Journal of Pharmaceutical and Biopharmaceutical Research

TAAR1 as a new target for the treatment of bipolar disorder: Anti-manic and anti-depressant activity of the novel agonist PCC0105004

Mon, 25 Mar 2024 10:02:31 +0800

Background: Bipolar disorder (BD) is a deleterious psychiatric disorder, and the available pharmacotherapies have limited efficacy with significant side effects. Trace amine-associated receptor 1 (TAAR1) is an emerging drug target for neuropsychiatric disorders such as schizophrenia and substance user disorders. However, it is unknown whether TAAR1 is involved in the pathogenesis of BD. This study examined the effects and underlying mechanisms of a novel TAAR1 agonist, PCC0105004, in a rat model of ouabain (OUA)-induced BD.
Methods: Intracerebroventricular (ICV) administration of OUA-induced BD model was established. The in vitro cell-based cAMP assay was used to examine TAAR1 agonism of PCC0105004. The receptor specificity of PCC0105004 was determined by an off-target panel assay that included radioligand binding and enzymatic assays. The effects of PCC0105004 on manic-like and depressive-like behaviors were evaluated in the rat BD model. TAAR1-mediated signaling and oxidative stress parameters were biochemically determined in the prefrontal cortex and the hippocampus of rats.
Results: Western blotting revealed reduced TAAR1 expression level in the prefrontal cortex but unchanged in the hippocampus in model rats. PCC0105004, a TAAR1 agonist with the agonism EC₅₀ value of 0.06182 μM, attenuated the manic-like behaviors on the 7th day and the depressive-like behaviors on the 14th day at doses that did not affect locomotor activity in the BD rats. Mechanistically, PCC0105004 exerted its behavioral effects via the reduction of ROS damage through the phosphorylation activation of the TAAR1/Akt/GSK3β/BDNF signaling pathway.
Conclusion: These results demonstrated the potential antimanic-like and antidepressant-like efficacy of a novel TAAR1 agonist PCC0105004 in rats and revealed its underlying molecular basis, which supports the possibility of TAAR1 agonists as candidate pharmacotherapeutics for BD.

A novel role of NK3 receptor signaling in bipolar disorder

Thu, 14 Mar 2024 00:00:00 +0800

Objective: Bipolar disorder (BD) affects more than 1% of the global population with limited therapeutic options. The neurokinin B (NKB)-neurokinin B receptor (NK3R) is involved in a variety of emotional activities. This study explored the role of NK3 receptor signaling in bipolar disorder.
Materials and methods: In this study, a model of intracerebroventricular (ICV) administration of OUA-induced BD was used to investigate the possible role of NK3R signaling in BD. The involvement of NK3R in the expression of OUA-induced BD was assessed by genetically knocking down the NK3R-encoding TACR3 gene with shRNA approach in the hippocampus and systemic administration of a NK3R antagonist ESN364,. Biochemical techniques were used to examine the NK3R-associated signaling changes and the oxidative stress parameters in the hippocampus of BD rats.
Results: The NK3R expression level was elevated in the hippocampus BD rats. Both TACR3 knockdown in the hippocampus and ESN364 treatment reversed the manic-like and depression-like behaviors in BD rats Inhibition of the NK3R signaling reversed oxidative stress-induced damage via upregulating the BDNF signaling pathway in the hippocampus.
Conclusion: These results demonstrated that NK3R signaling plays a key role in the pathogenesis of BD and that pharmacological antagonist of NK3R such as ESN364 could represent a novel therapeutic strategy for the management of BD.

Network pharmacology-based prediction for therapeutic mechanism of FuYueKang Lotion on acute eczema

Xiaowen Wen, Shaokang Cui, Minzhi Li, Yongping Zheng, Haoyou Xu — Wed, 01 Nov 2023 11:53:05 +0800

Objective: Fuyuekang Lotion (FYKL) is an improved traditional Chinese medicine (TCM) prescription widely used to treat acute eczema (AE). However, the mechanism of action remains unclear. This study aimed to explore the therapeutic mechanism of FYKL in AE.
Methods: We revealed the underlying mechanism by utilizing a network pharmacology approach, molecular docking studies, and in vitro verification. The active compounds in FYKL were identified, and their targets were predicted. These targets were subsequently mapped to a component-target interaction network, with their therapeutic mechanisms predicted through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking was used to verify protein-binding efficacy. Potential key targets of FYKL against AE were further confirmed via reverse transcription quantitative polymerase chain reaction (RT-qPCR).
Results: The study identified 59 potential active compounds of FYKL, with quercetin, luteolin, and gallic acid suggested as critical active ingredients. Our findings suggest that these ingredients could exert their effects mainly by modulating the inflammatory immune response and promoting epidermal repair. FYKL was found to be a multi-target, multi-component drug that could potentially regulate the inflammatory immune response in AE through numerous pathways.
Conclusions: The findings from this study provide a scientific basis for further research into the therapeutic effects and mechanisms of FYKL in treating AE, underscoring the potential of TCM in modern therapeutics.

