Identifying compounds to treat opiate use disorder by leveraging multi-omic data integration and multiple drug repurposing databases

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 18, 2024

ABSTRACT Genes influencing opioid use disorder (OUD) biology have been identified via genome-wide association studies (GWAS), gene expression, and network analyses. These discoveries provide opportunities to identifying existing compounds targeting these genes for drug repurposing studies. However, systematically integrating discovery results relevant available pharmacotherapies OUD is challenging. To address this, we’ve constructed a framework that leverages databases identify candidate pharmacotherapies. For this study, two independent related meta-analyses were used including GWAS differential expression (DGE) study of post-mortem human brain. Protein-Protein Interaction (PPI) sub-networks enriched risk loci Drug Pharos, Open Targets, Therapeutic Target Database (TTD), DrugBank queried clinical status target selectivity. Cross-omic query then integrated compounds. DGE analyses revealed 3 335 (FDR q<0.05), respectively, while analysis detected 70 in 22 PPI networks. Four selection strategies implemented, which yielded between 72 676 with statistically significant support 110 683 drugs genes, respectively. After filtering out less specific or those well-established psychiatric-related receptors ( OPRM1 DRD2 ), 2 329 approved remained across the four strategies. By leveraging multiple lines biological evidence resources, we many FDA associated OUD. This approach a) allows high-throughput querying OUD-related b) detects not using single domain resource, c) produces succinct summary eligible efficient expert review. Identifying larger pools summarizing supporting bridges gap

Язык: Английский

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New perspective on sustained antidepressant effect: focus on neurexins regulating synaptic plasticity

Cell Death Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Май 1, 2024

Depression is highly prevalent globally, however, currently available medications face challenges such as low response rates and short duration of efficacy. Additionally, depression mostly accompany other psychiatric disorders, further progressing to major depressive disorder without long-term effective management. Thus, sustained antidepressant strategies are urgently needed. Recently, ketamine psilocybin gained attention potential antidepressants. Review recent studies highlights that synaptic plasticity changes key events downstream long-lasting in effect. This underscores the significance Moreover, neurexins, molecules involved regulation plasticity, act critical links between effects, involving mechanisms including protein level, selective splicing, epigenetics, astrocytes, positional redistribution structure. Based on by several drugs with for effect also discussed. Focusing neurexins regulating promises much understanding underlying next step new drug development. research represents a promising future direction.

Язык: Английский

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GM-1020: a novel, orally bioavailable NMDA receptor antagonist with rapid and robust antidepressant-like effects at well-tolerated doses in rodents

Neuropsychopharmacology, Год журнала: 2024, Номер 49(6), С. 905 - 914

Опубликована: Янв. 4, 2024

Abstract The NMDA receptor (NMDAR) antagonist ketamine has shown great potential as a rapid-acting antidepressant; however, its use is limited by poor oral bioavailability and side effect profile that necessitates in-clinic dosing. GM-1020 novel NMDAR was developed to address these limitations of treatment for depression. Here, we present the preclinical characterization alongside ketamine, comparison. In vitro, profiled binding functional inhibition using patch-clamp electrophysiology. vivo, assessed antidepressant-like efficacy Forced Swim Test (FST) Chronic Mild Stress (CMS), while motor effects were in spontaneous locomotor activity on rotarod. pharmacokinetic properties across multiple species. Electroencephalography (EEG) performed determine indirect target engagement provide potentially translational biomarker. These results demonstrate an orally bioavailable with at exposures do not produce unwanted effects.

