Neuropharmacology最新文献

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Prefrontal TNRC6A mediates anxiety-like behaviour by regulating CRF through the maintenance of miR-21-3p stability 前额叶 TNRC6A 通过维持 miR-21-3p 的稳定性来调节 CRF,从而介导焦虑样行为。
IF 4.6 2区 医学
Neuropharmacology Pub Date : 2024-10-16 DOI: 10.1016/j.neuropharm.2024.110194
Gui-Feng Lu , Xin Yang , Zhi Xiao , Jia-Zhan Huang , Yi-Han Jiang , Meng-Qi Huang , Fei Geng
{"title":"Prefrontal TNRC6A mediates anxiety-like behaviour by regulating CRF through the maintenance of miR-21-3p stability","authors":"Gui-Feng Lu ,&nbsp;Xin Yang ,&nbsp;Zhi Xiao ,&nbsp;Jia-Zhan Huang ,&nbsp;Yi-Han Jiang ,&nbsp;Meng-Qi Huang ,&nbsp;Fei Geng","doi":"10.1016/j.neuropharm.2024.110194","DOIUrl":"10.1016/j.neuropharm.2024.110194","url":null,"abstract":"<div><div>Anxiety is an emotional response to a potential threat. It is characterized by worry, feelings of tension, and physical changes. Trinucleotide repeat containing adaptor 6A (TNRC6A) binds to argonaute (AGO) proteins and microRNAs to form the miRNA-induced silencing complex (miRISC), which mediates mRNA degradation, storage, and translational repression functions. However, whether TNRC6A is involved in anxiety regulation remains unknown.</div><div>In this study, TNRC6A was downregulated in the prefrontal cortex (PFC) of mice exposed to acute restraint stress. Inhibition of TNRC6A in PFC induced anxious behaviour. RNA immunoprecipitation, RNA pull-down and real-time quantitative PCR revealed that TNRC6A directly binds to miR-21-3p and maintains its stability. Intriguingly, miR-21-3p was downregulated in the PFC of acute stress mice, whereas overexpression of miR-21-3p significantly reduced anxiety-like behaviour. Furthermore, miR-21-3p knockdown significantly increased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in the PFC pyramidal neurons. Dual luciferase assay and western blotting confirmed that miR-21-3p binds to the 3 ‘UTR region of corticotropin-releasing factor (CRF) mRNA and regulates CRF and cAMP-response element binding protein (CREB) expression. These results confirm that low levels of TNRC6A in the PFC decrease the stability of miR-21-3p which promotes the up-regulation of CRF, leading to the development of anxiety-like behaviours. This research provides insight into a novel molecular mechanism by which TNRC6A regulates anxiety behaviour through the miR-21-3p/CRF signalling axis.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"262 ","pages":"Article 110194"},"PeriodicalIF":4.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470905","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}
引用次数: 0
Glyphosate impairs both structure and function of GABAergic synapses in hippocampal neurons 草甘膦会损害海马神经元中伽马能突触的结构和功能。
IF 4.6 2区 医学
Neuropharmacology Pub Date : 2024-10-12 DOI: 10.1016/j.neuropharm.2024.110183
Giuseppe Chiantia , Debora Comai , Enis Hidisoglu , Antonia Gurgone , Claudio Franchino , Valentina Carabelli , Andrea Marcantoni , Maurizio Giustetto
{"title":"Glyphosate impairs both structure and function of GABAergic synapses in hippocampal neurons","authors":"Giuseppe Chiantia ,&nbsp;Debora Comai ,&nbsp;Enis Hidisoglu ,&nbsp;Antonia Gurgone ,&nbsp;Claudio Franchino ,&nbsp;Valentina Carabelli ,&nbsp;Andrea Marcantoni ,&nbsp;Maurizio Giustetto","doi":"10.1016/j.neuropharm.2024.110183","DOIUrl":"10.1016/j.neuropharm.2024.110183","url":null,"abstract":"<div><div>Glyphosate (Gly) is a broad-spectrum herbicide responsible for the inhibition of the enzyme 5-enolpyruvylshikimate-3-phosphate synthase known to be expressed exclusively in plants and not in animals. For decades Gly has been thought to be ineffective in mammals, including humans, until it was demonstrated that rodents treated with the Gly-based herbicide Roundup showed reduced content of neurotransmitters (e.g., serotonin, dopamine, norepinephrine, and acetylcholine), increased oxidative stress in the brain associated with anxiety and depression-like behaviors and