Pharmacological Reports最新文献

{"title":"Potential antidepressant properties of aminophylline in male mice exposed to chronic restraint stress.","authors":"Florence Ingred Samante, Christine Gale Galangue, Debbie Chenn Avelino, Antoneitte Joy Beltran, Michaela Rapada, Eldan Greg Pabia, Niel Andrew Bustamante, Chrislean Jun Botanas, Fred Lawrence Samante, Katrina Joy Bormate, Raly James Perez Custodio","doi":"10.1007/s43440-026-00851-9","DOIUrl":"10.1007/s43440-026-00851-9","url":null,"abstract":"<p><strong>Background: </strong>Aminophylline, a bronchodilator used for treating airway obstruction, has been predicted through in silico models to exert antidepressant effects. However, there are still no studies that have validated these claims in a biological system. In this paper, we evaluated the antidepressant effects of aminophylline in mice subjected to chronic restraint stress (CRS).</p><p><strong>Methods: </strong>CRS was conducted for a duration of 15 days, with 4-hour daily stress exposure. Aminophylline (5 mg/kg, 10 mg/kg, and 20 mg/kg) and fluoxetine (10 mg/kg, positive control) were administered daily via intraperitoneal injection. Behavioral assessments, including the tail suspension test (TST), forced swimming test (FST), and sucrose splash test (SST), were conducted on days 0, 5, 10, and 15. Molecular docking and pathway analyses were performed to provide insight into its possible mechanism of action.</p><p><strong>Results: </strong>CRS exposure successfully induced depressive-like behavior, characterized by prolonged immobility in the TST and FST and diminished grooming activity in the SST. Administration of aminophylline attenuated these behavioral deficits, reducing immobility time and increasing grooming time in a dose-dependent manner. Molecular docking analysis demonstrated favorable binding of aminophylline to phosphodiesterase 3, phosphodiesterase 4, and the serotonin transporter, targets associated with antidepressant activity. Pathway analysis revealed upregulation of PPAR signaling, calcium signaling, and the synaptic vesicle cycle, while downregulating the glutamatergic synapse pathway.</p><p><strong>Conclusion: </strong>The study provides the first evidence of the antidepressant activity of aminophylline in a validated model of depression, prompting further clinical investigation into its therapeutic potential. Moreover, molecular and biochemical analyses are warranted to validate its precise mechanism of action.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"748-761"},"PeriodicalIF":4.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13275603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147628456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rifaximin's therapeutic spectrum: approved indications and experimental insights into emerging uses.","authors":"Irene Palenca, Silvia Basili Franzin, Marcella Pesce, Giovanni Sarnelli, Giuseppe Esposito","doi":"10.1007/s43440-026-00830-0","DOIUrl":"10.1007/s43440-026-00830-0","url":null,"abstract":"<p><p>Since its 1987 approval, rifaximin has emerged as a gut-targeted, minimally absorbed antibiotic achieving high intestinal levels. Rifaximin works by blocking bacterial RNA polymerase to stop bacterial growth, which helps treat both traveler’s diarrhea and irritable bowel syndrome with diarrhea. It effectively modulates gut microbiota and alleviates dysbiosis-related symptoms. Beyond antimicrobial activity, rifaximin modulates dysbiosis, strengthens the epithelial barrier, and exerts pregnane X receptor (PXR)-mediated anti-inflammatory and anti-angiogenic effects, with implications along the gut–liver and gut–brain axes. These pleiotropic properties support expanding uses in small intestinal bacterial overgrowth (SIBO), inflammatory bowel diseases (IBD), functional dyspepsia, bloating, and lactose intolerance. However, high cost and potential resistance with prolonged exposure highlight the need for antimicrobial stewardship. The aims of this review are to summarize licensed and emerging indications and delineate non-conventional mechanisms. Patient stratification and further controlled clinical studies are required to optimize rifaximin’s precision-medicine potential.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"627-640"},"PeriodicalIF":4.