Pharmacological Reports最新文献

{"title":"Exploring the anti-inflammatory activity of sulforaphane metabolites.","authors":"Barbara Pagliarani, Letizia Pruccoli, Chiara Chemello, Morena Zusso, José Cláudio Fonseca Moreira, Andrea Tarozzi, Henrique Mautone Gomes","doi":"10.1007/s43440-026-00823-z","DOIUrl":"10.1007/s43440-026-00823-z","url":null,"abstract":"<p><p>BACKGROUND: Isothiocyanate sulforaphane (SFN), found in cruciferous vegetables, is known for its anti-inflammatory properties in vitro, in vivo, and in humans. After intestinal absorption, SFN forms metabolites such as SFN-glutathione, SFN-cysteine, and SFN-N-acetylcysteine in plasma and tissues, which may contribute to its anti-inflammatory effects. This study aimed to compare the anti-inflammatory profiles of these metabolites with that of SFN, focusing on proinflammatory pathways such as TLR4/NF-κB and NLRP3 inflammasome. METHODS: The study utilized human TLR4 Reporter HEK293 cells and human THP-1 macrophages to investigate the pro-inflammatory effects of lipopolysaccharide (LPS). TLR4 activation was assessed in the HEK293 cells, while the activation of NF-κB p65, NLRP3, and Keap1/Nrf2, as well as the release of the pro-inflammatory cytokines IL-1β and TNF-α, were evaluated in THP-1 macrophages through western blotting, RT-PCR, and ELISA techniques. RESULTS: SFN and its metabolites decreased the activation of TLR4, NLRP3 inflammasome, and nuclear NF-κB p65. Further, they reduced the expression and release of the cytokines IL-1β and TNF-α. While all compounds disrupted the Keap1/Nrf2 complex and released individual proteins, only SFN promoted the nuclear translocation of Nrf2, suggesting a different crosstalk with the NF-κB pathway. CONCLUSIONS: SFN metabolites, including SFN-glutathione, SFN-cysteine, and SFN-N-acetylcysteine, have demonstrated anti-inflammatory effects mainly through the TLR4/NF-κB pathway, which involves the NLRP3 inflammasome. This data indicates their direct contribution to the overall anti-inflammatory effects of SFN. </p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"615-624"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146029743","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":"Docosahexaenoic acid modulates myo-inositol and myo-inositol biosynthetic genes expression: implications for bipolar disorder.","authors":"Marlene Murray, Haley Kang, Taejun Ok, Kimberly Park, Joanne Jee Yeon Lee, Bomi Kim, Hyukje Sung, Talisa Tait, Daniel Colon Hidalgo, Yudy Guzman","doi":"10.1007/s43440-025-00815-5","DOIUrl":"10.1007/s43440-025-00815-5","url":null,"abstract":"<p><p>BACKGROUND: Bipolar disorder (BD) is a mood disorder affecting approximately 1–2% of the population. It is treated primarily with mood stabilizers, which have variable efficacy and tolerability. Omega-3 polyunsaturated fatty acids, particularly docosahexaenoic acid (DHA), have emerged as potential adjunctive treatments, though clinical findings and underlying mechanisms remain inconsistent. Given that myo-inositol depletion is proposed as a common mechanism for conventional mood stabilizers, we hypothesized that DHA, which modulates components of the phosphatidylinositol pathway, would alter intracellular myo-inositol and thus modulate myo-inositol homeostasis. The aim of this study was to determine the effect of DHA on intracellular myo-inositol and the expression of key genes involved in its biosynthesis. METHODS: Using an enzymatic assay, intracellular myo-inositol levels were measured in the extracts of cells grown in the presence of DHA. The effect of DHA on the expression of the myo-inositol biosynthetic genes INO1 (inositol-1-phosphate synthase) and INM1 (inositol monophosphatase) was assessed by RT-qPCR. RESULTS: DHA altered intracellular myo-inositol in a concentration-dependent manner, with low concentrations decreasing levels and higher concentrations producing increases relative to untreated controls. RT-qPCR analysis showed corresponding modulation of INO1 and INM1 expression, consistent with changes in myo-inositol homeostasis. While some group differences reached statistical significance, particularly in comparisons with valproate (VPA)-treated controls, most contrasts among DHA-treated groups were not significant. CONCLUSION: These findings provide preliminary evidence that DHA modulates intracellular myo-inositol levels and the expression of key biosynthetic genes in yeast. The biphasic response observed suggests a dose-sensitive effect that may help explain inconsistencies in clinical outcomes. While