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Acta Pharmacologica Sinica Apr 2022Intracerebral hemorrhage (ICH) is a devastating disease, in which neuroinflammation substantially contributes to brain injury. Uncoupling protein 2 (UCP2) is a member of...
Intracerebral hemorrhage (ICH) is a devastating disease, in which neuroinflammation substantially contributes to brain injury. Uncoupling protein 2 (UCP2) is a member of the mitochondrial anion carrier family, which uncouples oxidative phosphorylation from ATP synthesis by facilitating proton leak across the mitochondrial inner membrane. UCP2 has been reported to modulate inflammation. In this study we investigated whether and how UCP2 modulated neuroinflammation through microglia/macrophages following ICH in vitro and in vivo. We used an in vitro neuroinflammation model in murine BV2 microglia to mimic microglial activation following ICH. ICH in vivo model was established in mice through collagenase infusion into the left striatum. ICH mice were treated with anetholetrithione (ADT, 50 mg· kg ·d, ip) or the classical protonophoric uncoupler FCCP (injected into hemorrhagic striatum). We showed that the expression and mitochondrial location of microglial UCP2 were not changed in both in vitro and in vivo ICH models. Knockdown of UCP2 exacerbated neuroinflammation in BV2 microglia and mouse ICH models, suggesting that endogenous UCP2 inhibited neuroinflammation and therefore played a protective role following ICH. ADT enhanced mitochondrial ROS production thus inducing mitochondrial uncoupling and activating UCP2 in microglia. ADT robustly suppressed neuroinflammation, attenuated brain edema and improved neurological deficits following ICH, and these effects were countered by striatal knockdown of UCP2. ADT enhanced AMP-activated protein kinase (AMPK) activation in the hemorrhagic brain, which was abrogated by striatal knockdown of UCP2. Moreover, striatal knockdown of AMPK abolished the suppression of neuroinflammation by ADT following ICH. On the other hand, FCCP-induced mitochondrial uncoupling was independent of UCP2 in microglia; and striatal knockdown of UCP2 did not abrogate the suppression of neuroinflammation by FCCP in ICH mice. In conclusion, the uncoupling activity is essential for suppression of neuroinflammation by UCP2. We prove for the first time the concept that activators of endogenous UCP2 such as anetholetrithione are a new class of uncouplers with translational significance.
Topics: Anethole Trithione; Animals; Cerebral Hemorrhage; Mice; Microglia; Neuroinflammatory Diseases; Uncoupling Protein 2
PubMed: 34183754
DOI: 10.1038/s41401-021-00698-1 -
European Journal of Pharmacology May 1992The present study examines the mechanism(s) of action of anethole trithione (Sulfarlem S25) compared to the sialogogue pilocarpine. The chronic effects (7 days of... (Comparative Study)
Comparative Study
The present study examines the mechanism(s) of action of anethole trithione (Sulfarlem S25) compared to the sialogogue pilocarpine. The chronic effects (7 days of treatment) of anethole trithione, pilocarpine and/or amitriptyline on autonomic receptor binding (homogenates) were measured together with parallel tests of stimulation-induced rises in delta [Ca2+]i in collagenase-isolated rat parotid acini. The results revealed that chronic treatment with amitriptyline resulted in significantly increased rises in delta [Ca2+]i after stimulation with 20 microM of carbachol or adrenaline, and a significant increase in muscarinic acetylcholine receptor density. In addition, anethole trithione also increased cholinergic and adrenergic responsiveness. The double treatment of amitriptyline and anethole trithione or amitriptyline and pilocarpine did, however, prevent the rise in delta [Ca2+]i observed under conditions when these drugs were administered alone. Furthermore, anethole trithione, but not pilocarpine, was able to prevent the amitriptyline-induced upregulation in muscarinic acetylcholine receptor density. In conclusion, the experimental data presented in this study are compatible with the hypothesis that anethole trithione might stimulate some post-receptor effect in the coupling to the secretory response. In addition, this study supports the beneficial effects of anethole trithione in treating drug-induced xerostomia.
