Neuropharmacology最新文献

{"title":"The effects of social loss and isolation on partner odor investigation and dopamine and oxytocin receptor expression in female prairie voles","authors":"Adrianna Kirckof ,&nbsp;Emma Kneller ,&nbsp;Erika M. Vitale ,&nbsp;Michael A. Johnson ,&nbsp;Adam S. Smith","doi":"10.1016/j.neuropharm.2025.110298","DOIUrl":"10.1016/j.neuropharm.2025.110298","url":null,"abstract":"<div><div>In humans, grief is characterized by intense sadness, intrusive thoughts of the deceased, and intense longing for reunion with the deceased. Human fMRI studies show hyperactivity in emotional pain and motivational centers of the brain when an individual is reminded of a deceased attachment figure, but the molecular underpinnings of these changes in activity are unknown. Prairie voles (<em>Microtus ochrogaster</em>), which establish lifelong social bonds between breeding pairs, also display distress and motivational shifts during periods of prolonged social loss, providing a model to investigate these behavioral and molecular changes at a mechanistic level. Here, a novel odor preference test was used to assess social vs non-social odor investigation, and a sucrose preference test was used to assess non-social, reward-driven motivation. Females that lost a male partner investigated partner- and food-associated cues significantly more than females that lost a female cagemate or remained intact with a male partner. However, females experiencing the loss of a male partner did not change investigation of stranger-associated cues. Western blotting revealed significant increases of dopamine receptor type 1 (DRD1) and oxytocin receptor protein content in specific brain regions in response to the loss of distinct social relationships. Such effects included an increase in DRD1 in the medial preoptic area of the hypothalamus (mPOA) in females experiencing loss of a male partner compared to all other conditions. Pharmacological antagonism of DRD1 in the mPOA blocked the loss-associated increase of investigation of the partner odor but did not affect investigation of food or stranger odors. This reveals a novel dopamine-mediated mechanism for partner-seeking behavior during periods of partner loss in female prairie voles.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"267 ","pages":"Article 110298"},"PeriodicalIF":4.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952410","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":"Leveling up: Strategies for taking Neuropharmacology and us all to new heights","authors":"Jared W. Young Ph.D","doi":"10.1016/j.neuropharm.2025.110297","DOIUrl":"10.1016/j.neuropharm.2025.110297","url":null,"abstract":"","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"266 ","pages":"Article 110297"},"PeriodicalIF":4.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952409","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":"Cholesterol metabolites modulate ionotropic P2X4 and P2X7 receptor current in microglia cells","authors":"Michele Barraco ,&nbsp;Eva Kudova ,&nbsp;Claudio Bucolo ,&nbsp;Lucia Ciranna ,&nbsp;Maria Angela Sortino ,&nbsp;Mariangela Chisari","doi":"10.1016/j.neuropharm.2024.110294","DOIUrl":"10.1016/j.neuropharm.2024.110294","url":null,"abstract":"<div><div>The central nervous system is a well-known steroidogenic tissue producing, among others, cholesterol metabolites such as neuroactive steroids, oxysterols and steroid hormones. It is well known that these endogenous molecules affect several receptor classes, including ionotropic GABAergic and NMDA glutamatergic receptors in neurons. It has been shown that also ionotropic purinergic (P2X) receptors are cholesterol metabolites’ targets. Among P2X receptors, purinergic P2X4 and P2X7 receptors are expressed in microglia, the innate immune cells involved in the brain inflammatory response. In this study, we explore the ionotropic purinergic receptors modulation by cholesterol metabolites in microglia. Patch-clamp experiments were performed in BV2 cells, a murine microglia cell line, to evaluate effects of cholesterol metabolites using micro- and nanomolar concentrations. About P2X4 receptor, we found that testosterone butyrate (20 μM and 200 nM) and allopregnanolone (10 μM and 100 nM) both potentiated its current, while neither 25-hydroxycholesterol (10 μM and 100 nM) nor 17β-estradiol (1 μM) showed any effects. On the other hand, P2X7 receptor current was potentiated by allopregnanolone (10 μM) and 25-hydroxycholesterol (10 μM and 100 nM). Taken together, our data show that modulation of either P2X4 and P2X7 current is affected differently by cholesterol metabolites, suggesting a structure-activity relationship among these players. Identifying the possible link between purinergic transmission, microglia and cholesterol metabolites will allow to define new targets for drug development to treat neuroinflammation.