Язык: Английский

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Neuron‐Derived Extracellular Vesicles miRNA Profiles Identify Children Who Experience Adverse Events after Ketamine Administration for Procedural Sedation

Clinical Pharmacology & Therapeutics, Год журнала: 2024, Номер 117(1), С. 174 - 183

Опубликована: Авг. 20, 2024

Ketamine provides the highest safety profile among sedatives for procedural sedation and analgesia in pediatric emergency setting. However, it can cause vomiting recovery agitation. No studies have examined epigenetic factors, such as microRNAs, predicting occurrence of these adverse events. Neuronal-derived extracellular vesicle microRNA profiles were studied to predict ketamine-induced agitation children. For this aim, a single-center prospective pharmacoepigenetic study was performed 50 children who underwent with intravenous ketamine only sedative drug enrolled between October 2019 November 2022. MiRNA profiling plasma neural-derived vesicles analyzed through next-generation sequencing measured before treatment ketamine. Twenty-two patients experienced or Among 16 differentially expressed upregulated miR-15a-5p miR-484 targeted genes related N-methyl-D-aspartate (NMDA) receptor activity, including glutamate ionotropic NMDA type subunit 2A (GRIN2A). Preliminary data confirmed lower GRIN2A levels developed Downregulated miR-126-3p miR-24-3p AMPA receptor-associated genes. Functional analyses gene targets revealed enrichment glutamatergic neurotrophins signaling. Recovery associated network. Vomiting dopaminergic cholinergic systems. Three miRNAs (miR-18a-3p, miR-484, miR-548az-5p) identified predictive biomarkers (AUC 0.814; 95% CI: 0.632-0.956) MicroRNA development This contributes understanding mechanisms underlying

Язык: Английский

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Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(23), С. 13098 - 13098

Опубликована: Дек. 5, 2024

Brain-derived neurotrophic factor (BDNF) is critical for neuroplasticity, synaptic transmission, and neuronal survival. Studies have implicated it in the pathophysiology of depression, as its expression significantly reduced brain areas such prefrontal cortex hippocampus patients with depression. Our narrative review focuses on relationship between BDNF, ketamine, esketamine, specifically by summarizing human studies investigating BDNF variations treated these two drugs. plays a pivotal role neuroplasticity mechanisms that can be enhanced traditional antidepressants, which been shown to increase levels both peripherally targeted regions. Ketamine S-enantiomer, exert rapid sustained antidepressant effects through activation glutamate-related pathways, involving demonstrated experimental studies. However, clinical findings mixed results, most indicating an plasma intravenous although some contradict findings. In addition this, there are few esketamine. Currently, limited number suggests need further research, including larger sample sizes investigations intranasal has approved several regulatory agencies treatment treatment-resistant

Язык: Английский

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Subanesthetic Ketamine Ameliorates Activity‐Based Anorexia of Adult Mice

Synapse, Год журнала: 2025, Номер 79(1)

Опубликована: Янв. 1, 2025

Abstract Objective Anorexia nervosa (AN) is an eating disorder with the second highest mortality of all mental illnesses and high relapse rate, especially among adult females, yet no accepted pharmacotherapy. A small number studies have reported that females who struggled severe relapsing AN experienced sustained remission illness following ketamine infusions. Two other reports showed 30 mg/kg IP can reduce vulnerability adolescent mice to activity‐based anorexia (ABA), animal model AN. However, study has tested efficacy on ABA mice. This aimed fill this gap in knowledge. Methods Forty‐one female underwent three cycles (ABA1, ABA2, ABA3) assess adulthood. Of them, 13 received injections (30 mg/kg, 3 doses) during ABA2 (KET) adulthood ketamine's acute effects potential for ABA3, 10–13 days later. The remaining 28 vehicle or (CON). Results Severe weight loss (>20% baseline) ABA3 was observed 89% CON but only 69% KET. Overall wheel running per day significantly less KET than ( p < 0.01) throughout including hours food availability, these reductions were through ABA3. Food consumption not altered by ketamine. Discussion These findings suggest may females’ protect women from reducing hyperactivity.