Topics: Amitriptyline; Anethole Trithione; Animals; Binding Sites; Calcium; Carbachol; Epinephrine; Male; Parotid Gland; Pilocarpine; Rats; Rats, Wistar; Receptors, Neurotransmitter; Signal Transduction; Specific Pathogen-Free Organisms; Up-Regulation
PubMed: 1327842
DOI: 10.1016/0922-4106(92)90081-6 -
Methods in Enzymology 1995
Review
Topics: Anethole Trithione; Animals; Antioxidants; Cholagogues and Choleretics; Humans; Mice; Salivary Glands
PubMed: 7476368
DOI: 10.1016/0076-6879(95)52034-1 -
European Journal of Medicinal Chemistry Jul 2010A metabolite-based prodrug strategy to increase the solubility of anethole trithione was reported to facilitate the clinical application of this hepatoprotective agent....
A metabolite-based prodrug strategy to increase the solubility of anethole trithione was reported to facilitate the clinical application of this hepatoprotective agent. Water-soluble analogs of anethole trithione were synthesized via substituting the methyl group of anethole trithione with the simple hydrophilic alkylamino group, and subjected to physiochemical, pharmacological and metabolic studies. The prodrugs displayed increased solubility as well as other physiochemical properties favorable for parenteral use. Among the analogs synthesized, the compound 5a exhibited best hepatoprotective activity at the dose of 2.0 mg/kg in mice equal to that of anethole trithione. The in vivo metabolic investigation demonstrated that the straight-side chain prodrug 5a could convert to desmethyl anethole trithione in vivo, while the ring-side chain prodrug 5d could not. The hepatoprotective activity of the prodrugs might result from the active metabolite desmethyl anethole trithione.
Topics: Anethole Trithione; Animals; Drug Design; Drug Stability; Hydrophobic and Hydrophilic Interactions; Liver; Male; Mice; Prodrugs; Solubility; Water
PubMed: 20392547
DOI: 10.1016/j.ejmech.2010.03.029 -
Journal of Pharmaceutical and... Nov 2006To evaluate the relative bioavailability of anethole trithione (ATT) from self-microemulsifying drug delivery system (SMEDDS) and tablet, a sensitive, accurate and... (Comparative Study)
Comparative Study
To evaluate the relative bioavailability of anethole trithione (ATT) from self-microemulsifying drug delivery system (SMEDDS) and tablet, a sensitive, accurate and reliable liquid chromatography method was developed and validated to determine ATT in rabbit plasma. Chromatographic separation was performed on a Diamonsil C18 column by using a mixture of methanol-water (90:10, v/v) delivered at a flow rate of 1.0 ml/min. The wavelength was set at 348 nm and mifepristone was used as the internal standard. A linear relationship for ATT was found in the range of 0.5-32 ng/ml. The mean extraction recoveries of ATT determined over three concentrations were 84.7+/-5.8, 92.3+/-3.4 and 89.9+/-5.1%. After administration of SMEDDS and tablets to rabbits, significant differences were found in main pharmacokinetic parameters of Tmax, Cmax and AUC(0-infinity) between these two formulations, and a 2.5-fold enhancement of relative bioavailability of ATT was observed from the SMEDDS compared with tablets.
Topics: Anethole Trithione; Animals; Biological Availability; Chromatography, High Pressure Liquid; Drug Delivery Systems; Emulsions; Male; Rabbits; Reproducibility of Results; Sensitivity and Specificity; Tablets
PubMed: 16824723
DOI: 10.1016/j.jpba.2006.05.013 -
ACS Omega Mar 2020Anethol trithione (ATT) has a wide range of physiological activities, but its use is limited due to its poor water solubility. To improve the solubility of ATT, we...
