International Journal of Neuropsychopharmacology最新文献

{"title":"Premorbid characteristics of the SAPAP3 mouse model of obsessive-compulsive disorder: behavior, neuroplasticity, and psilocybin treatment.","authors":"Michal Lazar, Michal Brownstien, Alexander Botvinnik, Chloe Shevakh, Orr Shahar, Tzuri Lifschytz, Bernard Lerer","doi":"10.1093/ijnp/pyaf022","DOIUrl":"10.1093/ijnp/pyaf022","url":null,"abstract":"<p><strong>Background: </strong>SAPAP3-knockout (SAPAP3-KO) mice develop excessive self-grooming behavior at 4-6 months of age, serving as a model for obsessive-compulsive disorder (OCD). Given that anxiety often precedes OCD diagnosis in humans, this study investigated whether juvenile SAPAP3-KO mice exhibit anxiety-like behaviors before developing the self-grooming phenotype, and whether such behaviors respond to psilocybin (PSIL) treatment. The study also examined 4 key neuroplasticity-related synaptic proteins-GAP43, PSD95, synaptophysin, and SV2A-as SAPAP3 is a postsynaptic scaffold protein that interacts with PSD95 and may affect synaptic function.</p><p><strong>Methods: </strong>Two studies were conducted using male and female juvenile (10-13 weeks) SAPAP3-KO mice. Study 1 compared behavioral phenotypes between homozygous (HOM), heterozygous, and wild-type (WT) mice. Study 2 evaluated a different sample of HOM and WT mice and assessed the effect of PSIL (4.4 mg/kg) on identified behavioral differences. Both studies included comprehensive behavioral testing focused on anxiety-like behavior, social interaction, and cognitive function. Additionally, levels of 4 synaptic proteins were measured by western blots in the frontal cortex, hippocampus, amygdala, and striatum of juvenile and adult SAPAP3-KO mice.</p><p><strong>Results: </strong>In both studies, juvenile HOM SAPAP3-KO mice showed significant anxiety-like behaviors compared to WT mice, spending less time in open field center, and elevated plus maze open arms. They also buried fewer marbles and found fewer buried Oreos than WT mice. Psilocybin treatment did not improve these behavioral manifestations. Analysis of synaptic proteins revealed significant increases in GAP43, synaptophysin, and SV2A across multiple brain regions in adult male HOM mice and of SV2A in the frontal cortex of HOM females compared to WT, but not in juvenile mice of either sex.</p><p><strong>Conclusions: </strong>Juvenile SAPAP3-KO mice exhibit anxiety-like behaviors before developing the characteristic excessive self-grooming phenotype, paralleling the prodromal anxiety often seen in human OCD. Unlike in adult SAPAP3-KO mice, these manifestations were not responsive to PSIL treatment. The age-dependent increases in synaptic proteins observed in adult (but not juvenile) male SAPAP3-KO mice HOM for the deletion and to a lesser extent in female homozygotes, may represent compensatory plasticity changes in response to the phenotype. These results provide insights into the developmental trajectory of OCD-like behaviors and associated neuroplastic adaptations.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activating Group II Metabotropic Glutamate Receptors in the Basolateral Amygdala Inhibits Increases in Reward Seeking Triggered by Discriminative Stimuli in Rats.","authors":"Mandy Rita LeCocq, Amélie Mainville-Berthiaume, Isabel Laplante, Anne-Noël Samaha","doi":"10.1093/ijnp/pyaf030","DOIUrl":"https://doi.org/10.1093/ijnp/pyaf030","url":null,"abstract":"<p><strong>Background: </strong>Reward-associated cues guide reward-seeking behaviours. These cues include conditioned stimuli (CSs), which occur following seeking actions and predict reward delivery, and discriminative stimuli (DSs), which occur response-independently and signal that a seeking action will produce reward. Metabotropic group II glutamate (mGlu2/3) receptors in the basolateral amygdala (BLA) modulate CS-guided reward seeking; however, their role in DS effects is unknown.