Pharmacological Reports最新文献

Background: Our recent studies showed that prolonged administration of novel atypical antipsychotics affected the expression and activity of cytochrome P450 (CYP), as demonstrated in vitro on human hepatocytes and in vivo on the rat liver. The aim of the present work was to study the effect of repeated treatment with asenapine, iloperidone, and lurasidone on the expression of transcription factors regulating CYP drug-metabolizing enzymes in rat liver.

Methods: The hepatic mRNA (qRT-PCR) and protein levels (Western blotting) of aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor (PPARγ) were measured in male Wistar rats after 2 week-treatment with asenapine, iloperidone or lurasidone.

Results: The 2-week treatment with asenapine significantly diminished the AhR and PXR expression (mRNA, protein level), and CAR mRNA level in rat liver. Iloperidone lowered the AhR and CAR expression and PXR protein level. Lurasidone did not affect the expression of AhR and CAR, but increased PXR expression. The antipsychotics did not affect PPARγ.

Conclusions: Prolonged treatment with asenapine, iloperidone, or lurasidone affects the expression of transcription factors regulating the CYP drug-metabolizing enzymes. The changes in the expression of AhR, CAR, and PXR mostly correlate with alterations in the expression and activity of respective CYP enzymes found in our previous studies. Since these transcription factors are also engaged in the expression of phase II drug metabolism and drug transporters, changes in their expression may affect the metabolism of endogenous substrates and pharmacokinetics of concomitantly used drugs.

Background: Elevated brain levels of kynurenic acid (KYNA), a metabolite in the kynurenine pathway, are associated with cognitive dysfunctions, which are nowadays often considered as fundamental characteristics of several psychopathologies; however, the role of KYNA in mental illnesses, such as schizophrenia, is not fully elucidated. This study aimed to assess KYNA levels in the prefrontal cortex (PFC) of rats prenatally treated with methylazoxymethanol (MAM) acetate, i.e., a well-validated neurodevelopmental animal model of schizophrenia. The effects of an early pharmacological modulation of the endogenous cannabinoid system were also evaluated.

Methods: Pregnant Sprague-Dawley rats were treated with MAM (22 mg/kg, ip) or its vehicle at gestational day 17. Male offspring were treated with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day, ip) or with the typical antipsychotic haloperidol (0.6 mg/kg/day, ip) from postnatal day (PND) 19 to PND39. The locomotor activity and cognitive performance were assessed in the novel object recognition test and the open field test in adulthood. KYNA levels in the PFC of prenatally MAM-treated rats were also assessed.

Results: A significant cognitive impairment was observed in prenatally MAM-treated rats (p < 0.01), which was associated with enhanced PFC KYNA levels (p < 0.05). The peripubertal AM251, but not haloperidol, treatment ameliorated the cognitive deficit (p < 0.05), by normalizing the PFC KYNA content in MAM rats.

Conclusions: The present findings suggest that the cognitive deficit observed in MAM rats may be related to enhanced PFC KYNA levels which could be, in turn, mediated by the activation of cannabinoid CB1 receptor. These results further support the modulation of brain KYNA levels as a potential therapeutic strategy to ameliorate the cognitive dysfunctions in schizophrenia.

Asthma is a lifelong condition with varying degrees of severity and susceptibility to symptom control. Recent studies have examined the effects of individual genus, species, and strains of probiotic microorganisms on the course of asthma. The present review aims to provide an overview of current knowledge on the use of probiotic microorganisms, mainly bacteria of the genus Lactobacillus and Bifidobacterium, in asthma prevention and treatment. Recent data from clinical trials and mouse models of allergic asthma indicate that probiotics have therapeutic potential in this condition. Animal studies indicate that probiotic microorganisms demonstrate anti-inflammatory activity, attenuate airway hyperresponsiveness (AHR), and reduce airway mucus secretion. A randomized, double-blind, placebo-controlled human trials found that combining multi-strain probiotics with prebiotics yielded promising outcomes in the treatment of clinical manifestations of asthma. It appears that probiotic supplementation is safe and significantly reduces the frequency of asthma exacerbations, as well as improved forced expiratory volume and peak expiratory flow parameters, and greater attenuation of inflammation. Due to the small number of available clinical trials, and the use of a wide range of probiotic microorganisms and assessment methods, it is not possible to draw clear conclusions regarding the use of probiotics as asthma treatments.

Background: Currently, povidone-iodine (PVP-I) and hydrogen peroxide (H₂O₂) are frequently used antiseptics in joint infections, but the cytotoxic effects of these solutions are already reported. N-chlorotaurine (NCT) shows a broad-spectrum bactericidal activity and is well tolerated in various tissues, but its effect on human chondrocytes is unknown. The purpose of this study was to assess the cytotoxic effect of NCT, PVP-I, and H₂O₂ on human chondrocytes compared to a control group in an in vitro setting to get first indications if NCT might be a promising antiseptic in the treatment of septic joint infections for the future.