learning and memory deficits. Despite compelling evidence pointing to a neurotoxic effect of Gly, an in-depth functional description of its effects on synaptic transmission is still lacking. To investigate the synaptic alterations dependent on Gly administration we performed whole-cell patch-clamp recordings and immunocytochemistry on mouse primary cultured hippocampal neurons. Our findings reveal that 30 min incubation of Gly at the acceptable daily intake dose severely impaired inhibitory GABAergic synapses. Further analysis pointed out that Gly decreased the number of postsynaptic GABA<sub>A</sub> receptors and reduced the amplitude of evoked inhibitory postsynaptic currents, the readily releasable pool size available for synchronous release and the quantal size. Finally, a decreased number of release sites has been observed. Consistently, morphological analyses showed that the density of both pre- and post-synaptic inhibitory compartments decorating pyramidal cell dendrites was reduced by Gly. In conclusion, our experiments define for the first time the effects induced by Gly on GABAergic synapses, and reveal that Gly significantly impairs both pre- and postsynaptic mechanisms.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"262 ","pages":"Article 110183"},"PeriodicalIF":4.6,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470904","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}
引用次数: 0
Clinically-probed mechanisms of action in Fragile-X syndrome fail to normalize translational EEG phenotypes in Fmr1 knockout mice 临床探究的脆性 X 综合征作用机制未能使 Fmr1 基因敲除小鼠的翻译脑电图表型正常化。
IF 4.6 2区 医学
Neuropharmacology Pub Date : 2024-10-11 DOI: 10.1016/j.neuropharm.2024.110182
Philipp Janz , Marie Bainier , Samuel Marashli, Simon Gross, Roger L. Redondo
{"title":"Clinically-probed mechanisms of action in Fragile-X syndrome fail to normalize translational EEG phenotypes in Fmr1 knockout mice","authors":"Philipp Janz ,&nbsp;Marie Bainier ,&nbsp;Samuel Marashli,&nbsp;Simon Gross,&nbsp;Roger L. Redondo","doi":"10.1016/j.neuropharm.2024.110182","DOIUrl":"10.1016/j.neuropharm.2024.110182","url":null,"abstract":"<div><div>Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by Fragile X Messenger Ribonucleoprotein (FMRP) deficiency. Electroencephalogram (EEG) changes in FXS include alterations of oscillatory activity and responses to sensory stimuli, some of which have been back-translated into rodent models by knocking-out the Fragile X messenger ribonucleoprotein 1 gene (Fmr1-KO). However, the validity of these EEG phenotypes as objective biomarkers requires further investigation.</div><div>Potential pharmacotherapies such as mGluR5 inhibitors (e.g. CTEP; 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazole-4-yl)ethynyl)pyridine), GABA<sub>B</sub>R agonists (e.g. arbaclofen) and δ-containing GABA<sub>A</sub>R agonists (e.g. gaboxadol) have not translated into clinical success despite rescuing many phenotypes in the Fmr1-KO model. Yet none of these treatments have been assessed on EEG phenotypes in the Fmr1-KO model. Therefore, we set out to discover new EEG phenotypes in Fmr1-KO mice, using “task-free” and auditory-evoked (AEPs) and visually-evoked potential (VEP) paradigms, and probe their modulation by CTEP, arbaclofen and gaboxadol, using within-subjects designs.</div><div>First, we report Fmr1-KO-associated EEG abnormalities that closely resemble those observed in FXS, including elevated gamma-band power, reduced alpha/beta-band coherence, increased AEPs and delayed VEPs. Secondly, we found that pharmacological treatment, at best, only partially normalized EEG phenotypes. CTEP restored alpha/beta-band coherence and AEP amplitudes but failed to normalize gamma power and VEP latencies. Conversely, arbaclofen reduced gamma power but did not restore coherence or AEP amplitudes and further delayed VEPs. Gaboxadol did not normalize any EEG phenotypes.</div><div>We conclude that these compounds have limited ability to normalize these EEG phenotypes.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"262 ","pages":"Article 110182"},"PeriodicalIF":4.6,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470903","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}