</p><p><strong>Methods: </strong>We developed a procedure to assess DS and CS effects on reward seeking in the same subjects within the same test session. Female and male rats self-administered sucrose where DSs signaled periods of sucrose availability (DS+) and unavailability (DS-). During DS+ trials, active lever presses produced sucrose paired with a CS+. During DS- trials, active lever presses produced a CS- and no sucrose. Across 14 sessions, rats learned to load up on sucrose during DS+ trials and inhibit responding during DS- trials. We then compared the effects of intra-BLA microinfusions of the mGlu2/3 receptor agonist LY379268 on cue-evoked sucrose seeking during a test where the DSs and CSs were presented response-independently, without sucrose. Before testing, rats received intra-BLA microinjections of artificial cerebrospinal fluid (aCSF) or LY379268.</p><p><strong>Results: </strong>Under aCSF, only the DS+ and DS+CS+ combined triggered increases in reward-seeking behaviour. The CS+ alone was ineffective. Intra-BLA LY379268 reduced the sucrose seeking triggered by the DS+ and DS+CS+ combination.</p><p><strong>Conclusions: </strong>Using a new procedure to test reward seeking induced by DSs and CSs, we show that BLA mGlu2/3 receptor activity mediates the conditioned incentive motivational effects of reward-predictive DSs.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sedative and hypnotic effects of nuciferine: enhancing rodent sleep via serotonergic system modulation.","authors":"Luo-Xuan Wang, Yu-Meng Liu, Yong-Fang Gu, Lu Li, Ren-Hong Qiu, Yan-Kai Wang, Jin Yang, Ji Wang, Yang Zhang, Shuo Li, Qiong-Yin Fan, Rui Xue, Jing-Cao Li, You-Zhi Zhang","doi":"10.1093/ijnp/pyaf019","DOIUrl":"10.1093/ijnp/pyaf019","url":null,"abstract":"<p><strong>Background: </strong>Insomnia is the most prevalent sleep disorder globally. Nuciferine (NF), a bioactive constituent extracted from Nelumbo nucifera leaves, is recognized for its diverse pharmacological activities. However, its sleep-regulating effects have not been investigated. This study aimed to delineate the therapeutic effects and underlying mechanisms of NF in mitigating insomnia.</p><p><strong>Methods: </strong>The sedative-hypnotic effects of NF were assessed employing locomotor activity test, pentobarbital-induced sleep test, and electroencephalography-based sleep profiling. Insomnia symptoms in rodents were induced by serotonin (5-HT) depletion and environmental stress. The potential mechanisms of NF's action through the regulation of central serotonin system were also explored.</p><p><strong>Results: </strong>Nuciferine attenuated locomotor activity and extended pentobarbital-induced sleep duration in a dose-dependent manner. It also significantly augmented total and non-rapid eye movement (NREM) sleep time and enhanced delta power at frequencies of 0.5 and 1 Hz in normal rats. Sleep analysis revealed that NF effectively reversed the reduction in total and NREM sleep time caused by environmental stress from cage changing. NF treatment also proved effective against insomnia induced by 5-HT depletion, as evidenced by increased sleep duration and reduced sleep latency. Further investigation revealed a synergetic effect of NF and 5-hydroxytryptophan, alone with increased 5-HT and 5-HT1A receptor levels in the hypothalamus of insomniac mice following NF administration.</p><p><strong>Conclusions: </strong>The results demonstrate NF's hypnotic effects and its ability to alleviate insomnia, providing preclinical evidence for its potential as a naturally derived treatment for insomnia.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143752513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of relapse with all-cause mortality in adult patients with stable schizophrenia.","authors":"Christoph U Correll, Brahim K Bookhart, Carmela Benson, Zhiwen Liu, Zhongyun Zhao, Wenze Tang","doi":"10.1093/ijnp/pyaf018","DOIUrl":"10.1093/ijnp/pyaf018","url":null,"abstract":"<p><strong>Background: </strong>Schizophrenia shortens the average lifespan by an estimated 15 years. This retrospective study evaluated whether relapse independently increases all-cause mortality risk in patients with stable schizophrenia.</p><p><strong>Methods: </strong>Eligible adults had ≥2 outpatient claims on separate dates or ≥1 inpatient claim with a schizophrenia diagnosis code, had ≥12 months of continuous pre-index enrollment without a relapse, and received ≥1 antipsychotic medication during the baseline period. Occurrence and number of inpatient and non-inpatient relapses and all-cause mortality were evaluated during follow-up. A marginal structural model adjusting for both baseline and time-varying confounding was used to estimate hazard ratios (HRs) and 95% CIs.