the results support the idea that omega-3 fatty acids influence inositol homeostasis, they should be considered hypothesis-generating and warrant confirmation in mammalian models and clinical settings. CLINICAL TRIAL NUMBER: Not applicable. </p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"607-614"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900921","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":"Metformin in skin diseases: the role of gut microbiota and immune response.","authors":"Aneta Kiecka, Barbara Macura, Marian Szczepanik","doi":"10.1007/s43440-026-00825-x","DOIUrl":"10.1007/s43440-026-00825-x","url":null,"abstract":"<p><p>Metformin is one of the most commonly prescribed drugs for the treatment of type 2 diabetes (T2D). Its mechanism of action involves lowering blood glucose levels by enhancing peripheral tissue sensitivity to insulin, inhibiting hepatic glucose production, and decreasing intestinal glucose absorption. Recent research has shown that metformin may also have therapeutic potential beyond diabetes, including the treatment of chronic pain, cancer, and polycystic ovary syndrome. Additionally, metformin is used in managing various skin diseases such as atopic dermatitis (AD), allergic contact dermatitis (ACD), and psoriasis. It has also been found to influence skin aging processes and promote wound healing. These effects may be attributed to metformin’s immunomodulatory properties and its ability to modulate the gut microbiota. The aim of this review is to summarize the current evidence on the effects of metformin on gut microbial composition and the immune system, as well as its potential role in the treatment of skin diseases.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"391-404"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030045","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":"Effects of psilocybin and chronic mild stress on microglial activation in rat spinal cord: an ex vivo analysis.","authors":"Piotr Olejnik, Katarzyna Kamińska, Krystyna Gołembiowska, Kaja Kasarełło","doi":"10.1007/s43440-026-00824-y","DOIUrl":"10.1007/s43440-026-00824-y","url":null,"abstract":"<p><p>INTRODUCTION: Psilocybin, a classic serotonergic psychedelic, has antidepressant, anxiolytic, anti-inflammatory, and analgesic properties. However, the immunomodulatory effects of psilocybin within the central nervous system, particularly on microglial activation, remain poorly understood. Therefore, this study aimed to investigate the effects of psilocybin on microglial activation markers and cytokine levels in the spinal cord isolated from rats subjected to chronic mild stress (CMS). METHODS: Tissues were isolated from four groups of adult male Wistar Han rats, each consisting of seven animals: not subjected to CMS (control), receiving two injections of saline (0.9% NaCl ip) or psilocybin (0.6 mg/kg ip) at 7-day intervals, and subjected to CMS, receiving two injections of NaCl (0.9% NaCl ip) or psilocybin (0.6 mg/kg ip) at 7-day intervals. Spinal cords were collected 1 week after the second dose of saline/psilocybin from the sacrificed rats and stored at -80 °C. The levels of microglial activation markers (iNOS and Arg1) and pro- and anti-inflammatory cytokines (TNF-α and IL-10) were analyzed using an enzyme-linked immunosorbent assay. RESULTS: The spinal cords isolated from CMS rats treated with psilocybin revealed significantly increased levels of Arg1 (p = 0.0306), TNF-α (p = 0.0357), and IL-10 (p = 0. 0081) compared to tissues from control rats administered with psilocybin. Additionally, although not statistically significant, iNOS levels showed an increasing trend in CMS rats treated with psilocybin compared to those in psilocybin-receiving controls (p = 0.0755). CONCLUSIONS: CMS activates the immune system/microglia non-specifically despite psilocybin administration. CLINICAL TRIAL NUMBER: Not applicable. </p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"423-430"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011629","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":"The Sigma₁ receptor antagonist CM304 potentiates the antinociceptive effects of the cannabinoid receptor agonist delta⁹-tetrahydrocannabinol in rats and mice.","authors":"Elmira Zolali, Mallory Burns, Sebastiano Intagliata, Avi Patel, Nicholas P Ho, Luis F Restrepo, Lea R Gamez-Jimenez, Manuel A Alvarez, Lisa L Wilson, Stephen J Cutler, Lance R McMahon, Takato Hiranita, Samuel Obeng, Christopher R