引用次数: 0
Intranasal AdipoRon mitigates motor and cognitive deficits in hemiparkinsonian rats through neuroprotective mechanisms against oxidative stress and synaptic dysfunction 通过针对氧化应激和突触功能障碍的神经保护机制,鼻内注射 AdipoRon 可减轻半帕金森大鼠的运动和认知障碍。
IF 4.6 2区 医学
Neuropharmacology Pub Date : 2024-10-10 DOI: 10.1016/j.neuropharm.2024.110180
Soraya Alimohammadi , Gisou Mohaddes , Rana Keyhanmanesh , Seyed Zanyar Athari , Negin Azizifar , Fereshteh Farajdokht
{"title":"Intranasal AdipoRon mitigates motor and cognitive deficits in hemiparkinsonian rats through neuroprotective mechanisms against oxidative stress and synaptic dysfunction","authors":"Soraya Alimohammadi ,&nbsp;Gisou Mohaddes ,&nbsp;Rana Keyhanmanesh ,&nbsp;Seyed Zanyar Athari ,&nbsp;Negin Azizifar ,&nbsp;Fereshteh Farajdokht","doi":"10.1016/j.neuropharm.2024.110180","DOIUrl":"10.1016/j.neuropharm.2024.110180","url":null,"abstract":"<div><div>While motor symptoms are the most well-known manifestation of Parkinson's disease (PD), patients may also suffer from non-motor signs like cognitive impairments. The adiponectin receptor agonist AdipoRon (Adipo) has shown neuroprotective effects in preclinical studies. The objective of this study was to determine the potential benefits of chronic intranasal treatment of Adipo on motor function and cognitive performance in a hemiparkinsonian rat model caused by injecting 6-hydroxydopamine (6-OHDA) into the left forebrain bundle. After one week, PD rats were given either a vehicle or one of three dosages of Adipo (0.1, 1, and 10 μg) or levodopa (10 mg/kg orally) daily for 21 days. Recognition and spatial memory were determined using the novel object recognition test (NORT) and the Barnes maze test, respectively. The hippocampal tissues of the animals were harvested to examine oxidative stress status as well as the protein expressions of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD-95). In hemiparkinsonian rats, motor impairments, recognition memory, and spatial memory were all improved by chronic intranasal Adipo at 1 and 10 μg. Furthermore, we found that unilateral 6-OHDA injection elevated hippocampal oxidative stress (ROS) while concurrently reducing total antioxidant capacity (TAC), BDNF, PSD-95, and antioxidant enzymes (SOD, GPx). However, Adipo 10 μg significantly reduced these biochemical alterations in the hippocampus of 6-OHDA-lesioned rats. Chronic intranasal Adipo ameliorated spatial and recognition memory deterioration in hemiparkinsonian rats, presumably by increasing hippocampal synaptic protein levels, reducing oxidative stress, and increasing BDNF.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"262 ","pages":"Article 110180"},"PeriodicalIF":4.6,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406642","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}
引用次数: 0
Activation of ventral pallidum-projecting neurons in the nucleus accumbens via 5-HT2C receptor stimulation regulates motivation for wheel running in male mice 通过5-HT2C受体刺激激活脊髓灰质核中的腹侧苍白球投射神经元可调节雄性小鼠车轮跑步的动机。
IF 4.6 2区 医学
Neuropharmacology Pub Date : 2024-10-10 DOI: 10.1016/j.neuropharm.2024.110181
Kazuhei Niitani, Ryoma Nishida, Yusaku Futami, Naoya Nishitani, Satoshi Deyama, Katsuyuki Kaneda