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13275752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147271937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting epigenetic and DNA topology mechanisms: histone deacetylases and topoisomerase inhibitors in combination and dual inhibition approaches.","authors":"Yashaswini Reddy, Vyasraj G Bhat, Mukirala Vasanth Kumar, Ipshita Das, Babitha Kampa Sundara","doi":"10.1007/s43440-026-00868-0","DOIUrl":"https://doi.org/10.1007/s43440-026-00868-0","url":null,"abstract":"<p><p>Cancer is a complex and multifactorial disease, often characterized by disruptions in key cellular processes such as gene expression and DNA topology. Histone deacetylases (HDACs) and topoisomerases (Topo) are two major molecular targets for cancer therapeutics due to their key role in maintaining DNA topology and contributing to cancer development. HDACs modify chromatin accessibility, while Topos resolve DNA supercoiling during replication. Targeting these pathways individually has shown therapeutic potential; however, recent advancements emphasize combination therapies and dual inhibitors as promising strategies to enhance anticancer efficacy. Combination therapies involving HDAC and Topo inhibitors leverage their complementary mechanisms of action to induce synergistic effects, leading to improved tumor suppression. Similarly, dual inhibitors, which integrate the functionalities of HDAC and Topo inhibitors into a single molecule, offer the potential to streamline treatment regimens, overcome drug resistance, and minimize adverse effects. This review provides a comprehensive overview of the therapeutic potential of HDAC-Topo combination therapies and dual inhibitors, emphasizing their mechanistic synergy, pharmacological benefits, and associated clinical challenges. It highlights the need for continued research to address limitations and improve their effectiveness and safety for broader applications in oncology.Clinical trial numberNot applicable.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148043257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of the safety profile of glucagon-like peptide-1 receptor agonists: a focus on thyroid cancer-related adverse events by using the European pharmacovigilance database.","authors":"Antonietta Anatriello, Valerio Liguori, Ciro Pentella, Alessia Zinzi, Miriam Longo, Paola Caruso, Maria Ida Maiorino, Katherine Esposito, Annalisa Capuano","doi":"10.1007/s43440-026-00864-4","DOIUrl":"https://doi.org/10.1007/s43440-026-00864-4","url":null,"abstract":"<p><strong>Introduction: </strong>The therapeutic landscape for the treatment of type 2 diabetes mellitus (T2DM) has greatly evolved with the introduction of glucagon-like peptide-1 receptor agonists (GLP-1 RAs); however, concerns regarding their potential association with thyroid cancer have emerged. The aim of this study is to analyze individual case safety reports (ICSRs) involving GLP-1 RAs, focusing on thyroid cancer-related adverse events (AEs) using the European pharmacovigilance database.</p><p><strong>Methods: </strong>ICSRs reporting GLP-1 RAs (semaglutide, liraglutide, exenatide, lixisenatide, dulaglutide) or the dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide as suspected drugs were retrieved from the EudraVigilance (EV) database from 1st January 2022 to 26th September 2024. A disproportionality analysis was performed to compare the probability of reporting thyroid cancer-related AEs among these drugs using the reporting odds ratio (ROR) and its 95% confidence interval (95% CI). Considering the different therapeutic indications, a sensitivity analysis was also conducted.</p><p><strong>Results: </strong>A total of 34,956 ICSRs were included in the analysis. The majority of AEs were experienced by adult and elderly female patients. The most reported system organ classes (SOCs) were: \"gastrointestinal disorders\", \"general disorders and administration site conditions\", and \"injury, poisoning and procedural complications\". Disproportionality analysis revealed that semaglutide had a lower probability of reporting thyroid cancer-related AEs than tirzepatide (ROR = 0.54, 95% CI 0.37-0.81, p < 0.05), whereas sensitivity analysis revealed no significant signals across stratified therapeutic groups.</p><p><strong>Conclusion: </strong>These findings should be interpreted with caution, given the inherent limitations of pharmacovigilance databases. Further studies are recommended to better assess the potential causal relationship between GLP-1 RAs and thyroid cancer.