McCurdy","doi":"10.1007/s43440-026-00834-w","DOIUrl":"10.1007/s43440-026-00834-w","url":null,"abstract":"<p><p>BACKGROUND: Mu opioid receptor (MOR) agonists are the primary medication class used to treat moderate to severe pain; however, the ongoing opioid overdose crisis underscores the need for alternatives to MOR agonists for pain treatment. Delta9-tetrahydrocannabinol (THC), a cannabinoid CB1 receptor (CB1R) agonist, and sigma1 receptor (σ1R) antagonists elicit antinociceptive effects albeit less effectively than MOR agonists. Co-administration of σ1R antagonists with THC may offer a safer alternative for pain management. METHODS: Antinociception (warm water tail withdrawal in mice and hot plate assays in rats), hypothermia (mice and rats), locomotion (mice), and drug discrimination (rats) assays were employed to evaluate the effects of the σ1R antagonist CM304 alone and in combination with THC. RESULTS: In naïve mice, CM304 (ip) shifted the antinociceptive time-effect function of 32 mg/kg (ip) THC upward. Similarly, greater hypothermia was observed with combinations of THC and CM304 than each compound alone. Only the high dose of CM304 (56 mg/kg) induced hypolocomotion. In naïve rats, CM304 (1.0 and 3.2 mg/kg, iv) dose-dependently shifted the antinociceptive dose-effect function of THC to the left. In rats trained to discriminate THC (3.2 mg/kg, ip), CM304 (10 and 17.8 mg/kg) did not elicit THC-like discriminative stimulus effects. In contrast to the antinociceptive experiments, CM304 (10 mg/kg) did not significantly shift the discrimination dose-effect function of THC. These results suggest that σ1R antagonists like CM304 can potentiate the antinociceptive effects of THC without potentiating its adverse effects, supporting their potential as adjuncts to CB1R agonists for acute pain treatment. </p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"431-445"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143190","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":"Differential effects of isopropyl alcohol on glucose-induced insulin secretion in INS-1 and MIN6 cells.","authors":"Valérie Pawlowski, Valérie Plaisance, Mathilde Lucas, Emerson Giovanelli, Chloé Derasse, Alexandre Barras, Amar Abderrahmani","doi":"10.1007/s43440-026-00828-8","DOIUrl":"10.1007/s43440-026-00828-8","url":null,"abstract":"<p><p>BACKGROUND: Solvents such as isopropyl alcohol (IPA, propan-2-ol, also called isopropanol) can occasionally be used for drug solubilization in in vitro screening of antidiabetic agents. However, their potential to interfere with pancreatic β-cell function remains poorly characterized. OBJECTIVE: This study aimed to assess the effects of IPA on insulin secretion and viability in two widely used β-cell models, INS-1 and MIN6. METHODS: INS-1 and MIN6 cells were exposed to increasing concentrations of IPA (0–10% v/v). Cell viability, total insulin content, and glucose-stimulated insulin secretion (GSIS) were evaluated. Mechanistic insights were investigated using co-incubation with the K(ATP) channel opener diazoxide (200 µM), the protein kinase A (PKA) inhibitor H89 (10 µM), and antioxidants N-acetylcysteine (NAC, 2 mM) and quercetin (20 µM). RESULTS: IPA up to 1% (v/v) was non-cytotoxic in both cell lines. In MIN6 cells, IPA did not affect GSIS. In contrast, IPA dose-dependently enhanced GSIS in INS-1 cells, without altering basal secretion or total insulin content. This effect was unaffected by NAC or quercetin, but it was abolished by diazoxide and significantly reduced by H89, suggesting a mechanism involving K(ATP) channel closure, protein kinase A (PKA) activation, and its downstream signaling. However, intracellular cAMP levels remained unchanged, indicating a cAMP-independent activation of PKA. CONCLUSIONS: IPA can enhance insulin secretion in a cell-line-specific manner via PKA-dependent, cAMP-independent pathways involving K(ATP) channels. These findings underscore the importance of solvent choice in drug screening, as IPA may confound β-cell functional assays. </p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"535-545"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011572","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":"Targeting mitochondrial deubiquitinase USP30 to induce mitophagy in heteroplasmic mitochondrial diseases.","authors":"Brígida R Pinho, Vasco Martins, Anitta R Chacko, Célia Nogueira, Michael R Duchen, Jorge M A Oliveira","doi":"10.1007/s43440-026-00829-7","DOIUrl":"10.1007/s43440-026-00829-7","url":null,"abstract":"<p><p>BACKGROUND: Mitochondrial DNA (mtDNA) diseases