LPM570065 ameliorates anxiety-like and depressive-like behaviors in CUMS rats through regulating DNA methylation in hippocampus
Objective: This study aims to analyze the effects and underlying mechanisms of LPM570065 on behavioral phenotypes in rats with generalized anxiety disorder (GAD).
Methods: The chronic unpredictable mild stress (CUMS) rats were used to observe the results of LPM570065. Total 72 male Sprague Dawley rats were divided into control, vehicle (0.5% CMC-Na), LPM570065 (32 mg/kg) and diazepam (3 mg/kg) groups, 12 rats in each group. Anxiety-like behaviors of rats were observed by elevated zero maze test and novelty-suppressed feeding test. Depressive-like behaviors of rats were detected by forced swimming test. DNA methylation in hippocampi of rats were measured by reduced representation bisulfite sequencing (RRBS). In hippocampi of rats, expressions of DNA methyltransferase (DNMT) 1 and DNMT3a proteins were measured by western blot, and density of dendritic spines was observed by Golgi staining.
Results: Compared with the control group, the weights of rats were obviously decreased (p < 0.001) and the rats showed anxiety-like and depressive-like behaviors (p < 0.001) in the vehicle group. Compared with the vehicle group, the weights of rats were significantly increased (p < 0.001) and the anxiety-like and depressive-like behaviors were improved (p < 0.001) in the LPM570065 group. The results of RRBS showed that there were 49964 promoters showed hypermethylation in the LPM570065 treatment rats contrasted to the vehicle treatment rats. In addition, these promoters were enriched in signal transduction and immune function. Furthermore, the expressions of DNMT1 and DNMT3a were significantly decreased, the density of dendritic spines was significantly increased in hippocampi of LPM570065 treatment rats compared with the vehicle treatment rats.
Conclusions: LPM570065 ameliorates anxiety-like and depressive-like behaviors in CUMS rats, and its mechanism is possible associated with downregulating DNA methylation in hippocampus.
(E)-2-Benzylidenecyclanones: Part XVII. An LC-MS study of microsomal transformation reactions of (E)-2-[(4'-methoxyphenyl)methylene]-benzosuberon-1-one: A cyclic chalcone analog
Biotransformation of the antiproliferative (E)-2-[(4’-methoxyphenyl)methylene]-benzosuberon-1-one (2c) was studied using rat liver microsomes. As a result of the CYP-catalyzed transformations, one monooxygenated (2c+O) and the demethylated (2c-CH2) metabolites were identified by HPLC-MS. (E)-2-[(4’-methoxyphenyl)methylene]-benzosuberon-1-ol, the expected product of rat liver microsomal carbonyl reductase, was not found in the incubates. Microsomal GST-catalyzed reaction of the compound resulted in formation of diastereomeric GST-conjugates. Under the present HPLC conditions, the diastereomeric adducts were separated into two chromatographic peaks (2c-GSH-1 and 2c-GSH-2).
Therapeutic efficacies of nano carriers in delivering drugs
The drug release rates of poorly soluble medications such as doxorubicin has been investigated in this paper. Since the drug was fixed, different carriers used to deliver it and their release rates compiled from literature were evaluated in this paper. Even though targeting of drugs is very important in drug delivery, it is not within the scope of this paper. However, functionalization of the carrier may provide this benefit, those constructs are included for comparison in terms of hybrid constructs. Dendrimer, micelles and hybrid constructs used in the delivery of doxorubicin compared in this paper with respect to carrier size and drug loading. Assuming that the dissolution follows a slow release, 40-50% of the drug in the phase I representing a sudden or the burst release, followed by a steady release of 50-60% of the drug in phase II, not all the carriers and their sizes exhibited this behavior. Carriers and hybrid constructs 38nm size were more effective where phases I and II observed, however, as the size decreased to 34 nm or increased above 40nm, minimal release occurred meaning the carriers were too big to penetrate the vasculature permeability. Nano-carriers, dendrimers, micelle, hybrid dendrimers and micelles were found to be effective with the carrier manufacturing, generation, polymer, molecular weight of the carrier and other parameters. The release rate of doxorubicin was found to be effective with dendrimers together with hybrid dendrimer exhibiting a bilinear behavior. Micelles 20nm were more effective representing 60% of release in 10 hours followed by additional 25% in 35 hours exhibiting a bilinear behavior. Size greater than 20nm resulted in slow release reaching less than 10 to 40% of drug. Several drugs exhibited multiple slopes in their kinetics when micelle was used. The therapeutic efficacy of hybrid micelle was superior to other nano-carriers.
Effect of experimental hyperglycemia on intestinal elimination and biliary excretion of ibuprofen enantiomers in hyperglycemic rats
Diabetic complications are mostly due to hyperglycemia. Hyperglycemia is reported to be associated with oxidative stress. It can result in changes in the activities of drug-metabolizing enzymes and membrane-integrated transporters, which can modify the fate of drugs and other xenobiotics. An in vivo intestinal perfusion model was used to investigate how experimental hyperglycemia affects intestinal elimination and biliary excretion of ibuprofen enantiomers in the rat. Experimental diabetes was induced by intravenous (i.v.) administration of streptozotocin. The intestinal perfusion medium contained 250 µM racemic ibuprofen. A validated isocratic chiral HPLC method with UV detection was developed to determine the amount of the two enantiomers in the intestinal perfusate and the bile. The results indicated that experimental diabetes doesn’t cause a statistically significant difference in the disappearance of ibuprofen enantiomers from the small intestine. Analysis of the bile samples detected only the (S)-IBP enantiomer. Excretion of the ibuprofen enantiomer to the bile decreased in experimental diabetes. The observed changes can affect the pharmacokinetics of drugs administered in hyperglycemic individuals.
How antidepressants affect the cerebral ischemic injury and ischemic stroke
Ischemic stroke is the main cause of long-term disability and death worldwide. Studies have pointed out that antidepressants not only can be used to treat depression, but also promote nerve regeneration, nerve plasticity, and recovery of nerve function after stroke. Some evidences indicated that antidepressants have beneficial effects on ischemic stroke. At the same time, there are also risks in treatment process. The mechanisms of the effects of antidepressants on ischemic stroke are complicated and rarely reported. This review summarizes the roles of antidepressants in patients and animal models of stroke, the possible mechanisms of antidepressants against brain injury induced by stroke, and the risks and challenges of antidepressants treatment in patients with ischemia.