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148043233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the therapeutic potential of luteolin in renal pathology: a comprehensive pathway oriented approach.","authors":"Lovedeep Singh, Anish Singh, Ayush Kattna, Diksha Dalal","doi":"10.1007/s43440-026-00858-2","DOIUrl":"10.1007/s43440-026-00858-2","url":null,"abstract":"<p><p>Kidney diseases, particularly chronic kidney disease (CKD), represent a significant global health challenge, affecting over 9.5% of the world’s population. Both systemic inflammation and oxidative stress are strongly associated with the development of CKD and contribute to the emergence of numerous complications. Renal injury is driven by interconnected molecular pathways that collectively exacerbate inflammation, oxidative stress, and fibrotic responses. The activation of mitogen-activated protein kinase (MAPK)/nuclear factor kappa-B (NF-κB) signaling cascades, along with NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome assembly, synergistically amplifies the inflammatory response. Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) promotes excessive generation of reactive oxygen species (ROS), whereas impairment of sirtuin 1 (SIRT1)/nuclear factor erythroid 2-related factor 2 (Nrf-2) signaling weakens antioxidant defenses; together, these mechanisms exacerbate oxidative stress. In addition to oxidative stress, hyperglycemia also exacerbates renal damage by activating the transforming growth factor-beta (TGF-β)/hypoxia-inducible factor-1 alpha (HIF-1α) signaling axis, thereby promoting renal fibrosis. Collectively, these events culminate in progressive renal dysfunction. In addition to conventional therapies involving anti-inflammatory and antioxidant agents, emerging studies highlight the therapeutic potential of plant-derived agents in mitigating these pathological disturbances. Luteolin is a naturally occurring flavonoid abundantly distributed in a variety of dietary and medicinal plants, such as parsley, celery, green pepper, and carrots. It is predominantly found in members of the Lamiaceae, Asteraceae, Apiaceae, Fabaceae, and Poaceae families. Several studies highlight luteolin’s potential in alleviating renal diseases by targeting key mediators, including NF-κB, NLRP3, MAPK, NOX4, ROS, SIRT1, TGF-β, cytokines, and antioxidants, among others. Thus, considering the broad therapeutic potential of luteolin and the complex pathophysiology of renal diseases, the present study aims to elucidate the mechanisms through which luteolin mitigates renal injury.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147841424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Redox rewiring in glioblastoma: the thioredoxin system as a precision therapeutic target.","authors":"Hilda Espinoza, Agustín Gómez-Barrientos, Francisco López-Godoy, Pablo J Tapia, Mariela Puebla","doi":"10.1007/s43440-026-00857-3","DOIUrl":"10.1007/s43440-026-00857-3","url":null,"abstract":"<p><p>The thioredoxin system, comprising thioredoxin (Trx) and thioredoxin reductase (TrxR), is a central regulator of cellular redox homeostasis and plays essential roles in normal brain physiology and redox signaling. In glioblastoma (GBM), this system undergoes profound pathological rewiring, creating a redox dependency that represents a potential therapeutic vulnerability. The overexpression of Trx and TrxR in GBM promotes tumor proliferation, invasion, angiogenesis, and resistance to chemotherapy and radiotherapy, while the endogenous Trx inhibitor, thioredoxin-interacting protein (TXNIP), is frequently downregulated. This imbalance drives redox adaptation and sustains tumor survival under metabolic and therapeutic stress. Pharmacological modulation of the Trx system using synthetic inhibitors, such as auranofin, platinum-based compounds, and PX-12, as well as selected natural compounds including curcumin analogs and flavonoids, has shown efficacy in preclinical GBM models by inducing oxidative stress and enhancing sensitivity to standard therapies. Emerging evidence also suggests that Trx system targeting may modulate the tumor immune microenvironment, providing a rationale for combination strategies with immunomodulatory approaches. Overall, targeting the Trx system represents a promising precision oncology strategy for GBM. Future efforts should focus on the development of brain-penetrant inhibitors, rational combination therapies, and predictive biomarkers to facilitate clinical translation. Given the essential role of the Trx system in normal brain homeostasis, therapeutic targeting requires careful consideration of safety, therapeutic index, and tumor-selective vulnerabilities. This narrative review discusses current evidence on the physiological functions of the Trx system in the brain, its dysregulation in GBM, and its relevance as a precision therapeutic target.