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"266 ","pages":"Article 110294"},"PeriodicalIF":4.6,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927702","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":"Microglial activation and neuroinflammation in acute and chronic cognitive deficits in sepsis","authors":"Paul Denver ,&nbsp;Colm Cunningham","doi":"10.1016/j.neuropharm.2024.110285","DOIUrl":"10.1016/j.neuropharm.2024.110285","url":null,"abstract":"<div><div>Sepsis is characterised by dysregulated immune responses to infection, leading to multi-organ dysfunction and high rates of mortality. With increasing survival rates in recent years long-term neurological and psychiatric consequences have become more apparent in survivors. Many patients develop sepsis associated encephalopathy (SAE) which encompasses the profound but usually transient neuropsychiatric syndrome delirium but also new brain injury that emerges in the months and years post-sepsis. It is now clear that systemic inflammatory signals reach the brain during sepsis and that very significant neuroinflammation ensues. The major brain resident immune cell population, the microglia, has been implicated in acute and chronic cognitive dysfunction in animal models of sepsis based on a growing number of studies using bacterial endotoxin and in polymicrobial sepsis models such as cecal ligation and puncture. The current review explores the effects of sepsis on the brain, focussing on how systemic insults translate to microglial activation and neuroinflammation and how this disrupts neuronal function and integrity. We examine what has been demonstrated specifically with respect to microglial activation, revealing robust evidence for a role for neuroinflammation in sepsis-induced brain sequelae but less clear information on the extent of the specific microglial contribution to this, arising from findings using global knockout mice, non-selective drugs and treatments that equally target peripheral and central compartments. There is, nonetheless, clear evidence that microglia do become activated and do contribute to brain consequences of sepsis thus arguing for improved understanding of these neuroinflammatory processes toward the prevention and treatment of sepsis-induced brain dysfunction.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"267 ","pages":"Article 110285"},"PeriodicalIF":4.6,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142922398","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":"A term as Editor-in-Chief of Neuropharmacology: Ups and downs and highs and lows","authors":"Bruno G. Frenguelli","doi":"10.1016/j.neuropharm.2024.110270","DOIUrl":"10.1016/j.neuropharm.2024.110270","url":null,"abstract":"","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"266 ","pages":"Article 110270"},"PeriodicalIF":4.6,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142910081","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":"Thank you to our reviewers","authors":"","doi":"10.1016/j.neuropharm.2024.110274","DOIUrl":"10.1016/j.neuropharm.2024.110274","url":null,"abstract":"","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"265 ","pages":"Article 110274"},"PeriodicalIF":4.6,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143133138","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":"Clozapine and rapamycin reverse behavioral abnormalities in an animal model of autoimmune schizophrenia","authors":"Duilin Liu ,&nbsp;Caiyun Zhu ,&nbsp;Hui Wei","doi":"10.1016/j.neuropharm.2024.110286","DOIUrl":"10.1016/j.neuropharm.2024.110286","url":null,"abstract":"<div><h3>Objective</h3><div>Autoantibody-associated psychosis represents a distinct disease subgroup of patients with schizophrenia with a suspected autoimmune origin. Although preliminary studies have suggested adjunctive drug treatment strategies targeting the immune system, further validation of these findings is warranted. Autoantibodies against SFT2D2 have been identified in patients with schizophrenia. ApoE^−/− mice immunized with SFT2D2-peptides can be used as a model for testing immunotherapy in this subgroup of patients. We used the atypical antipsychotic drug clozapine and immunosuppressant rapamycin to test their effects in this mouse model.