are heterogeneous and lack effective treatments. Their severity correlates with mutant mtDNA load. Mitophagy degrades dysfunctional mitochondria, contributing to a healthy mitochondrial pool. USP30, a mitochondrial deubiquitinase, limits mitophagy by removing the ubiquitin tagging mitochondria for degradation. We investigated whether inhibiting USP30 could enhance mitophagy and reduce mutant mtDNA load in a heteroplasmic mitochondrial disease. METHODS: Cybrids cells harboring mutant m.8993T > G mtDNA - common cause of NARP syndrome and maternally inherited Leigh syndrome (MILS) - were treated with USP30 inhibitor MF-094 under glycolytic and oxidative phosphorylation conditions. On-target activity of MF-094 was assessed by mitochondrial ubiquitination (western-blot) and mitolysosome formation (microscopy). The mutation’s effects were investigated on cell proliferation and metabolism (respirometry and ATP levels). The impact of MF-094 on mutant mtDNA load and mtDNA copy number was quantified by PCR. RESULTS: Comparing with control cells (0% mutant mtDNA), cells with mutant mtDNA exhibited reduced proliferation and ATP levels under oxidative phosphorylation conditions; and reduced oxygen consumption, increased extracellular acidification, and sustained resazurin metabolism after mitochondrial inhibition under glycolytic conditions. MF-094 induced mitophagy via increased mitolysosome formation. Mechanistically, MF-094 showed on-target effects, increasing mitochondrial ubiquitination. However, chronic treatment (3–6 weeks) evoked only a small (5%) non-significant reduction in mutant mtDNA load. CONCLUSIONS: Despite inducing mitophagy, the USP30 inhibitor MF-094 showed little potential to manage m.8993T > G related diseases, as it did not significantly reduce the load of this NARP/MILS causing mtDNA mutation. These results highlight the complexity of mutant mtDNA management and the need for innovative strategies for these disorders. </p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"519-534"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12975861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146053405","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":"WIN55,212-2 attenuates intestinal fibrosis in a DSS-induced mouse model.","authors":"Zofia Misztal, Maria Wołyniak, Ewa Małecka-Wojciesko, Adam Fabisiak","doi":"10.1007/s43440-026-00822-0","DOIUrl":"10.1007/s43440-026-00822-0","url":null,"abstract":"<p><p>BACKGROUND: Inflammatory bowel diseases (IBD) are often associated with intestinal fibrosis. There is increased interest in new methods for managing intestinal fibrosis, among which the endocannabinoid system (ECS) is an interesting therapeutic target. The primary purpose of the study was to evaluate the effect of CB1/2 agonist, WIN 55,212-2 (WIN) on expression of fibrosis regulatory proteins: alpha smooth muscle Actin 2 (ACTA2), Collagen I (COLIA1), Fibronectin 1 (FN1) and SMAD family member 3 (SMAD3) in a mice model of dextran sulfate sodium (DSS)-induced intestinal fibrosis. METHODS: Chronic intestinal fibrosis was induced by oral administration of 1.5% DSS in rotation with tap water for 3 weeks in three cycles. WIN was administered intraperitoneally, once daily starting from day 10th and continued every other day until day 77th. The expression of genes encoding ACTA2, COL1A1, FN1, SMAD3, Col1a1, Fn1 both in mouse and human colon, was assessed with real-time PCR. RESULTS: We found lower relative expression of genes encoding fibrosis regulatory proteins in colonic mucosa of mice treated with WIN than in inflamed mice: ACTA2 (–51%), COL1A1 (–44%), FN1 (–60%), and SMAD3 (–22%). Human colonic mucosal patients with UC showed higher expression of COL1A1 (+ 57%) and SMAD3 (+ 34%) compared to healthy controls. CONCLUSIONS: Our results show that regulation of ECS activity may play a role in the inhibition of intestinal fibrosis in IBD and appears as a potential therapeutic target in patients at high risk of developing strictures. </p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"479-486"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12975791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146053376","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 PERK inhibitor GSK2606414 evokes developmental defects in zebrafish consistent with Wolcott-Rallison syndrome phenotypes.","authors":"Liliana M Almeida, Leonor Pereira Lima, Nuno A S Oliveira, Rui F O Silva, Bruno Sousa, José Bessa, Brígida R Pinho, Jorge M A