Pharmacological Reports最新文献

Psychopharmacotherapy of major psychiatric disorders is mostly based on drugs that modulate serotonergic, dopaminergic, or noradrenergic neurotransmission, either by inhibiting their reuptake or by acting as agonists or antagonists on specific monoamine receptors. The effectiveness of this approach is limited by a significant delay in the therapeutic mechanism and self-perpetuating growth of treatment resistance with a consecutive number of ineffective trials. A growing number of studies suggest that drugs targeting glutamate receptors offer an opportunity for rapid therapeutic effect that may overcome the limitations of monoaminergic drugs. In this article, we present a review of glutamate-modulating drugs, their mechanism of action, as well as preclinical and clinical studies of their efficacy in treating mental disorders. Observations of the rapid, robust, and long-lasting effects of ketamine and ketamine encourages further research on drugs targeting glutamatergic transmission. A growing number of studies support the use of memantine and minocycline in major depressive disorder and schizophrenia. Amantadine, zinc, and Crocus sativus extracts yield the potential to ameliorate depressive symptoms in patients with affective disorders. Drugs with mechanisms of action based on glutamate constitute a promising pharmacological group in the treatment of mental disorders that do not respond to standard methods of therapy. However, further research is needed on their efficacy, safety, dosage, interactions, and side effects, to determine their optimal clinical use.

Background: The benefits of pharmacotherapy with sirolimus (SIR) in pediatric transplant recipients are well established. Traditionally, whole blood samples have been used to measure SIR concentrations. Volumetric Absorptive Microsampling (VAMS) is an alternative sampling strategy suitable for Therapeutic Drug Monitoring (TDM). In this study, we developed and validated two liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods for determining SIR concentrations in whole blood (WB) and capillary whole blood samples collected using a VAMS-Mitra™ device.

Methods: We used protein precipitation during WB sample preparation and dispersive liquid-liquid microextraction (DLLME) with methyl tert-butyl ether for VAMS sample preparation to optimise the analyte extraction process. The described validation protocols were cross-validated, confirming the equivalence of the whole-blood and VAMS-based methods. Furthermore, the developed methods were evaluated in two three-level rounds of an external proficiency-testing scheme.

Results: The analytical methods were successfully validated within the calibration range of SIR (0.5-60 ng/ml). The validation parameters met the European Medicines Agency (EMA) and the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDM&CT) acceptance criteria. No hematocrit (tested in the range of 24.3-64.1%), matrix, or carry-over effects were observed. Cross-validation confirmed the interchangeability between VAMS-LC-MS/MS and WB-LC-MS/MS methods. The developed methods were successfully implemented for SIR determination in 140 clinical samples (70 each of WB and VAMS) from pediatric renal transplant recipients, demonstrating their practicality and reliability.

Conclusion: The VAMS-based method has been rigorously tested and is clinically equivalent to the reference WB-LC-MS/MS method. Additionally, clinical validation confirmed the utility of the presented methods for TDM of the SIR in the pediatric population after renal transplantation.

In recent decades, psilocybin has gained attention as a potential drug for several mental disorders. Clinical and preclinical studies have provided evidence that psilocybin can be used as a fast-acting antidepressant. However, the exact mechanisms of action of psilocybin have not been clearly defined. Data show that psilocybin as an agonist of 5-HT2A receptors located in cortical pyramidal cells exerted a significant effect on glutamate (GLU) extracellular levels in both the frontal cortex and hippocampus. Increased GLU release from pyramidal cells in the prefrontal cortex results in increased activity of γ-aminobutyric acid (GABA)ergic interneurons and, consequently, increased release of the GABA neurotransmitter. It seems that this mechanism appears to promote the antidepressant effects of psilocybin. By interacting with the glutamatergic pathway, psilocybin seems to participate also in the process of neuroplasticity. Therefore, the aim of this mini-review is to discuss the available literature data indicating the impact of psilocybin on glutamatergic neurotransmission and its therapeutic effects in the treatment of depression and other diseases of the nervous system.

Background: Ethanol disrupts brain activity and memory. There is evidence supporting the beneficial effect of levetiracetam on alcohol consumption. Therefore, the aim of the study was to examine whether levetiracetam has a protective activity against ethanol-induced memory impairment, alterations in selected neurotransmission activities, oxidative stress, and selected essential elements in rats.

Methods: The rats were given levetiracetam (300 mg/kg b.w. po) with ethanol for three weeks prior to behavioral tests. Spatial memory was tested using the Morris water maze, while recognition memory was evaluated using the Novel object recognition test. The GABA and glutamate concentration was determined in three rat brain regions (cerebellum, hippocampus, and cerebral cortex). Serum oxidative stress parameters and selected essential elements concentration (Cu, Mn, Zn, Fe, Mg) in the rat brain were analyzed.