Anethol trithione (ATT) has a wide range of physiological activities, but its use is limited due to its poor water solubility. To improve the solubility of ATT, we synthesized and characterized a novel phosphate prodrug (ATXP) relying on the availability of the hydroxy group in 5-(4-hydroxyphenyl)-3-1,2-dithiole3-thione (ATX), which was transformed from ATT rapidly and extensively in vivo. Our results showed that ATXP significantly improved drug solubility. ATXP was rapidly converted to ATX and reached a maximum plasma concentration with a of approximately 5 min after intravenous (iv) administration. Furthermore, after the oral administration of ATXP, the was 3326.30 ± 566.50 ng/mL, which was approximately 5-fold greater than that of the parent drug form, indicating that ATXP has greater absorption than that of ATT. Additionally, the oral phosphate prodrug ATXP increased the ATX in the area under the plasma concentration vs time curves (AUC = 3927.40 ± 321.50 and AUC = 4579.0 ± 756.30), making its use in practical applications more meaningful. Finally, compared to the vehicle, ATXP was confirmed to maintain the bioactivity of the parent drug for a significant reduction in infarct volume 24 h after reperfusion. Based on these findings, the phosphate prodrug ATXP is a potentially useful water-soluble prodrug with improved pharmacokinetic properties.
PubMed: 32175506
DOI: 10.1021/acsomega.9b04129 -
International Journal of Cancer Jul 1997The chemopreventive efficacy of N-acetyl-L-cysteine (NAC), anethole trithione, miconazole and phenethylisothiocyanate (PEITC), each of which would be expected to alter...
The chemopreventive efficacy of N-acetyl-L-cysteine (NAC), anethole trithione, miconazole and phenethylisothiocyanate (PEITC), each of which would be expected to alter carcinogen metabolism, was examined in the dimethylbenzanthracene (DMBA) mammary carcinogenesis model. In this protocol, animals were exposed to non-toxic doses of the chemopreventives in the diet beginning 7 days prior to DMBA administration and then continuously throughout the duration of the assay (100 days post carcinogen). Miconazole, an antifungal agent with relatively broad inhibitory activity toward a variety of cytochromes P450, increased mammary tumor latency, decreased tumor incidence at the highest dose and decreased tumor multiplicity up to 60%. Anethole trithione, a substituted dithiolthione and an analog of the relatively broad-spectrum chemopreventive oltipraz, was administered in the diet and significantly inhibited mammary cancer multiplicity but not cancer incidence. NAC, an antimucolytic agent, failed to inhibit DMBA-induced mammary tumorigenesis. Surprisingly, treatment with DMBA plus PEITC, a potent inhibitor of cytochrome P450 2E1, actually increased the multiplicity of tumors relative to that observed with DMBA alone.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Acetylcysteine; Anethole Trithione; Animals; Anticarcinogenic Agents; Body Weight; Female; Isothiocyanates; Mammary Neoplasms, Experimental; Miconazole; Rats; Rats, Sprague-Dawley; Time Factors
PubMed: 9212229
DOI: 10.1002/(sici)1097-0215(19970703)72:1<95::aid-ijc14>3.0.co;2-9 -
The Journal of Pharmacy and Pharmacology Dec 2001Anethole trithione, a choleretic, has been reported to be effective in the treatment of dry mouth. We have examined the effects of chronic treatment with anethole...
Anethole trithione, a choleretic, has been reported to be effective in the treatment of dry mouth. We have examined the effects of chronic treatment with anethole trithione on salivary secretion, substance P immunoreactive substance (SP-IS) and alpha-calcitonin gene-related peptide immunoreactive substance (alpha-CGRP-IS) concentrations in human saliva. Anethole trithione caused significant increases of saliva SP-IS concentrations from the day 13 (25.3 +/- 1.6 pg mL(-1)) to day 14 (25.8 +/- 1.7 pg mL(-1)) compared with day 1 (19.9 +/- 1.9 pg mL(-1)). Anethole trithione caused significant increase in saliva alpha-CGRP-IS concentration on day 14 (39.9 +/- 4.7 pg mL(-1)) compared with day 1 (27.7 +/- 4.7 pg mL(-1)). Anethole trithione significantly increased the sialosis volumes from day 11 to day 14 (1.6 +/- 0.1-1.7 +/- 0.2 mL) compared with the day 1 (1.2 +/- 0.2 mL). Simple linear regression of the increase in sialosis volume with saliva SP-IS (r = 0.94) and alpha-CGRP-IS (r = 0.97) concentrations was found. These results demonstrated that chronic treatment with anethole trithione affected saliva SP-IS and alpha-CGRP-IS concentration in human saliva and sialosis volume.