{"title":"Activation of ventral pallidum-projecting neurons in the nucleus accumbens via 5-HT2C receptor stimulation regulates motivation for wheel running in male mice","authors":"Kazuhei Niitani,&nbsp;Ryoma Nishida,&nbsp;Yusaku Futami,&nbsp;Naoya Nishitani,&nbsp;Satoshi Deyama,&nbsp;Katsuyuki Kaneda","doi":"10.1016/j.neuropharm.2024.110181","DOIUrl":"10.1016/j.neuropharm.2024.110181","url":null,"abstract":"<div><div>Rodents have a strong motivation for wheel running; however, the neural mechanisms that regulate their motivation remain unknown. We investigated the possible involvement of serotonin (5-HT) systems in regulating motivation for wheel running in male mice. Systemic administration of a 5-HT<sub>1A</sub> receptor antagonist (WAY100635) increased the number of wheel rotations, whereas administration of a 5-HT<sub>2A</sub> or 5-HT<sub>2C</sub> receptor antagonist (volinanserin or SB242084, respectively) decreased it. In the open field test, neither WAY100635 nor volinanserin affected locomotor activity, whereas SB242084 increased locomotor activity. To identify the brain regions on which these antagonists act, we locally injected these into the motivational circuitry, including the nucleus accumbens (NAc), dorsomedial striatum (DM-Str), and medial prefrontal cortex (mPFC). Injection of SB242084 into the NAc, but not the DM-Str or mPFC, reduced the number of wheel rotations without altering locomotor activity. The local administration of WAY100635 or volinanserin to these brain regions did not affect the number of wheel rotations. Immunohistochemical analyses revealed that wheel running increased the number of c-Fos-positive cells in the NAc medial shell (NAc-MS), which was reduced by systemic SB242084 administration. <em>In vitro</em> slice whole-cell recordings showed that bath application of the 5-HT<sub>2C</sub> receptor agonist lorcaserin increased the frequency of spontaneous excitatory and inhibitory postsynaptic currents in the ventral tegmental area (VTA)-projecting neurons, whereas it only increased the frequency of spontaneous excitatory postsynaptic currents in ventral pallidum (VP)-projecting neurons in the NAc-MS. These findings suggest that the activation of VP-projecting NAc-MS neurons via 5-HT<sub>2C</sub> receptor stimulation regulates motivation for wheel running.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"261 ","pages":"Article 110181"},"PeriodicalIF":4.6,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406641","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}
引用次数: 0
Binge ethanol consumption can be attenuated by systemic administration of minocycline and is associated with enhanced neuroinflammation in the central amygdala 全身服用米诺环素可减轻狂饮乙醇的情况,而狂饮乙醇与杏仁核中枢神经炎症的增强有关。
IF 4.6 2区 医学
Neuropharmacology Pub Date : 2024-10-05 DOI: 10.1016/j.neuropharm.2024.110174
Sean Schrank , Joshua P. Sevigny , N. Ika Yunus , Katherine R. Vetter , Oscar D. Aguilar , Vivek Ily , Mikaela Valchinova , Alexandra T. Keinath , Dennis R. Sparta
{"title":"Binge ethanol consumption can be attenuated by systemic administration of minocycline and is associated with enhanced neuroinflammation in the central amygdala","authors":"Sean Schrank ,&nbsp;Joshua P. Sevigny ,&nbsp;N. Ika Yunus ,&nbsp;Katherine R. Vetter ,&nbsp;Oscar D. Aguilar ,&nbsp;Vivek Ily ,&nbsp;Mikaela Valchinova ,&nbsp;Alexandra T. Keinath ,&nbsp;Dennis R. Sparta","doi":"10.1016/j.neuropharm.2024.110174","DOIUrl":"10.1016/j.neuropharm.2024.110174","url":null,"abstract":"<div><div>Alcohol use disorder (AUD) has a complicated pathophysiology. Binge ethanol intoxication may produce long-lasting changes throughout extended amygdala neurocircuitry including neuroinflammation, often leading to relapse. Therefore, understanding the role of binge drinking induced neuroinflammation on extended amygdala neurocircuitry is critically important for treatment. We sought to understand the role of neuroinflammation in a naturalized form of rodent binge ethanol drinking (Drinking in the Dark (DID)). In a 5-week DID paradigm, we demonstrate that acute intraperitoneal (IP) injection of the anti-inflammatory drug minocycline significantly reduced binge drinking repeatedly in male and female Cx3CR1-GFP and C57BL/6J mice. Importantly, IP administration transiently decreased intermittent access sucrose consumption, was not observed on the second IP injection, but did not significantly alter food or water consumption, suggesting that minocycline may produce initial acute aversive effects and may not alter long-term consumption