Results: Levetiracetam administered with ethanol improved spatial memory, but did not affect abstinence-induced impairment. The drug also decreased ethanol-induced long-term recognition memory impairment. No alterations in glutamate levels were observed. GABA levels were elevated by levetiracetam in the cerebral cortex and by ethanol in the cerebellum. Ethanol increased catalase activity (CAT) and decreased superoxide dismutase activity (SOD) in the serum. Levetiracetam significantly increased the activity of SOD. Alcohol disrupted the levels of trace elements (Mn, Zn, Mg) in the rat brain. Additionally, levetiracetam alone increased Mg, Fe, and Cu concentrations while all animals receiving the drug also had significantly lower concentrations of Zn.

Conclusions: Levetiracetam had differential effects against ethanol-induced impairments. These findings could have important implications for future levetiracetam treatment in patients.

Background: The treatment of painful diabetic neuropathy is still a clinical problem. The aim of this study was to determine whether astaxanthin, a substance that inhibits mitogen-activated protein kinases, activates nuclear factor erythroid 2-related factor 2 and influences N-methyl-D-aspartate receptor, affects nociceptive transmission in mice with diabetic neuropathy.

Methods: The studies were performed on streptozotocin-induced mouse diabetic neuropathic pain model. Single intrathecal and intraperitoneal administrations of astaxanthin at various doses were conducted in both males and females. Additionally, repeated twice-daily treatment with astaxanthin (25 mg/kg) and morphine (30 mg/kg) were performed. Hypersensitivity was evaluated with von Frey and cold plate tests.

Results: This behavioral study provides the first evidence that in a mouse model of diabetic neuropathy, single injections of astaxanthin similarly reduce tactile and thermal hypersensitivity in both male and female mice, regardless of the route of administration. Moreover, repeated administration of astaxanthin slightly delays the development of morphine tolerance and significantly suppresses the occurrence of opioid-induced hyperalgesia, although it does not affect blood glucose levels, body weight, or motor coordination. Surprisingly, astaxanthin administered repeatedly produces a better analgesic effect when administered alone than in combination with morphine, and its potency becomes even more pronounced over time.

Conclusions: These behavioral results provide a basis for further evaluation of the potential use of astaxanthin in the clinical treatment of diabetic neuropathy and suggest that the multidirectional action of this substance may have positive effects on relieving neuropathic pain in diabetes.

Background: Pathophysiological changes associated with obesity might impact various drug pharmacokinetics (PK) parameters. The liver and kidneys are the primary organs involved in drug clearance, and the function of hepatic and renal transporters is critical to efficient drug elimination (or reabsorption). Considering the impact of an increased BMI on the drug's PK is crucial in directing dosing decisions. Given the critical role of transporters in drug biodisposition, this study investigated how overweight and obesity affect the gene expression of renal and hepatic drug transporters.

Methods: Human liver and kidney samples were collected post-mortem from 32 to 28 individuals, respectively, which were divided into the control group (lean subjects; 18.5 ≤ BMI < 25 kg/m²) and the study group (overweight/obese subjects; BMI ≥ 25 kg/m²). Real-time quantitative PCR was performed for the analysis of 84 drug transporters.

Results: Our results show significant changes in the expression of genes involved in human transporters, both renal and hepatic. In liver tissue, we found that ABCC4 was up-regulated in overweight/obese subjects. In kidney tissue, up-regulation was only observed for ABCC10, while the other differentially expressed genes were down-regulated: ABCA1, ABCC3, and SLC15A1.

Conclusions: The observed alterations may be reflected by the differences in drug PK between lean and obese populations. However, these findings need further evaluation through the proteomic and functional study of these transporters in this patient population.