</div></div><div><h3>Methods</h3><div>The mice were evaluated for cognitive and schizophrenia-like behaviors. Following behavioral testing, brain samples were collected for analyzing specific pathological changes and dendritic spine formation.</div></div><div><h3>Results</h3><div>Clozapine and rapamycin reversed impaired pre-pulse inhibition, motor impairment, and improved cognitive ability in ApoE ^−/− mice exposed to anti-SFT2D2 immunoglobulin G. Immunohistochemical assays revealed that both clozapine and rapamycin significantly reduced activated microglial infiltration and restored neuronal dendritic spine density.</div></div><div><h3>Conclusions</h3><div>Our study results suggested that clozapine and rapamycin possess therapeutic benefits for managing autoimmune psychosis and provide mechanistic insights into immunotherapies involving immunosuppressive agents.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"266 ","pages":"Article 110286"},"PeriodicalIF":4.6,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902851","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":"Angiotensin 1-7 injected into the rat paraventricular nucleus of hypothalamus increases blood pressure and heart rate via various receptors","authors":"K. Mińczuk ,&nbsp;E. Schlicker ,&nbsp;A. Krzyżewska ,&nbsp;B. Malinowska","doi":"10.1016/j.neuropharm.2024.110279","DOIUrl":"10.1016/j.neuropharm.2024.110279","url":null,"abstract":"<div><div>Although angiotensin 1-7 (Ang 1–7) and its role as a part of the “protective” axis of the renin-angiotensin system are well described in the literature, the mechanisms of its angiotensin II-like pressor and tachycardic effects following its acute central administration are not fully understood. It was the aim of the present study to examine which receptors contribute to the aforementioned cardiovascular effects. Ang 1–7 and antagonists for glutamate, GABA, vasopressin, thromboxane A₂ (TP), α₁-adrenergic, and P2X purinoceptors or modulators of oxidative stress were injected into the paraventricular nucleus of the hypothalamus (PVN) of urethane-anesthetized male Wistar rats. Acute injection of Ang 1–7 into the PVN increased blood pressure (BP) by about 15 mmHg and heart rate (HR) by about 14 beats/min. After preinjection with bicuculline (GABA_A receptor antagonist), CNQX + D-AP5 (AMPA/kainate and NMDA receptor antagonists) and SQ29548 (TP receptor antagonist) the BP and HR reactions to Ang 1–7 were attenuated or abolished. The vasopressin V_1A and V_1B receptor antagonists conivaptan and nelivaptan, and the NADPH oxidase inhibitor apocynin even reversed the pressor and tachycardic effects of Ang 1–7. Antagonists of P2X (PPADS) and α₁-adrenergic receptors (prazosin), the free radical scavenger tempol and the superoxide dismutase inhibitor DETC did not modify the cardiovascular effects of Ang 1–7. The (Mas receptor-related) rise in BP and HR evoked by Ang 1-7 administered to the rat PVN is linked to glutamate, vasopressin, GABA_A and thromboxane receptors, and to oxidative stress, but does not seem to involve α₁-adrenergic or P2X receptors.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"266 ","pages":"Article 110279"},"PeriodicalIF":4.6,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896344","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":"Curcumin analog C16 attenuates bone cancer pain induced by MADB 106 breast cancer cells in female rats and inhibits the CREB/NLGN2 signaling axis by targeting CaMKⅠα","authors":"Liping Chen ,&nbsp;Chaobo Ni ,&nbsp;Dashan Lu ,&nbsp;Shuyao Zhang ,&nbsp;Yuhua Li ,&nbsp;Dongjie Wang ,&nbsp;Bohan Hua ,&nbsp;Huadong Ni ,&nbsp;Longsheng Xu ,&nbsp;Ming Yao","doi":"10.1016/j.neuropharm.2024.110284","DOIUrl":"10.1016/j.neuropharm.2024.110284","url":null,"abstract":"<div><div>Bone cancer pain (BCP) is one of the most severe complications faced by patients with cancer; however, current pharmacological options are limited. Curcumin has been demonstrated to possess anti-inflammatory and analgesic properties; however, our