</p><p><strong>Results: </strong>Mean age at index of the 32 071 patients included in the analysis was 57.6 (SD, 15.3) years; 51.0% of patients were male and 55.4% were White. During a mean follow-up of 40 (range, 1-127) months, 3974 (12.4%) patients died. Of the 9170 (28.6%) patients with relapse(s) during follow-up, most experienced 1 (53.4%) or 2 (20.0%) relapses. After adjustment for covariates, the HR for all-cause mortality was significantly higher for patients with 1 relapse vs no relapses (1.20 [95% CI, 1.14-1.26]). For the first 5 relapses, each subsequent relapse increased all-cause mortality hazard by approximately 20%. Estimated 5-year survival was 78% in patients with 1 relapse and 58% in patients with 10 relapses.</p><p><strong>Conclusions: </strong>The observed increase in all-cause mortality associated with schizophrenia relapse underscores the need for heightened attention to relapse prevention, including greater utilization of effective treatment strategies early in the course of disease.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12076073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct effects of psychiatric disorder diagnoses and severe emotional dysregulation on matrix metalloproteinase-9, proinflammatory cytokines, and inhibitory control function in adolescents with attention-deficit hyperactivity disorder or first-episode major affective disorders.","authors":"Ju-Wei Hsu, Li-Chi Chen, Ya-Mei Bai, Shih-Jen Tsai, Mu-Hong Chen","doi":"10.1093/ijnp/pyaf024","DOIUrl":"10.1093/ijnp/pyaf024","url":null,"abstract":"<p><strong>Background: </strong>Severe emotional dysregulation (SED) may represent an endophenotype of attention-deficit hyperactivity disorder (ADHD) and major affective disorders. However, the specific effects of SED and related psychiatric disorders, including ADHD, bipolar disorder (BD), and major depressive disorder (MDD), on matrix metalloproteinase-9 (MMP-9), proinflammatory cytokine levels, and inhibitory control function remain unclear.</p><p><strong>Methods: </strong>This study included 48 adolescents with ADHD, 39 with first-episode BD, 53 with first-episode MDD, and 46 healthy adolescents. SED was defined according to total T scores ≥210 on the Child Behavior Checklist Dysregulation Profile. Levels of MMP-9, interleukin (IL)-6, and C-reactive protein (CRP) were measured. Inhibitory control was assessed using the go/no-go task.</p><p><strong>Results: </strong>Generalized linear models adjusted for demographic and clinical data revealed significant main effects of diagnoses on MMP-9 (P = .009), CRP (P < .001), and IL-6 (P = .029) levels and on the standard deviation of mean response time on the go/no-go task (P = .004). A significant main effect of SED on MMP-9 levels (P = .048) was also observed. Adolescents with BD exhibited the highest MMP-9 and CRP levels and the poorest performance on the go/no-go task compared with the other groups. Adolescents with SED had significantly elevated MMP-9 levels than did those without SED.</p><p><strong>Discussion: </strong>Diagnoses of adolescent psychiatric disorder were associated with increased MMP-9, IL-6, and CRP levels and with inhibitory control dysfunction. In particular, SED was associated with elevated MMP-9 levels.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":"28 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12076074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144017677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuropathic pain impairs sleep architecture, non-rapid eye movement sleep, and reticular thalamic neuronal activity.","authors":"Martha López-Canul, Anahita Oveisi, Qianzi He, Maria Luisa Vigano, Antonio Farina, Stefano Comai, Gabriella Gobbi","doi":"10.1093/ijnp/pyaf017","DOIUrl":"10.1093/ijnp/pyaf017","url":null,"abstract":"<p><strong>Background: </strong>Neuropathic pain (NP) is a chronic and debilitating condition frequently comorbid with insomnia. However, the alterations in sleep architecture under NP conditions and the mechanisms underlying both pain and sleep disturbances remain poorly understood. The reticular thalamic nucleus (RTN) plays a crucial role in non-rapid eye movement sleep (NREMS) and pain processing, but its involvement in NP-related sleep disruptions has not been fully elucidated.