Neuroprotection, defined as safeguarding neurons from damage and death by inhibiting diverse pathological mechanisms, continues to be a promising approach for managing a range of central nervous system (CNS) disorders, including acute conditions such as ischemic stroke and traumatic brain injury (TBI) and chronic neurodegenerative diseases like Parkinson's disease (PD), Alzheimer's disease (AD), and multiple sclerosis (MS). These pathophysiological conditions involve excessive glutamatergic (Glu) transmission activity, which can lead to excitotoxicity. Inhibiting this excessive Glu transmission has been proposed as a potential therapeutic strategy for treating the CNS disorders mentioned. In particular, ligands of G protein-coupled receptors (GPCRs), including metabotropic glutamatergic receptors (mGluRs), have been recognized as promising options for inhibiting excessive Glu transmission. This review discusses the complex interactions of mGlu receptors with their subtypes, including the formation of homo- and heterodimers, which may vary in function and pharmacology depending on their protomer composition. Understanding these intricate details of mGlu receptor structure and function enhances researchers' ability to develop targeted pharmacological interventions, potentially offering new therapeutic avenues for neurological and psychiatric disorders. This review also summarizes the current knowledge of the neuroprotective potential of ligands targeting group III mGluRs in preclinical cellular (in vitro) and animal (in vivo) models of ischemic stroke, TBI, PD, AD, and MS. In recent years, experiments have shown that compounds, especially those activating mGlu4 or mGlu7 receptors, exhibit protective effects in experimental ischemia models. The discovery of allosteric ligands for specific mGluR subtypes has led to reports suggesting that group III mGluRs may be promising targets for neuroprotective therapy in PD (mGlu4R), TBI (mGlu7R), and MS (mGlu8R).

Background: A promising approach to the treatment of bacterial infections involves inhibiting the quorum sensing (QS) mechanism to prevent the formation and growth of bacterial biofilm. While antibiotics are used to kill remaining bacteria, QS inhibitors (QSIs) allow for antibiotic doses to be reduced. This study focuses on evaluating the synergy between gentamicin sulphate (GEN), tobramycin (TOB), or azithromycin (AZM) with linolenic acid (LNA) against the formation of an early Staphylococcus aureus biofilm.

Methods: Minimum biofilm inhibitory concentration (MBIC) was determined using the resazurin reduction assay for all antibiotics and LNA. The reduction of biofilm mass was assessed using the crystal violet (CV) assay. We have also evaluated the effect of dimethyl sulfoxide with TWEEN (DMSO_T) on early biofilm formation. Synergy was determined by metabolic activity assay and fractional biofilm inhibitory concentration (FBIC).

Results: DMSO_T at a concentration of 1% enhanced early biofilm formation, but also decreased the doses of antibiotic needed to reduce the biofilm by up to 8 times. Adding LNA at a concentration of 32 µg/ml or 64 µg/ml allowed up to a 32-fold reduction of antibiotic doses for GEN and TOB and a 4-fold reduction for AZM.

Conclusions: LNA's use in combination with various antibiotics could reduce their doses and help fight drug-resistant bacteria in the biofilm.

The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in governing stress-related disorders such as major depressive disorder (MDD), anxiety, and post-traumatic stress disorder. Chronic stress or early life trauma, known risk factors of disease, alter HPA axis activity and pattern of glucocorticoid (GC) secretion. These changes have consequences for physiological processes controlled by glucocorticoid receptor (GR) signaling, such as immune response and metabolism. In the brain, the aberrant GR signaling translates to altered behavior, making the GR pathway a viable target for therapies of stress-related disorders. One of the crucial elements of the pathway is FKBP5, a regulator of GR sensitivity and feedback control within the HPA axis, in which genetic variants were shown to moderate the risk of developing psychiatric conditions. The difficulty in targeting the GR-FKBP5 pathway stems from tailoring the intervention to specific brain regions and cell types, in the context of personalized genetic variations in GR and GR-associated genes, like FKBP5. The development of selective inhibitors, antagonists, and approaches based on targeted protein degradation offer insights into mechanistic aspects of disease and pave the way for improved therapy. These strategies can be employed either independently or in conjunction with conventional medications. Concomitant advancements in personalized drug screening (e.g. in vitro models exploiting induced pluripotent stem cells, iPSCs) bring the potential for optimization of therapy aiming to rescue central deficits originating from the HPA imbalance. In this mini-review, we discuss potential therapeutic strategies targeting GR signaling in stress-related disorders, with a focus on personalized approaches and advancements in drug development.

Metabotropic glutamate receptors (mGluRs) are part of the G protein-coupled receptors (GPCRs) family. They are coupled to G_αq (group I) or G_i/o (groups II and III) proteins, which result in the generation of diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP₃) or the inhibition of adenylyl cyclase, respectively. mGluRs have been implicated in anxiety, depression, learning, and synaptic plasticity. Similarly, CB1 cannabinoid receptors (CB1Rs), also GPCRs, play roles in cognitive function and mood regulation through G_αi/o-mediated inhibition of adenylyl cyclase. Both mGluRs and CB1Rs exhibit surface labeling and undergo endocytosis. Given the similar cellular distribution and mechanisms of action, this review complies with fundamental data on the potential interactions and mutual regulation of mGluRs and CB1Rs in the context of depression, anxiety, and cognition, providing pioneering insights into their interplay.