Exploring the mechanism of three herb pairs for the treatment of atherosclerosis through network pharmacology and molecular modeling

Minjun Wang — Wed, 19 Apr 2023 16:45:35 +0800

Background: Atherosclerosis (AS) is one of the leading causes of cardiovascular diseases. The traditional China herb pairs such as Huanglian-Gualou, Honghua-Taoren, and Suhexiang-Bingpian showed therapeutic effects on AS by clearing heat and resolving phlegm, invigorating blood and removing blood stasis, as well as aromatic resuscitation, respectively. However, the common and specific mechanisms of these pairs against the same disease are elusive.
Objective: This study aimed to explore the molecular mechanisms of 3 herb pairs treating AS by network pharmacology, molecular modeling and mechanism experiments.
Methods: The components and their corresponding targets of 3 herb pairs, as well as AS-related targets, were collected from multiple databases and literature. Then the protein-protein interaction network was built to identify the key components and targets associated with AS. The pathway enrichment analysis using KEGG was carried out for analyzing the common mechanisms of 3 herb pairs against AS. Finally, the binding modes of the key components and targets were analyzed by molecular docking and molecular dynamic simulation.
Results: The PPI network indicated that the common targets of 3 herb pairs focused on four pathways, including regulated vascular shear stress, TNF, ARE-RAGE, and IL-17 pathways. The molecular docking analysis indicated that the key component quercetin showed highest docking score with PTGS2 in comparison to other targets. Molecular dynamics simulations revealed that quercetin stably anchored to the active pocket of PTGS2 by forming hydrogen bonds with Thr175, Asn351, and Trp356.
Conclusion: The molecular mechanism of Huanglian-Gualou, Honghua-Taoren, and Suhexiang-Bingpian against AS was preliminarily expounded, and we wish to provide a theoretical instruction for clinical treatment of AS.

LPM570065 ameliorates anxiety-like and depressive-like behaviors in CUMS rats through regulating DNA methylation in hippocampus

Mon, 17 Apr 2023 15:55:48 +0800

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

Fatemeh Kenari, Szilárd Molnár, Zoltán Pintér, Sobhan Bitaraf, Pál Perjési — Wed, 22 Mar 2023 13:53:43 +0800

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).

How antidepressants affect the cerebral ischemic injury and ischemic stroke

Xiaohui Sun, Tian Wang, Lin Zhou, Yawen Yu, Zhaofeng Liu, Runchen Ma, Fenghua Fu — Fri, 17 Feb 2023 14:19:00 +0800

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.

Therapeutic efficacies of nano carriers in delivering drugs

Bailey Krueger, Taylor Frazier, Sheila Galbreath, Tarun Goswami — Mon, 17 Oct 2022 12:03:21 +0800

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

Hawsar Othman Mohamed, Attila Almási, Pal Perjesi — Tue, 04 Oct 2022 13:34:02 +0800

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.

Effectiveness of mesoporous bioglass in drug delivery

Sheila Galbreath, Bailey Krueger, Taylor Frazier, Tarun Goswami — Mon, 27 Jun 2022 14:27:00 +0800

Since the invention of bioactive glass 50 years ago, it has become a versatile material used in healthcare in a variety of applications and compositions. Bioactive glass has shown superior capabilities of drug delivery compared to traditional carriers. For example, time-released medications are less likely to reach toxic levels, while delivering a specific, therapeutic dose to a localized area. The objective of this paper is to investigate the properties and effectiveness of mesoporous bioglass (MBG) as a drug delivery carrier. A literature review of various polymer coated 45S5 Bioglass^® loaded with vancomycin was analyzed to determine their drug release response. Since MBG continues to be a preferred carrier with numerous combinations; size, coating, doped with ions, medications, and other physical conditions, there is a need to understand more fully their effectiveness. For a given loading efficiency of 5-15% the burst release % for day 1 remained 15-30% for given surface area, pore volume and pore size of 3.5 to 5 nm. The mechanical properties summarized in this paper are compared with the drug release kinetics. In general, for a given fracture toughness and compressive strength, the ratio of Young’s modulus to bending strength around 250 determined poor apatite mineralization resulting in slow release. As this ratio increased the apatite mineralization and dissolution rate increased. Doping MBG with ions enhanced the drug efficacy to treat a particular condition, for example, silver. Polymer coated MBG exhibited slower dissolution rate than uncoated MBG. Dissolution time increased with the drug loading rate, drying time of the coating, multi-layer coats of drug and polymer for the drug studied in this paper to more than 50%.