Material and methods: Chondrocytes extracted from human cartilage were incubated with various concentrations of NCT, PVP-I, and H₂O₂ for 5 and 30 min respectively. EZ4U cell viability kit was used according to the manufacturer's recommendations determining cell viability. To assess cell viability based on their nuclear morphology, cells were stained with acridine-orange and identified under the fluorescence microscope.

Results: EZ4U kit showed after 5 and 30 min of incubation a significant decrease in cell viability at NCT 1%, NCT 0.1%, PVP-I, and H₂O₂, but not for NCT 0.001% and NCT 0.01%. Acridine-orange staining likewise presented a significant decrease in vital cells for all tested solutions except NCT 0.001% and NCT 0.01% after 5 and 30 min of incubation.

Conclusion: Our results demonstrate that NCT is well tolerated by chondrocytes in vitro at the tested lower NCT concentrations 0.01% and 0.001% in contrast to the higher NCT concentrations 1% and 0.1%, PVP-I (1.1%), and H₂O₂ (3%), for which a significant decrease in cell viability was detected. Considering that the in vivo tolerability is usually significantly higher, our findings could be an indication that cartilage tissue in vivo would tolerate the already clinically used 1% NCT solution. In combination with the broad-spectrum bactericidal activity, NCT may be a promising antiseptic for the treatment of septic joint infections.

Neurodegenerative diseases (NDDs) encompass a range of conditions characterized by the specific dysfunction and continual decline of neurons, glial cells, and neural networks within the brain and spinal cord. The majority of NDDs exhibit similar underlying causes, including oxidative stress, neuroinflammation, and malfunctioning of mitochondria. Elevated levels of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), alongside decreased expression of brain-derived neurotrophic factor (BDNF) and glutamate transporter subtype 1 (GLT-1), constitute significant factors contributing to the pathogenesis of NDDs. Additionally, the dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) gene has emerged as a significant target for the treatment of NDDs at the preclinical level. It significantly contributes to developmental brain defects, early onset neurodegeneration, neuronal loss, and dementia in Down syndrome. Moreover, an impaired ubiquitin-proteosome system (UPS) also plays a pathological role in NDDs. Malfunctioning of UPS leads to abnormal protein buildup or aggregation of α-synuclein. α-Synuclein is a highly soluble unfolded protein that accumulates in Lewy bodies and Lewy neurites in Parkinson's disease and other synucleinopathies. Recent research highlights the promising potential of natural products in combating NDDs relative to conventional therapies. Alkaloids have emerged as promising candidates in the fight against NDDs. Harmine is a tricyclic β-carboline alkaloid (harmala alkaloid) with one indole nucleus and a six-membered pyrrole ring. It is extracted from Banisteria caapi and Peganum harmala L. and exhibits diverse pharmacological properties, encompassing neuroprotective, antioxidant, anti-inflammatory, antidepressant, etc. Harmine has been reported to mediate its neuroprotective via reducing the level of inflammatory mediators, NADPH oxidase, AChE, BChE and reactive oxygen species (ROS). Whereas, it has been observed to increase the levels of BDNF, GLT-1 and anti-oxidant enzymes, along with protein kinase-A (PKA)-mediated UPS activation. This review aims to discuss the mechanistic interplay of various mediators involved in the neuroprotective effect of harmine.

Background: Phencyclidine, an NMDA receptor antagonist, is frequently used to model behavioral and neurochemical changes correlated with schizophrenia in laboratory animals. The present study aimed to examine the effects of repeated administration of phencyclidine during early postnatal development on the contents of glutathione and sulfur-containing amino acids, as well as the activity of antioxidant enzymes in the brain of 12-day-old rats, and schizophrenia-like symptoms in adulthood.

Methods: Male Sprague-Dawley pups were administered phencyclidine (10 mg/kg) or saline subcutaneously on the postnatal days p2, p6, p9 and p12. In 12-day-old pups, 4 h after the last dose of phencyclidine, the levels of glutathione, cysteine, methionine, and homocysteine, and the enzymatic activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) were measured in the frontal cortex, hippocampus, and striatum. In 70-72-day-old rats, schizophrenia-like symptoms were assessed using behavioral tests.

Results: Biochemical data showed that perinatal phencyclidine treatment significantly reduced glutathione and cysteine levels in all brain structures studied, methionine was diminished in the striatum, and homocysteine in both the frontal cortex and striatum. GR activity was increased in the frontal cortex while SODactivity was decreased in the hippocampus. Behaviorally, perinatal phencyclidine induced long-term deficits in social and cognitive function and a decrease in locomotor activity assessed as the time of walking. Finally, perinatal treatment with phencyclidine resulted in a significant reduction in body weight gain over time.