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147841353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A preliminary proof-of-concept trial on the effects of ketamine on fatigue: a randomized crossover trial.","authors":"Taichi Goto, Joy D Kreskow, Alexander L R Ross, Catherine L Blumhorst, Justin J Zhao, Andrew J Mannes, Miroslav Bačkonja, Carlos A Zarate, Leorey N Saligan","doi":"10.1007/s43440-025-00808-4","DOIUrl":"10.1007/s43440-025-00808-4","url":null,"abstract":"<p><strong>Background: </strong>Fatigue, a prevalent symptom of chronic illness, impacts quality of life. This proof-of-concept, randomized, double-blind, crossover trial assessed the anti-fatigue effects of ketamine (0.5 mg/kg) versus midazolam (0.045 mg/kg), the active comparator.</p><p><strong>Methods: </strong>Ten participants, who were cancer survivors, with fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome, or systemic lupus erythematosus, were randomized into Arm 1 (n = 4, Period 1: ketamine to Period 2: midazolam) or Arm 2 (n = 6, Period 1: midazolam to Period 2: ketamine).</p><p><strong>Results: </strong>The two periods were separately analyzed because of carryover effects with baseline fatigue scores, assessed by the fatigue visual analog scale (VAS), between the study periods (p = 0.03). Looking at changes in fatigue VAS scores from baseline (pre-infusion) to 3 days post-infusion, the ketamine group had a 21.0% decrease in Period 1 and 10.9% in Period 2, while the midazolam group showed a 17.7% decrease in Period 1 and 12.6% in Period 2. We did not observe a statistically significant difference in both periods. The largest fatigue score reduction for the ketamine group was at 1 day post-infusion, at - 38.7% in Period 1.</p><p><strong>Conclusion: </strong>Despite no statistical significance, a reduction in real-time fatigue scores was observed, which exceeded the 20% efficacy threshold, the primary outcome, in the ketamine arm from pre-infusion to 3 days post-infusion. The carryover effects and the peak reduction in fatigue at 24 hours after ketamine administration suggest that future trials may need to consider a study design without cross-over and an optimal active placebo alternative.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"558-567"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146019271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Niraparib induces hyperglycemia in ovarian cancer patients: a preliminary pilot study.","authors":"Konrad Lewandowski, Joanna Stanisławiak-Rudowicz, Edyta Szałek, Anna Wolc, Agnieszka Karbownik","doi":"10.1007/s43440-025-00811-9","DOIUrl":"10.1007/s43440-025-00811-9","url":null,"abstract":"<p><p>BACKGROUND: Niraparib (Nir) is a poly(ADP-ribose) polymerase inhibitor (PARPi) used in the maintenance treatment of platinum-sensitive ovarian cancer (OC) patients, regardless of homologous recombination deficiency status. Being overweight or obese increases the risk of developing both OC and diabetes. Given this overlap, understanding the effect of Nir on glycemia is particularly important; however, it remains poorly understood. METHODS: The study included 22 normoglycemic OC patients. Fasting glucose (FG) concentrations were measured before therapy and after the second, third, and fourth treatment cycle (a cycle is approximately 28 days). A linear mixed-effects model treating body mass index (BMI) as a continuous variable was applied for statistical calculations. RESULTS: Impaired fasting glucose (IFG) (5.6–6.9 mmol/L) was observed in 55% of patients at some point during the study, and in 27% throughout its duration. A significant interaction between BMI and time was detected (p = 0.0412), with the influence of BMI on Nir-caused hyperglycemia increasing as the study progressed. CONCLUSIONS: Hyperglycemia appears to be an adverse effect of Nir. As there is some indication that BMI may influence this effect, glycemic control is recommended, particularly in patients with an elevated BMI. </p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"597-606"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12975802/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145715443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulation of store-operated calcium entry in fibroblast lines from adult and juvenile-onset Huntington's disease patients.","authors":"Samuel Oluwafemi Egbuwalo, Ewelina Latoszek, Hana Hansíková, Jiří Klempíř, Alžbeta Mühlbäck, Georg Bernhard Landwehrmeyer, Jacek Kuźnicki, Magdalena