</p><p><strong>Methods: </strong>To investigate sleep-related electrophysiological changes in NP, we performed continuous 24-hour electroencephalogram/electromyogram (EEG/EMG) recordings in rats exhibiting allodynia following L5-L6 spinal nerve lesions. Additionally, we assessed the in vivo neuronal activity of the RTN in both NP and sham-operated control rats. Spectral analyses were conducted to examine alterations in sleep oscillatory dynamics. Reticular thalamic nucleus neuronal responses to nociceptive pinch stimuli were classified as increased, decreased, or unresponsive.</p><p><strong>Results: </strong>Neuropathic pain rats exhibited a significant reduction in NREMS (-20%, P < .001) and an increase in wakefulness (+ 19.13%, P < .05) compared to controls, whereas rapid eye movement sleep (REMS) remained unchanged. Sleep fragmentation was pronounced in NP animals (P < .0001), with frequent brief awakenings, particularly during the inactive/light phase. Spectral analysis revealed increased delta and theta power during both NREMS and REMS. Reticular thalamic nucleus neurons in NP rats displayed a higher basal tonic firing rate, along with increased phasic activity (number of bursts), although the percentage of spikes in bursts remained unchanged.</p><p><strong>Conclusions: </strong>Neuropathic pain is characterized by disrupted sleep architecture, reduced NREMS, and heightened RTN neuronal firing activity with partial compensation of burst activity. Given that RTN burst activity is essential for optimal NREMS, its disruption may contribute to NP-induced sleep impairments. These findings suggest that altered EEG/EMG signals, alongside dysregulated RTN neuronal activity, may serve as potential brain markers for NP-related insomnia.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Moving toward precision and personalized treatment strategies in psychiatry.","authors":"Stefano Comai, Mirko Manchia, Marta Bosia, Alessandro Miola, Sara Poletti, Francesco Benedetti, Sofia Nasini, Raffaele Ferri, Dan Rujescu, Marion Leboyer, Julio Licinio, Bernhard T Baune, Alessandro Serretti","doi":"10.1093/ijnp/pyaf025","DOIUrl":"10.1093/ijnp/pyaf025","url":null,"abstract":"<p><p>Precision psychiatry aims to improve routine clinical practice by integrating biological, clinical, and environmental data. Many studies have been performed in different areas of research on major depressive disorder, bipolar disorder, and schizophrenia. Neuroimaging and electroencephalography findings have identified potential circuit-level abnormalities predictive of treatment response. Protein biomarkers, including IL-2, S100B, and NfL, and the kynurenine pathway illustrate the role of immune and metabolic dysregulation. Circadian rhythm disturbances and the gut microbiome have also emerged as critical transdiagnostic contributors to psychiatric symptomatology and outcomes. Moreover, advances in genomic research and polygenic scores support the perspective of personalized risk stratification and medication selection. While challenges remain, such as data replication issues, prediction model accuracy, and scalability, the progress so far achieved underscores the potential of precision psychiatry in improving diagnostic accuracy and treatment effectiveness.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and Efficacy with Esketamine in Treatment-Resistant Depression: Long-Term Extension Study.","authors":"Naim Zaki, Li Nancy Chen, Rosanne Lane, Teodora Doherty, Wayne C Drevets, Randall L Morrison, Gerard Sanacora, Samuel T Wilkinson, Allan H Young, Acioly L T Lacerda, Jong-Woo Paik, Vanina Popova, Dong-Jing Fu","doi":"10.1093/ijnp/pyaf027","DOIUrl":"https://doi.org/10.1093/ijnp/pyaf027","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;The rates of relapse and suicide risk are higher in treatment-resistant depression (TRD) versus non-treatment-resistant major depressive disorder. Even among patients with TRD who initially respond, the majority (70%) relapse within 6 months.