumor-specific uptake,...
Nanosized drug delivery systems have offered promising approaches for cancer theranostics. However, few are effective to simultaneously maximize tumor-specific uptake, imaging, and therapy in a single nanoplatform. Here, we report a simple yet stimuli-responsive anethole dithiolethione (ADT)-loaded magnetic nanoliposome (AML) delivery system, which consists of ADT, hydrogen sulfide (HS) pro-drug, doped in the lipid bilayer, and superparamagnetic nanoparticles encapsulated inside. HepG2 cells could be effectively bombed after 6 h co-incubation with AMLs. For in vivo applications, after preferentially targeting the tumor tissue when spatiotemporally navigated by an external magnetic field, the nanoscaled AMLs can intratumorally convert to microsized HS bubbles. This dynamic process can be monitored by magnetic resonance and ultrasound dual modal imaging. Importantly, the intratumoral generated HS bubbles imaged by real-time ultrasound imaging first can bomb to ablate the tumor tissue when exposed to higher acoustic intensity; then as gasotransmitters, intratumoral generated high-concentration HS molecules can diffuse into the inner tumor regions to further have a synergetic antitumor effect. After 7-day follow-up observation, AMLs with magnetic field treatments have indicated extremely significantly higher inhibitions of tumor growth. Therefore, such elaborately designed intratumoral conversion of nanostructures to microstructures has exhibited an improved anticancer efficacy, which may be promising for multimodal image-guided accurate cancer therapy.
Topics: Anethole Trithione; Animals; Antineoplastic Agents; Cell Line; Cell Survival; Contrast Media; Drug Delivery Systems; Drug Screening Assays, Antitumor; Female; Hep G2 Cells; Humans; Hydrogen Sulfide; Liposomes; Liver Neoplasms, Experimental; Magnetic Fields; Magnetic Resonance Imaging; Magnetite Nanoparticles; Mice; Mice, Inbred BALB C; Mice, Nude; Microbubbles; Multimodal Imaging; Prodrugs; Theranostic Nanomedicine; Ultrasonography
PubMed: 28045496
DOI: 10.1021/acsnano.6b06815 -
Methods in Enzymology 1995
Comparative Study
Topics: Acetaminophen; Anethole Trithione; Antioxidants; Bisbenzimidazole; Cells, Cultured; Drug Evaluation, Preclinical; Fluorescent Dyes; Fluorometry; Light; Molecular Mimicry; Neutral Red; Reproducibility of Results; Rhodamine 123; Rhodamines; Sensitivity and Specificity; Sulfhydryl Compounds; Titrimetry
PubMed: 7476370
DOI: 10.1016/0076-6879(95)52036-8 -
Free Radical Biology & Medicine May 2010The H(2)S-releasing aspirin (ACS14) containing a dithiolethione moiety has been demonstrated to maintain the thromboxane-suppressing activity of the parent compound, but...
The H(2)S-releasing aspirin (ACS14) containing a dithiolethione moiety has been demonstrated to maintain the thromboxane-suppressing activity of the parent compound, but it seems to spare the gastric mucosa by affecting redox imbalance through increased H(2)S/glutathione (GSH) formation. Nevertheless, the mechanisms by which ACS14 is able to elevate the levels of these agents has not been fully elucidated so far. In this manuscript the effect of an acute ip administration of ACS14 and of its dithiolethione moiety (5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione, ADTOH) on the overall thiol content of rat tissues and on the main enzymes involved in the maintenance of thiol homeostasis is reported. ACS14 and ADTOH treatments were shown to induce a significant increase not only of GSH but also of cysteine in plasma and in several rat tissues as well as of H(2)S plasma levels. Conversely, a significant decrease of homocysteine in most rat organs and in plasma was observed. Most of these phenomena are supposed to be linked to the elevated intracellular levels of cysteine induced by treatments with either ACS14 or ADTOH.
Topics: Anethole Trithione; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Chromatography, High Pressure Liquid; Glutathione; Homeostasis; Hydrogen Sulfide; Rats; Rats, Sprague-Dawley; Sulfhydryl Compounds
PubMed: 20171274
DOI: 10.1016/j.freeradbiomed.2010.02.014