preliminary research found that the analgesic efficiency of curcumin is not high in BCP. Consequently, curcumin analogs have emerged as a significant focus of our research. This study aimed to systematically investigate the analgesic effects of C16 in rats with BCP induced by MADB 106 breast cancer cells (MADB 106-induced BCP) and elucidate the underlying molecular mechanisms. A range of experimental methods, including kinase profiling, transcriptome sequencing, behavioral tests, immunofluorescence, and biochemical analyses, were employed to comprehensively assess the role of C16 in the MADB 106-induced BCP model. The results indicated that C16 significantly alleviated bone cancer pain induced by Luciferin-MADB 106 cells (10ˆ6 cells) in a dose-dependent manner. Importantly, kinase profiling and validation experiments identified CaMKIα in spinal dorsal horn neurons as the primary target of C16's analgesic effect on MADB 106-induced BCP. Continuous intrathecal administration of C16 markedly suppressed the expression of CREB and P-CREB and reduced the expression of neuroligin 2 in the spinal cords of BCP rats, thereby clarifying the mechanism of action of C16 in alleviating MADB 106-induced BCP. These findings suggest that C16 possesses significant therapeutic potential for mitigating MADB 106-induced BCP nociceptive hypersensitivity, providing a foundation for the future development of novel drugs targeting MADB 106-induced BCP.</div><div>This article is part of the Special Issue on \"Empathic Pain\".</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"266 ","pages":"Article 110284"},"PeriodicalIF":4.6,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896347","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":"Inosine exerts dopaminergic neuroprotective effects via mitigation of NLRP3 inflammasome activation","authors":"Shristi Khanal ,&nbsp;Eun-Joo Shin ,&nbsp;Chang Jae Yoo ,&nbsp;Jaekwang Kim ,&nbsp;Dong-Young Choi","doi":"10.1016/j.neuropharm.2024.110278","DOIUrl":"10.1016/j.neuropharm.2024.110278","url":null,"abstract":"<div><div>Neuroinflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Transformation of pro-interleukin (IL)-1β into a mature IL-1β via active inflammasome may be related to the progression of PD. Therefore, the modification of inflammasome activity may be a potential therapeutic strategy for PD. Inosine has been shown to exert anti-inflammatory effects in various disease models. In this study, we evaluated inosine's inhibitory effects on the microglial NLRP3 inflammasome, which may be related to the dopaminergic neuroprotective effects of inosine. Inosine suppresses lipopolysaccharides (LPS)-induced NLRP3 inflammasome activation in BV-2 microglial cells dose dependently. When SH-SY5Y cells were treated with conditioned medium from BV-2 cells treated with LPS and inosine, an NLRP3 inhibitor, or a caspase-1 inhibitor, the viability of SH-SY5Y cells was reduced indicating that LPS-induced microglial inflammasome activation could contribute to neuronal death. Inosine's modulatory effect on NLRP3 inflammasome activity appears to rely on the adenosine A_2A and A₃ receptors activation, as A_2A or A₃ receptor antagonists reversed the amelioration of NLRP3 activation by inosine. In addition, inosine treatment attenuated intracellular and mitochondrial ROS production mediated by LPS and this effect might be related to attenuation of NLRP3 inflammasome activity, as the antioxidant, N-acetyl cysteine ameliorated LPS-induced activation of the inflammasome. Finally, we assessed the inosine's neuroprotective effects via inflammasome activity modulation in mice receiving an intranigral injection of LPS. Immunohistochemical analysis revealed that LPS caused a significant loss of nigral dopaminergic neurons, which was mitigated by inosine treatment. LPS increased NLRP3 expression in IBA1-positive microglial cells, which was attenuated by inosine injection. These findings indicate that inosine can rescue neurons from LPS-induced injury by ameliorating NLRP3 inflammasome activity. Therefore, inosine could be applied as an intervention for neuroinflammatory diseases such as Parkinson's disease.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"266 ","pages":"Article 110278"},"PeriodicalIF":4.6,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896349","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}