Czeredys","doi":"10.1007/s43440-025-00820-8","DOIUrl":"10.1007/s43440-025-00820-8","url":null,"abstract":"<p><strong>Background: </strong>The pathology of Huntington's disease (HD) is marked by the aggregation of mutant huntingtin protein (mHTT), which results from expanded polyglutamine (polyQ) residues encoded by CAG repeats in the HTT gene. These repeats are differentially elongated in adult- and juvenile-onset HD. In striatal neurons, the mHTT disrupts cellular mechanisms such as store-operated calcium entry (SOCE), a process in which endoplasmic reticulum Ca²⁺ depletion triggers extracellular Ca²⁺ influx; however, this process can also be affected in peripheral cells. The aim of this study was to evaluate SOCE in fibroblasts derived from both HD onset patients and age-related controls.</p><p><strong>Methods: </strong>We conducted SOCE analysis in dermal fibroblasts from 12 HD patients (including adult- and juvenile-onset subtypes) and age-related healthy controls using Fura-2 AM ratiometric imaging paired with EGTA-based extracellular calcium chelation protocols. To evaluate SOCE response, we administered two SOC channel inhibitors, 6-bromo-N-(2-phenylethyl)-2,3,4,9-tetrahydro-1 H-carbazol-1-amine hydrochloride (C₂₀H₂₂BrClN₂) and EVP4593, in premanifest HD fibroblasts.</p><p><strong>Results: </strong>In healthy human fibroblast lines, a decline in SOCE was observed between juvenile and adult individuals. In fibroblast lines from adult-onset HD patients (premanifest, early manifest, and manifest stages), we observed increased SOC channel activity. Conversely, juvenile-onset HD fibroblast lines exhibited reduced SOC channel activity compared to controls. Notably, SOCE dysregulation was independent of CAG repeat length in HD lines. Both SOC channel inhibitors attenuated SOCE in adult-onset HD lines.</p><p><strong>Conclusion: </strong>The mHTT upregulates SOCE in adult-onset HD fibroblasts and downregulates it in juvenile-onset HD fibroblast lines; however, SOCE levels do not correlate with the length of CAG repeats encoding mHTT. Despite opposing trends compared to age-related controls, similar levels of SOCE in both HD-onset fibroblasts were detected. Both C₂₀H₂₂BrClN₂ and EVP4593 show potential for stabilizing SOCE in adult-onset HD. These findings suggest that dysregulated SOCE could be investigated as a peripheral target for studying pathological processes potentially associated with Huntington's disease.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"568-581"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12975840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The HPA axis and kynurenine pathway: exploring the role of stress and neuroinflammation in treatment-resistant depression.","authors":"Madhura M Bose, Anusha Govindula, Madhavan Nampoothiri, Devinder Arora, Jayesh Mudgal","doi":"10.1007/s43440-025-00806-6","DOIUrl":"10.1007/s43440-025-00806-6","url":null,"abstract":"<p><p>Treatment-resistant depression (TRD) continues to pose a major challenge in clinical practice, as a large proportion of patients fail to achieve remission despite multiple antidepressant drugs. Growing evidence indicates that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, together with epigenetic alterations, neuroinflammation, and kynurenine pathway metabolism, plays a central role in the pathophysiology of TRD. Particularly, prolonged stress-induced glucocorticoid receptor (GR) resistance, persistent hypercortisolaemia, and elevated pro-inflammatory cytokines contribute to neurotoxicity, hippocampal atrophy, and impaired neuroplasticity, aggravating depressive symptoms and reducing treatment response. Additionally, dysregulated tryptophan metabolism and the shift towards neurotoxic kynurenine metabolites further impair neuronal function and resulting in TRD. This review integrates recent findings on the complex interplay between HPA axis dysfunction, neuroimmune responses, and metabolic disturbances in TRD while highlighting novel therapeutic avenues such as ketamine, GR modulators, and anti-inflammatory agents. Further, disruption in the blood-brain barrier as one of the mechanisms of TRD was also reviewed. A deeper understanding of these mechanisms will enable the development of personalized treatment strategies to enhance clinical outcomes for TRD patients.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"374-390"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12975799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145550027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}