Oliveira","doi":"10.1007/s43440-026-00837-7","DOIUrl":"10.1007/s43440-026-00837-7","url":null,"abstract":"<p><p>BACKGROUND: Protein kinase RNA-like endoplasmic reticulum kinase (PERK) is an endoplasmic reticulum stress kinase whose loss of function disturbs human development, leading to skeletal dysplasia and permanent neonatal diabetes, as in the Wolcott-Rallison Syndrome (WRS). The lack of effective, less invasive therapies for developmental diseases highlights the need for animal models that replicate complex pathological phenotypes, while allowing scalable drug screening. Zebrafish high fecundity and rapid development enable efficient in vivo drug testing. We assessed zebrafish’s potential for studying PERK and its pharmacological modulation in developmental diseases like WRS. METHODS: To assess the similarity between human and zebrafish PERK we used bioinformatic analyses. To inhibit PERK we used GSK2606414. To evaluate effects on skeletal, neuromuscular, and cardiac development we combined behavioural and functional assays. To assess diabetic-like phenotypes we used fluorescent pancreatic markers and a glucose probe. RESULTS: Zebrafish PERK conserves 11 of 12 critical GSK2606414‑binding residues (predicted 3D structures highly similar). Functionally, GSK2606414 (10 µM) decreased levels of PERK pathway markers and induced WRS-relevant phenotypes: reduced body length, increased trunk–tail curvature, decreased cranial cartilage staining; neuromuscular impairment (altered reflexes, reduced muscle birefringence) and cardiac dysfunction (pericardial oedema, reduced stroke volume and cardiac output). However, parameters not associated with WRS like otolith area and eye/body ratio remained unaffected. Moreover, GSK2606414 decreased 𝛽-cell mass and lowered 2-NBDG-glucose uptake in neuromasts, consistent with diabetic-like phenotypes. CONCLUSION: These findings evidence zebrafish’s potential for studying PERK function and its pharmacological modulation in developmental disorders like WRS, aiding research on pathophysiology and experimental treatments. </p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"487-504"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12975795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146181585","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 synaptic triad in depression: how stress-related pathways converge on BDNF, NMDA receptor, and MMP-9.","authors":"Bartosz Adam Frycz, Magdalena Dutsch-Wicherek, Olga Płaza, Agata Szulc, Monika Bijata, Jakub Wlodarczyk, Joanna Dzwonek","doi":"10.1007/s43440-026-00827-9","DOIUrl":"10.1007/s43440-026-00827-9","url":null,"abstract":"<p><p>Chronic stress is a major precipitating factor in depression, engaging interconnected central and peripheral pathways. In this review, we propose an integrative model that organizes the neurobiological consequences of stress around five major mechanistic domains: neurotrophic dysfunction, disturbances in inhibition-excitation (E/I) balance, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, neuroinflammatory activation, and monoaminergic alterations. Although each hypothesis highlights distinct aspects of stress-related pathology, we argue that they ultimately converge on shared molecular mediators, including matrix metalloproteinase-9 (MMP-9), brain-derived neurotrophic factor (BDNF), and N-methyl-D-aspartate (NMDA) receptor-dependent signalling, that govern synaptic plasticity.In this model, synaptic plasticity emerges as the final common mechanism through which chronic stress produces enduring alterations in brain structure and function. Context-dependent modulation of MMP-9 activity, dysregulated BDNF processing, NMDA-dependent control of synaptic strength, and monoaminergic influences on neurotrophic and glial function collectively impair synaptic plasticity. As a result, stress-driven pathways lead to altered dendritic spine architecture, reduced neurogenesis, and maladaptive network-level changes underlying depressive behavior. By positioning synaptic plasticity as the convergent endpoint of diverse stress-responsive mechanisms, the model highlights common therapeutic targets, including MMP-9 modulation, BDNF-enhancing strategies, HPA-axis regulators, anti-inflammatory approaches, and NMDA receptor-based interventions, offering new directions for mechanism-based and personalized treatments in depression.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"351-373"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146065909","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}