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;To evaluate the long-term safety and efficacy of esketamine nasal spray, combined with an oral antidepressant, in patients with TRD.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Design: &lt;/strong&gt;Phase 3, open-label, single-arm long-term extension study (SUSTAIN-3) conducted from June 2016 to December 2022.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Setting: &lt;/strong&gt;Outpatient.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Participants: &lt;/strong&gt;Adults with TRD who participated in ≥1 of 6 phase 3 \"parent\" studies continued esketamine by either entering a 4-week induction phase followed by an optimization/maintenance phase of variable duration (n=458), or directly entering the optimization/maintenance phase of SUSTAIN-3 (n=690), based on their individual response to study drug at the endpoint of the parent study.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interventions: &lt;/strong&gt;Intranasal esketamine dosing was flexible, twice-weekly during induction and individualized to depression severity during optimization/maintenance (weekly, every-other-week, or every-4-weeks), under direct supervision by site staff.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Main outcomes and measures: &lt;/strong&gt;To assess long-term safety of esketamine. Efficacy endpoint included change in depressive symptoms, assessed by Montgomery-Åsberg Depression Rating Scale (MADRS).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;1,148 patients were enrolled. Total exposure to esketamine was 3,777 cumulative patient-years. Mean (median, range) exposure to esketamine in SUSTAIN-3 was 42.9 (45.8, range 0-79) months. The most common adverse events were headache (36.9%), dizziness (33.9%), nausea (33.6%), dissociation (25.5%), nasopharyngitis (23.8%), somnolence (23.1%), dysgeusia (20.2%), and back pain (20.0%). During the study, 5.3% and 6.4% of participants discontinued due to lack of efficacy or adverse event, respectively. Nine participants died: COVID-19 related (n=3), pneumonia (n=2), and completed suicide, myocardial infarction, multiple injuries, unknown cause (n=1 each). Mean MADRS total score decreased during induction, and this reduction persisted during optimization/maintenance (mean [SD] change from baseline-to-phase endpoint of each phase: induction: -12.8 [9.73]; optimization/maintenance: +0.2 [9.93]). 35.6% of participants were in remission at the induction endpoint, and 48.5% and 49.6% at week 112 and optimization/maintenance endpoint, respectively.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions and relevance: &lt;/strong&gt;In the SUSTAIN-3 final dataset, no new safety signals were identified during long-term treatment with intermittently-dosed esketamine, combined with oral antidepressant, and improvement in depression generally persisted among participants who remained on maintenance treatment. These results add to the accumulated evidence on TRD treatmen","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cognitive improvement effects of PF-04957325, a phosphodiesterase-8 inhibitor, in mouse models of Alzheimer's disease via modulating neuroinflammation.","authors":"Tian-Yang Guo, Meng Zhang, Yu-Li Lv, Nian-Zhuang Qiu, Rui-Min Chen, Fang-Fang Zhang, Wei Chen, Feng Zhang, Yong-Feng Gao, Xiao-Dan Wang, Xue-Hui Zhang, Mei-Hua Chen, Han-Ting Zhang, Hao Wang","doi":"10.1093/ijnp/pyaf028","DOIUrl":"https://doi.org/10.1093/ijnp/pyaf028","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory deficit and has emerged as a growing global health concern. Phosphodiesterase-8 (PDE8) is a cAMP-specific hydrolase and its correlation with AD pathogenesis remains underexplored. Here, the effects and mechanisms of PF-04957325 (denoted as PF), a PDE8 inhibitor, were investigated in reversing AD both in vitro and in vivo.</p><p><strong>Methods: </strong>Briefly, BV2 cells were incubated with amyloid-β oligomers (AβO) to construct an AD cell model. Then, 2-month-old male C57BL/6J mice injected with AβO into the hippocampus and 10-month-old-male APP/PS1 mice were used to construct AD animal models. Cells and mice were treated with PF to observe the effects of PDE8 on behavior and pathology related to AD. The Y maze, NOR, and MWM were performed to investigate cognitive function in mice. Western blot and immunofluorescence staining were used to identify microglial activation state. Lastly, Western blot and ELISA were conducted to determine the levels of inflammatory factors and the proteins of PDE8/cAMP/CREB signaling.