Topics: Adult; Anethole Trithione; Calcitonin Gene-Related Peptide; Cholagogues and Choleretics; Humans; Immunoenzyme Techniques; Male; Peptide Fragments; Saliva; Substance P
PubMed: 11804400
DOI: 10.1211/0022357011778098 -
European Journal of Pharmacology Dec 1991The present study examines the mechanism(s) of action of anethole trithione compared to the sialogogue pilocarpine. This was done by comparing the acute effects of these... (Comparative Study)
Comparative Study
The present study examines the mechanism(s) of action of anethole trithione compared to the sialogogue pilocarpine. This was done by comparing the acute effects of these drugs on autonomic receptor binding (homogenates) together with parallel tests evaluating the biological activities of the receptor systems in collagenase-isolated rat parotid acini. The responses were measured as receptor-activated changes in cyclic nucleotide formation and acinar oxygen consumption. The results revealed that anethole trithione was unable to bind to muscarinic acetylcholine receptors and unable to stimulate the dynamic processes directly. It did, however, inhibit part (about 50%) of the carbachol-induced cyclic guanosine 3',5'-monophosphate (cyclic GMP) formation and O2 uptake. Furthermore, anethole trithione (greater than 1 microM) displaced [3H]prazosin (but not [3H]dihydroalprenolol ([3H]DHA] binding, without any effect upon the adrenaline-induced cyclic adenosine 3',5'-monophosphate (cyclic AMP) formation and O2 uptake. In conclusion, this study has shown that anethole trithione is not to be considered as a simple cholinergic agonist like pilocarpine, and further elucidation of the mechanism(s) of action of this agent would be useful.
Topics: Anethole Trithione; Animals; Cyclic AMP; Cyclic GMP; Epinephrine; Kinetics; Male; Oxygen Consumption; Parotid Gland; Pilocarpine; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Receptors, Muscarinic; Salivation; Signal Transduction; Stimulation, Chemical
PubMed: 1667756
DOI: 10.1016/0922-4106(91)90074-r -
Arzneimittel-Forschung Oct 1988Pharmacological studies on trithio-p-methoxy-phenylpropene (anethole trithione, ANTT, Felviten) were performed. ANTT at a dose of 100 mg/kg, p.o. lowered the increased...
Pharmacological studies on trithio-p-methoxy-phenylpropene (anethole trithione, ANTT, Felviten) were performed. ANTT at a dose of 100 mg/kg, p.o. lowered the increased serum transaminases GOT and GPT, and protected the liver from injuries caused by CCl4 in mice. In other studies in vivo, ANTT at a dose of 1000 mg/kg showed no effect on the central nervous system or the autonomic nervous system. In vitro experiments with smooth muscle preparations showed no significant effects of ANTT.
Topics: Anethole Trithione; Animals; Anisoles; Autonomic Nervous System; Blood Pressure; Body Temperature; Central Nervous System; Diazepam; Electrolytes; Female; Gastrointestinal Motility; Guinea Pigs; Heart Rate; Hydrogen-Ion Concentration; Liver; Male; Mice; Motor Activity; Muscle Relaxation; Partial Thromboplastin Time; Prothrombin Time; Pupil; Rabbits; Rats; Rats, Inbred Strains; Seizures; Sleep; Uterine Contraction
PubMed: 3196385
DOI: No ID Found