Conclusion: Our research provides further evidence for the usefulness of the phencyclidine-induced neurodevelopmental model of schizophrenia for studying the pathogenesis of schizophrenia.

Neurodegenerative diseases (NDDs) pose a significant issue in healthcare, needing a thorough knowledge of their complex molecular mechanisms. A diverse set of cell signaling mediators and their interactions play critical roles in neuroinflammation. The release of pro-inflammatory mediators in response to neural dysfunction is detrimental to normal cell survival. Moreover, the important role of nuclear factor-κB (NF-κB) in the central nervous system through Toll-like receptor (TLR) activation has been well established. Therefore, through a comprehensive review of current research and experimentation, this investigation elucidates the interactions between novel pharmacological agents (TLR-4/NF-κB inhibitors) and neurodegeneration encompassing Alzheimer's, Parkinson's, Huntington's disease, amyotrophic lateral sclerosis and stroke. Insights garnered from this exploration underscore the potential of TLR-4 as a therapeutic target. Through the revelation of these insights, our aim is to establish a foundation for the development of enhanced and focused therapeutic approaches in the continuous endeavor to combat neurodegeneration. This review thus serves as a roadmap, guiding future research endeavors toward innovative strategies for combatting the complex interplay between TLR-4 signaling and NDDs.

Depression is the fourth most serious disease in the world. Left untreated, it is a cause of suicide attempts, emergence or exacerbation worsening of serious diseases, bodily and mental disorders, as well as increased risk of cardiovascular diseases, stroke, diabetes, and obesity, as well as endocrine and neurological diseases. Frequent coexistence of depression and other diseases requires the simultaneous use of several drugs from different therapeutic groups, which very often interact and intensify comorbidities, sometimes unrelated mechanisms. Sufficient awareness of potential drug interactions is critical in clinical practice, as it allows both to avoid disruption of proper pharmacotherapy and achieve substantive results. Therefore, this review aims to analyze the interactions of antidepressants with other concomitant medications. Against the backdrop of experimental research and a thorough analysis of the up-to-date literature, the authors discuss in detail the mechanisms and effects of action of individual drug interactions and adaptogens, including the latest antidepressants.

Among clinically highly efficient antiseizure medications (ASMs) there are modifiers of the presynaptic release machinery. Of them, levetiracetam and brivaracetam show a high affinity to the synaptic vesicle protein type 2 A (SV2A), whereas pregabalin and gabapentin are selective ligands for the α2δ1 subunits of the voltage-gated calcium channels. In this paper, we present recent progress in understanding the significance of presynaptic release machinery in the neurochemical mechanisms of epilepsy and ASMs. Furthermore, we discuss whether the knowledge of the basic mechanisms of the presynaptically acting ASMs might help establish a rational polytherapy for drug-resistant epilepsy.

Background: IA-0130 is a derivative of 3-(1,3-diarylallylidene)oxindoles, which is a selective estrogen receptor modulator (SERM). A previous study demonstrated that SERM exhibits anti-inflammatory effects on colitis by promoting the anti-inflammatory phenotype of monocytes in murine colitis. However, the therapeutic effects of oxindole on colitis remain unknown. Therefore, we evaluated the efficacy of IA-0130 on dextran sulfate sodium (DSS)-induced mouse colitis.

Methods: The DSS-induced colitis mouse model was established by administration of 2.5% DSS for 5 days. Mice were orally administered with IA-0130 (0.01 mg/kg or 0.1 mg/kg) or cyclosporin A (CsA; 30 mg/kg). Body weight, disease activity index score and colon length of mice were calculated and histological features of mouse colonic tissues were analyzed using hematoxylin and eosin staining. The expression of inflammatory cytokines and tight junction (TJ) proteins were analyzed using quantitative real-time PCR and enzyme-linked immunosorbent assay. The expression of interleukin-6 (IL-6) signaling molecules in colonic tissues were investigated using Western blotting and immunohistochemistry (IHC).

Results: IA-0130 (0.1 mg/kg) and CsA (30 mg/kg) prevented colitis symptom, including weight loss, bleeding, colon shortening, and expression of pro-inflammatory cytokines in colon tissues. IA-0130 treatment regulated the mouse intestinal barrier permeability and inhibited abnormal TJ protein expression. IA-0130 down-regulated IL-6 expression and prevented the phosphorylation of signaling molecules in colonic tissues.

Conclusions: This study demonstrated that IA-0130 suppressed colitis progression by inhibiting the gp130 signaling pathway and expression of pro-inflammatory cytokines, and maintaining TJ integrity.