of natural rewards. Examination of rodent behaviors post ethanol binge drinking reveals no lasting effects of minocycline treatment on locomotion or anxiety-like behavior. To assess neuroinflammation, we developed a novel analysis method using a Matlab image analysis script, which allows for non-biased skeletonization and evaluation of microglia morphology to determine a possible activation state in Cx3CR1-GFP knock-in mice after repeated DID. We observed significant morphological changes of microglia within the CeA, but no differences in the BLA. Taken together, this study demonstrates repeated binge ethanol consumption can produce significant levels of microglia morphology changes within the CeA, and that immunomodulatory therapies may be an intriguing pharmacological candidate for the treatment of AUD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"262 ","pages":"Article 110174"},"PeriodicalIF":4.6,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381349","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}
引用次数: 0
Abnormal increased mTOR signaling regulates seizure threshold in Dravet syndrome 异常增加的 mTOR 信号调节着德雷韦综合征的癫痫阈值。
IF 4.6 2区 医学
Neuropharmacology Pub Date : 2024-10-05 DOI: 10.1016/j.neuropharm.2024.110166
Che-Wen Tsai , Shih-Yin Ho , I Chun Chen , Kai-Chieh Chang , Hou-Jen Chen , Feng-Chiao Tsai , Horng-Huei Liou
{"title":"Abnormal increased mTOR signaling regulates seizure threshold in Dravet syndrome","authors":"Che-Wen Tsai ,&nbsp;Shih-Yin Ho ,&nbsp;I Chun Chen ,&nbsp;Kai-Chieh Chang ,&nbsp;Hou-Jen Chen ,&nbsp;Feng-Chiao Tsai ,&nbsp;Horng-Huei Liou","doi":"10.1016/j.neuropharm.2024.110166","DOIUrl":"10.1016/j.neuropharm.2024.110166","url":null,"abstract":"<div><div>Excessive activation of mTOR has been observed in the brains of mouse models for Dravet syndrome. We aim to confirm whether that the overactivation of mTOR contributes to the neuropathological changes leading to epileptogenesis and neurobehavior deficits to support a novel pharmacological therapeutic approach for Dravet syndrome. The mTOR inhibitor everolimus, as a clinical antiseizure medication, was utilized to investigate whether mTOR is involved in hyperthermia-induced seizures, anxiety-like, and autism-like behaviors, as well as to explore potential pathogenic mechanisms in <em>Scn1a</em><sup><em>E1099X/+</em></sup> mice, a model of Dravet syndrome. First, we found that mTOR signaling was upregulated in hippocampus tissues and neural cultures derived from <em>Scn1a</em><sup><em>E1099X/+</em></sup> mice prior to seizure onset. Behaviorally, everolimus increased the seizure threshold and improved anxiety-like and autism-like behaviors in <em>Scn1a</em><sup><em>E1099X/+</em></sup> mice. Electrophysiologically, everolimus reduced the frequency of spontaneous excitatory postsynaptic currents in dentate granule neurons from <em>Scn1a</em><sup><em>E1099X/+</em></sup> mice. Biochemically, everolimus prevented hyperthermia-induced phosphorylation of hippocampal S6 ribosome in hippocampus, and it delayed hyperthermia-induced increase of cytosolic Ca<sup>2+</sup> level in primary neuronal cultures derived from <em>Scn1a</em><sup><em>E1099X/+</em></sup> mice. Our results provide the evidence that overactivated mTOR as an important neuropathological change which regulates seizure threshold, impairments of neurobehavior, neuronal glutamatergic transmission and intracellular Ca<sup>2+</sup> levels in <em>Scn1a</em><sup><em>E1099X/+</em></sup> mice. Inhibition of mTOR is a potential pharmacological therapeutic approach.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"262 ","pages":"Article 110166"},"PeriodicalIF":4.6,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392046","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}
引用次数: 0
PET imaging identifies anti-inflammatory effects of fluoxetine and a correlation of glucose metabolism during epileptogenesis with chronic seizure frequency PET 成像确定了氟西汀的抗炎作用以及癫痫发生过程中葡萄糖代谢与慢性癫痫发作频率的相关性。
IF 4.6 2区 医学
