Effects of positive mGlu5 modulation on D2 signaling and nicotine-conditioned place preference: Mechanisms of epigenetic inheritance in a transgenerational model of drug abuse vulnerability in psychosis DOI
Loren D. Peeters, Liza J. Wills,

Anthony M. Cuozzo

et al.

Journal of Psychopharmacology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 27, 2024

Background: The metabotropic glutamate type 5 (mGlu5) receptor has emerged as a potential target for the treatment of psychosis that is suggested to have greater efficacy than antipsychotic medications are currently utilized. Aims: This study sought elucidate mechanisms therapeutic action associated with modulation mGlu5 in disordered system marked by dopamine dysfunction. We further explored epigenetic contributing heritable transmission psychosis-like phenotype novel model drug abuse vulnerability psychosis. Methods: F1 generation male and female Sprague-Dawley rats were offspring two neonatal quinpirole-treated (QQ) or saline-treated (SS) animals tested on nicotine-conditioned place preference (CPP). Regulators G protein signaling 9 (RGS9) β-arrestin 2 (βA2), which mediate (DA) D signaling, measured nucleus accumbens shell, prelimbic infralimbic cortices. Reduced Representation Bisulfite Sequencing (RRBS) was used analyze cytosine methylation these brain regions. Results: Pretreatment mGlu5-positive allosteric modulator 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) 20 min prior conditioning trials blocked enhanced nicotine CPP mitigated aberrant protein-dependent -independent QQ animals. RRBS analysis revealed region-specific changes several pathways, including addiction, synapses, neural connectivity. Conclusions: These results reveal an important mechanism CDPPB DAD signaling. Results additionally DNA heritability, validating current useful tool comorbid use.

Language: Английский

KEAP1‐NRF2/HO‐1 Pathway Promotes Ferroptosis and Neuronal Injury in Schizophrenia DOI Creative Commons
Feng Zhu, Dan Tang,

Sherwin E. Hua

et al.

Brain and Behavior, Journal Year: 2025, Volume and Issue: 15(3)

Published: Feb. 28, 2025

ABSTRACT Background This study investigates the role of KEAP1‐NRF2/HO‐1 signaling pathway in inducing ferroptosis and contributing to neuronal damage schizophrenia. Methods We retrieved schizophrenia‐related data ferroptosis‐related genes from RNA microarray dataset GSE27383 FerrDB database, respectively. Bioinformatics identified KEAP1 as a downregulated gene, which was validated using qRT‐PCR Western blot. assessed intracellular Fe 2 ⁺ content, MDA levels, GSH, GPX4 prefrontal cortex peripheral blood mononuclear cells (PBMCs) patients with Cortical interneurons (cINs) were generated human‐induced pluripotent stem (hiPSCs) schizophrenia used explore alterations during neurodevelopment. In addition, overexpression induced cINs via transfection pcDNA KEAP1. The Fe⁺ oxidative stress indicators, lipid peroxidation, inflammatory cytokines measured after transfection. To investigate molecular mechanisms, KI696—a high‐affinity probe that disrupts KEAP1–NRF2 interaction—was applied, changes stress, peroxidation (C11‐BODIPY staining), iron metabolism, pathways evaluated. Results Patients exhibited underexpression KEAP1, key regulator ferroptosis, along elevated levels increased concentrations, indicating enhanced stress. Reduced activity GSH also observed, suggesting an susceptibility ferroptosis. further this, derived hiPSCs studied. These showed decreased expression. Overexpression led reduction concentrations damage, highlighting KEAP1's regulatory treatment KI696 significant related antioxidant defenses, inflammation. Conclusion Our findings indicate contributes injury

Language: Английский

Citations

0
Molecular and Functional Analysis of TLR 1, 2 and 6 in Peripheral Blood Monocytes of Patients with Schizophrenia: A Pilot Study DOI Open Access
Carlo E Sotelo-Ramírez, Marcela Valdés‐Tovar, Julio Uriel Zaragoza-Hoyos

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 926 - 926

Published: Jan. 23, 2025

Schizophrenia (SZ) is a chronic disabling mental disorder with high heritability, and several immune-regulating genes have been implicated in its pathophysiology In this study, we investigated the expression of Toll-like receptors (TLRs) 1, 2, 6 peripheral blood monocytes from SZ patients healthy control subjects (HCSs) Mexican population, focusing on specific SZ-associated gene variants. Gene expressions were assessed by qPCR, protein was measured using flow cytometry. The secretory profiles MALP2-stimulated evaluated through immunoproteomic arrays. Our results indicate that carrying rs4833093/TLR1 GG genotype exhibited significantly lower TLR1 compared to TT carriers. Notably, HCSs showed markedly higher expression, while all reduced levels regardless genotype. Furthermore, displayed altered secretion upon TLR stimulation, significant elevations IL-18, uPAR, angiopoietin-2, serpin E1, alongside reductions MCP-1, IL-17A, IL-24, MIF, myeloperoxidase HCSs. These findings suggest dysfunctional TLR-mediated innate immune response SZ.