</p><p><strong>Results: </strong>PF pretreatment reversed the conversation of pro-inflammatory microglia in BV2 cells induced by AβO, while also suppressing the levels of inflammatory factors, including IL-1β, IL-6, TNF-α, iNOS, and COX-2. In addition, AβO incubation upregulated the expression of PDE8 and concurrently down-regulated that of BDNF, cAMP, p-PKA /PKA, and p-CREB /CREB in BV2 cells, all of which were reversed by PF. In vivo experiments, as evidenced by impaired performance in the Y maze, NOR, and MWM; these effects were reversed by PF. Similarly, PF treatment significantly attenuated microglia activation and the release of the inflammatory factors, and reversed the changes in the expression of BDNF and PDE8/cAMP/CREB signaling in AD mice. Finally, PF reduced the generation of Aβ1-42 by suppressing the expression of APP and PS1 in APP/PS1 mice.</p><p><strong>Conclusion: </strong>PF alleviated AD-like changes in behavior and pathology through various mechanisms, including attenuating microglia-mediated neuroinflammation, upregulating the expression of BDNF, restoring synaptic dysfunction and inhibiting Aβ generation, which appear to be involved by PDE8/cAMP/CREB signaling. These results highlight the therapeutic potential of targeting PDE8 inhibition for AD treatment.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144017616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular targets of vortioxetine mediating glioblastoma suppression revealed by gene and protein network analyses and molecular docking simulations.","authors":"Chuanjun Zhuo, Chao Li, Qiuyu Zhang, Lei Yang, Ying Zhang, Ximing Chen, Xiaoyan Ma, Ranli Li, Lina Wang, Hongjun Tian","doi":"10.1093/ijnp/pyaf029","DOIUrl":"https://doi.org/10.1093/ijnp/pyaf029","url":null,"abstract":"<p><strong>Background: </strong>Vortioxetine is a serotonin reuptake inhibitor and serotonin receptor modulator used for the treatment of major depressive disorder, but recent studies have also reported anticancer effects in models of glioblastoma. Given the well-established benefits of drug repositioning, we examined the pharmacological mechanism for these anticancer actions using bioinformatics and molecular docking.</p><p><strong>Methods: </strong>Putative molecular targets for vortioxetine were identified by searching DrugBank, GeneCards, SwissTargetPrediction, CTD, and SuperPred databases, while glioblastoma-related proteins were identified using GeneCards, OMIM, and TTD. A protein-protein interaction (PPI) network was constructed from vortioxetine targets also involved in glioblastoma to identify core (hub) targets, which were then characterized by GO and KEGG pathway enrichment analyses using DAVID. Cytoscape was utilized to generate a drug-pathway-target-disease network, and molecular docking simulations were performed to evaluate direct interactions between vortioxetine and core target proteins.</p><p><strong>Results: </strong>A total of 234 unique vortioxetine protein targets were identified. Among 234 vortioxetine targets identified, 48 were also related to glioblastoma. Topological analysis of the PPI network revealed five core targets: the serine/threonine kinase AKT1, transcription factor hypoxia-inducible factor (HIF)-1, cell adhesion molecule cadherin-E, NF-κB subunit p105, and prostaglandin-endoperoxide synthase 2. According to GO and KEGG pathway analyses, the anticancer efficacy of vortioxetine may be mediated by effects on glucose metabolism, cell migration, phosphorylation, inflammatory responses, apoptosis, and signaling via Rap1, chemical carcinogenesis-reactive oxygen species, and HIF-1. Molecular docking revealed moderately strong affinities between vortioxetine and four core targets.</p><p><strong>Conclusions: </strong>This study suggests that vortioxetine may inhibit glioblastoma development through direct effects on multiple targets, and further emphasizes the value of bioinformatics analyses for drug repositioning.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}