Neuropharmacology Pub Date : 2024-10-05 DOI: 10.1016/j.neuropharm.2024.110178
Marion Bankstahl , Ina Jahreis , Bettina J. Wolf , Tobias L. Ross , Jens P. Bankstahl , Pablo Bascuñana
{"title":"PET imaging identifies anti-inflammatory effects of fluoxetine and a correlation of glucose metabolism during epileptogenesis with chronic seizure frequency","authors":"Marion Bankstahl ,&nbsp;Ina Jahreis ,&nbsp;Bettina J. Wolf ,&nbsp;Tobias L. Ross ,&nbsp;Jens P. Bankstahl ,&nbsp;Pablo Bascuñana","doi":"10.1016/j.neuropharm.2024.110178","DOIUrl":"10.1016/j.neuropharm.2024.110178","url":null,"abstract":"<div><div>The serotonergic system has shown to be altered during epileptogenesis and in chronic epilepsy, making selective serotonin reuptake inhibitors interesting candidates for antiepileptogenic therapy. In this study, we aimed to evaluate disease-modifying effects of fluoxetine during experimental epileptogenesis.</div><div>Status epilepticus (SE) was induced by lithium-pilocarpine, and female rats were treated either with vehicle or fluoxetine over 15 days. Animals were subjected to <sup>18</sup>F-FDG (7 days post-SE), <sup>18</sup>F-GE180 (15 days post-SE) and <sup>18</sup>F-flumazenil positron emission tomography (PET, 21 days post-SE). Uptake (<sup>18</sup>F-FDG), volume of distribution (<sup>18</sup>F-GE180) and binding potential (<sup>18</sup>F-flumazenil) were calculated. In addition, hyperexcitability testing and video-EEG monitoring were performed.</div><div>Fluoxetine treatment did not alter brain glucose metabolism. <sup>18</sup>F-GE180 PET indicated lower neuroinflammation in the hippocampus of treated animals (−22.6%, p = 0.042), but no differences were found in GABA<sub>A</sub> receptor density. Video-EEG monitoring did not reveal a treatment effect on seizure frequency. However, independently of the treatment, hippocampal FDG uptake 7 days after SE correlated with seizure frequency during the chronic phase (r = −0.58; p = 0.015).</div><div>Fluoxetine treatment exerted anti-inflammatory effects in rats during epileptogenesis. However, this effect did not alter disease outcome. Importantly, FDG-PET in early epileptogenesis showed biomarker potential as higher glucose metabolism correlated to lower seizure frequency in the chronic phase<strong>.</strong></div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"261 ","pages":"Article 110178"},"PeriodicalIF":4.6,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381350","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}
引用次数: 0
The role of gene-environment interactions in social dysfunction: Focus on preclinical evidence from mouse studies 基因与环境的相互作用在社会功能障碍中的作用:关注小鼠研究的临床前证据。
IF 4.6 2区 医学
Neuropharmacology Pub Date : 2024-10-05 DOI: 10.1016/j.neuropharm.2024.110179
Giulia Castellano, Johana Bonnet Da Silva, Susanna Pietropaolo
{"title":"The role of gene-environment interactions in social dysfunction: Focus on preclinical evidence from mouse studies","authors":"Giulia Castellano,&nbsp;Johana Bonnet Da Silva,&nbsp;Susanna Pietropaolo","doi":"10.1016/j.neuropharm.2024.110179","DOIUrl":"10.1016/j.neuropharm.2024.110179","url":null,"abstract":"<div><div>Human and animal research has demonstrated that genetic and environmental factors can strongly modulate behavioral function, including the expression of social behaviors and their dysfunctionalities. Several genes have been linked to pathologies characterized by alterations in social behaviors, e.g., aggressive/antisocial personality disorder (ASPD), or autism spectrum disorder (ASD). Environmental stimulation (e.g., physical exercise, environmental enrichment) or adversity (e.g., chronic stress, social isolation) may respectively improve or impair social interactions. While the independent contribution of genetic and environmental factors to social behaviors has been assessed in a variety of human and animal studies, the impact of their interactive effects on social functions has been less extensively investigated. Genetic