Язык: Английский

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Preclinical Behavioral and Pharmacological Treatments for Enhancing Fear Extinction in Adolescence

Neuroscience & Biobehavioral Reviews, Год журнала: 2025, Номер unknown, С. 106090 - 106090

Опубликована: Март 1, 2025

Adolescence is a window of vulnerability for the development anxiety disorders but also opportunity treatments to minimize long-term impact such disorders. Current first-line treatments, primarily exposure-based cognitive-behavioral therapy (CBT), have limited efficacy in adolescents. The urgent need more effective interventions underscored by frequent reports extinction impairments adolescents as well rising rates youth, particularly post-COVID-19. Preclinical research on learned fear may contribute developing better treatment approaches this age group. Unfortunately, still largely under-explored area. However, both pharmacological and behavioral augmentation strategies can be used enhance learning consolidation. Here we describe work exploring adjuncts, focusing pre-clinical with rodents. Much date shows striking developmental differences response various only few shown Further, recent experience stress reduces these adolescence. This review highlights necessity tailored strategies, especially when it comes that address drug responses stressful experiences efficacy.

Язык: Английский

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Targeting HINT1 to improve synaptic plasticity: toward loganin as a new antidepressant strategy

Molecular Psychiatry, Год журнала: 2025, Номер unknown

Опубликована: Март 25, 2025

Язык: Английский

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S‐ketamine Alleviates Neuroinflammation and Attenuates Lipopolysaccharide‐Induced Depression Via Targeting SIRT2

Advanced Science, Год журнала: 2025, Номер unknown

Опубликована: Апрель 2, 2025

Depression, a pervasive mental health condition, has increasingly been linked to neuroinflammation, as evidenced by elevated levels of pro-inflammatory markers such TNF-α and IL-1β observed in patients, which underscores the role inflammation its pathophysiology. This study investigates differential effects S-ketamine (S-KET) R-ketamine (R-KET) on inflammation-induced depression using lipopolysaccharide (LPS)-induced mouse model. Results showed that S-KET, but not R-KET, significantly alleviated depressive-like behaviors reduced factors medial prefrontal cortex (mPFC). Activity-based protein profiling identified SIRT2 key intracellular target with direct binding at Q167 residue, whereas R-KET no binding. S-KET enhanced interaction NF-κB subunit p65, reducing acetylation suppressing gene expression, seen R-KET. In vitro studies RNA interference inhibitor AK-7, along vivo pharmacological blockade, confirmed is crucial for anti-inflammatory antidepressant actions S-KET. These findings suggest mediates therapeutic highlighting potential treating inflammation-associated depression. provides novel insights into stereospecific ketamine enantiomers promise targeting neuroinflammatory

Язык: Английский

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Ascorbic Acid and Esketamine for Mental Disorders in Women with Miscarriage: A Randomized Controlled Double-Blind Trial Protocol

Neuropsychiatric Disease and Treatment, Год журнала: 2025, Номер Volume 21, С. 815 - 825

Опубликована: Апрель 1, 2025

Pregnancy leads to vulnerabilities and susceptibilities mental disorders. Miscarriage, as an adverse pregnancy outcome, following curettage for treatment, add the risks of further psychiatric disorders, including depression, anxiety, insomnia, etc., current approaches prevention are unsatisfactory. Ketamine its S-enantiomer esketamine can prevent postpartum even treats depressive symptoms after miscarriage curettage, but their side effects bring limitations. Ascorbic acid (AA, Vitamin C) modulate mood enhance ketamine's antidepressant efficacy synergistically, reducing dosages potentially. The purpose this study is clarify beneficial modification AA on preventing depression other disorders in patients with painless well interaction between esketamine. This a 2×2 factorial, double-blinded, randomized, controlled trial that will recruit women undergoing curettage. A total 424 participants be recruited randomly 1:1:1:1 allocated four groups (106 each): Group A0K0 (normal saline normal saline), A0K1 esketamine), A1K0 (AA A1K1 esketamine). primary outcome incidence postoperative day 7, assessed Edinburgh Postnatal Depression Scale (EPDS). secondary outcomes include EPDS score, assessments sleep, pain, events, perianesthetic data patient satisfaction. provides clinical trial-based evidence alone or combination/interacting emerging rapid-acting Our expected suggest AA's potential application optimizing strategies promoting post-miscarriage health, possible adjunctive improvement (es)ketamine's usage antidepressants. One major limitation single-center study, results might biased due regional factors.

Язык: Английский

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