Language: Английский

Citations

0
Association between the COX-2 rs689466 polymorphism and antipsychotic treatment: Impact on HDL cholesterol changes in clozapine-treated psychosis patients DOI
Sergej Nadalin,

Ivan Ljoka,

Aleksandar Savić

et al.

Prostaglandins Leukotrienes and Essential Fatty Acids, Journal Year: 2025, Volume and Issue: unknown, P. 102665 - 102665

Published: Jan. 1, 2025

Language: Английский

Citations

0
What Remains to Be Discovered in Schizophrenia Therapeutics: Contributions by Advancing the Molecular Mechanisms of Drugs for Psychosis and Schizophrenia DOI Creative Commons
Christoph U. Correll, Massimo Tusconi, Mauro Giovanni Carta

et al.

Biomolecules, Journal Year: 2024, Volume and Issue: 14(8), P. 906 - 906

Published: July 25, 2024

Schizophrenia is a frequently debilitating and complex mental disorder affecting approximately 1% of the global population, characterized by symptoms such as hallucinations, delusions, disorganized thoughts behaviors, cognitive dysfunction, negative symptoms. Traditional treatment has centered on postsynaptic dopamine antagonists, commonly known antipsychotic drugs, which aim to alleviate improve functioning quality life. Despite availability these medications, significant challenges remain in schizophrenia therapeutics, including incomplete symptom relief, resistance, medication side effects. This opinion article explores advancements treatment, emphasizing molecular mechanisms, novel drug targets, innovative delivery methods. One promising approach strategies that target neural networks circuits rather than single neurotransmitters, acknowledging complexity brain region interconnections involved schizophrenia. Another development biased agonists, selectively activate specific signaling pathways downstream receptors, offering potential for more precise pharmacological interventions with fewer The concept polypharmacy, where targets multiple pathways, exemplified KarXT, combining xanomeline trospium address both psychosis dysfunction. represents comprehensive strategy potentially improving outcomes patients. In conclusion, advancing understanding exploring therapeutic hold promise addressing unmet needs aiming effective tailored interventions. Future research should focus approaches achieve better clinical functional level life individuals

Language: Английский

Citations

2
Editorial: Reviews in psychiatry 2023: schizophrenia DOI Creative Commons
Massimo Tusconi, Dennis Kätzel, Teresa Sánchez‐Gutiérrez

et al.

Frontiers in Psychiatry, Journal Year: 2024, Volume and Issue: 15

Published: July 4, 2024

Keywords: schizophrenia, biomarkers, therapeutic targets, systematic reviews, psychosocial functioning, psychological therapy, symptom domains, pharmacological therapy

Language: Английский

Citations

1
Effects of positive mGlu5 modulation on D2 signaling and nicotine-conditioned place preference: Mechanisms of epigenetic inheritance in a transgenerational model of drug abuse vulnerability in psychosis DOI
Loren D. Peeters, Liza J. Wills,

Anthony M. Cuozzo

et al.

Journal of Psychopharmacology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 27, 2024

Background: The metabotropic glutamate type 5 (mGlu5) receptor has emerged as a potential target for the treatment of psychosis that is suggested to have greater efficacy than antipsychotic medications are currently utilized. Aims: This study sought elucidate mechanisms therapeutic action associated with modulation mGlu5 in disordered system marked by dopamine dysfunction. We further explored epigenetic contributing heritable transmission psychosis-like phenotype novel model drug abuse vulnerability psychosis. Methods: F1 generation male and female Sprague-Dawley rats were offspring two neonatal quinpirole-treated (QQ) or saline-treated (SS) animals tested on nicotine-conditioned place preference (CPP). Regulators G protein signaling 9 (RGS9) β-arrestin 2 (βA2), which mediate (DA) D signaling, measured nucleus accumbens shell, prelimbic infralimbic cortices. Reduced Representation Bisulfite Sequencing (RRBS) was used analyze cytosine methylation these brain regions. Results: Pretreatment mGlu5-positive allosteric modulator 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) 20 min prior conditioning trials blocked enhanced nicotine CPP mitigated aberrant protein-dependent -independent QQ animals. RRBS analysis revealed region-specific changes several pathways, including addiction, synapses, neural connectivity. Conclusions: These results reveal an important mechanism CDPPB DAD signaling. Results additionally DNA heritability, validating current useful tool comorbid use.

Language: Английский

Citations

1