mutations and environmental changes can indeed influence each other through complex mutual effects, e.g., inducing synergistic, antagonistic or interactive behavioral outcomes. This complexity is difficult to be disentangled in human populations, thus encouraging studies in animal models, especially in the mouse species which is the most suitable for genetic manipulations. Here we review the available preclinical evidence on the impact of gene-environment interactions on social behaviors and their dysfunction, focusing on studies in laboratory mice. We included findings combining naturally occurring mutations, selectively bred or transgenic mice with multiple environmental manipulations, including positive (environmental enrichment, physical exercise) and aversive (social isolation, maternal separation, and stress) experiences. The impact of these results is critically discussed in terms of their generalizability across mouse models and social tests, as well as their implications for human studies on social dysfunction.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"261 ","pages":"Article 110179"},"PeriodicalIF":4.6,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381351","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}
引用次数: 0
P2X7 receptors modulate acquisition of cue fear extinction and contextual background memory generalization in male mice P2X7受体调节雄性小鼠对线索恐惧消退和背景记忆泛化的获得。
IF 4.6 2区 医学
Neuropharmacology Pub Date : 2024-10-02 DOI: 10.1016/j.neuropharm.2024.110177
Luana Barreto Domingos , Antonio Furtado da Silva Júnior , Cassiano Ricardo Alves Faria Diniz , Jessica Rosa , Ana Luisa B. Terzian , Leonardo Barbosa Moraes Resstel
{"title":"P2X7 receptors modulate acquisition of cue fear extinction and contextual background memory generalization in male mice","authors":"Luana Barreto Domingos ,&nbsp;Antonio Furtado da Silva Júnior ,&nbsp;Cassiano Ricardo Alves Faria Diniz ,&nbsp;Jessica Rosa ,&nbsp;Ana Luisa B. Terzian ,&nbsp;Leonardo Barbosa Moraes Resstel","doi":"10.1016/j.neuropharm.2024.110177","DOIUrl":"10.1016/j.neuropharm.2024.110177","url":null,"abstract":"<div><div>The purinergic P2X7 receptors (P2X7R) are activated by adenosine triphosphate (ATP) in several brain regions, particularly those involved with emotional control and the regulation of fear-related memories. Here, we investigate the role of P2X7R in fear learning memory, specifically in the acquisition and consolidation phases of the cued fear conditioning paradigm. C57Bl/6 wildtype (WT) male mice that received a single i.p. injection of the selective P2X7R antagonist A438079 prior the conditioning session showed generalization of cued fear memory and impaired fear extinction recall in the test session, while those treated prior the extinction session exhibited a similar behavior profile accompanied by resistance in the extinction learning. However, no effects were observed when this drug was administered immediately after the conditioning, extinction, or before the test session. Our results with P2X7R knockout (P2X7 KO) mice showed a behavioral profile that mirrored the collective effects observed across all pharmacological treatment conditions. This suggests that the P2X7R KO model effectively replicates the behavioral changes induced by the pharmacological interventions, demonstrating that we have successfully isolated the role of P2X7R in the fear and extinction phases of memory. These findings highlight the role of P2X7R in the acquisition and recall of extinction memory and supports P2X7R as a promising candidate for controlling abnormal fear processing, with potential applications for stress exposure-related disorders such as post-traumatic stress disorder (PTSD).</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"261 ","pages":"Article 110177"},"PeriodicalIF":4.6,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375712","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}
引用次数: 0
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