Neuropharmacology最新文献

{"title":"Serotonin 5-HT1A receptor biased agonists: The challenge of translating an innovative neuropharmacological concept into therapeutics","authors":"Luc Zimmer ,&nbsp;Adrian Newman-Tancredi","doi":"10.1016/j.neuropharm.2024.110267","DOIUrl":"10.1016/j.neuropharm.2024.110267","url":null,"abstract":"<div><div>Serotonin 5-HT_1A receptor agonists are prime candidates for CNS drug discovery due to their involvement physiological and pathological processes relevant to neurology and psychiatry. However, the lack of target specificity of many previously characterized agonists has long been a barrier to pharmacological and therapeutic progress. Some of the obstacles may be overcome through the recent concept of biased agonism, which has attracted considerable attention to the development of novel chemical entities at 5-HT, and particularly 5-HT_1A receptors, by specifically targeting intracellular signalling pathways that may themselves be linked to specific brain regions and therapeutic indications. There is now abundant translational data demonstrating distinct molecular and functional pharmacological signatures between different 5-HT_1A receptor agonists, opening new opportunities for research in neurology and psychiatry. Nevertheless, important limitations need to be overcome, including understanding the precise molecular basis for biased agonism, the need for improved translatable models, and the currently limited clinical data on biased agonists. Here, we review the current limits of our knowledge of 5-HT_1A receptor biased agonists and the limitations of available pharmacological tools, counterbalanced by the translational possibilities and therapeutic perspectives opened by novel, highly selective 5-HT1A receptor drug-candidates.</div><div>This article is part of the Special Issue on \"Ligand Bias\".</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"265 ","pages":"Article 110267"},"PeriodicalIF":4.6,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142838312","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":"Short chain fatty acids mediates complement C1q pathway alleviation of perioperative neurocognitive disorders","authors":"Xiang Liu ,&nbsp;Xiaona Tan ,&nbsp;Yaozong Yu ,&nbsp;Junfang Niu ,&nbsp;Bo Zhao ,&nbsp;Qiujun Wang","doi":"10.1016/j.neuropharm.2024.110266","DOIUrl":"10.1016/j.neuropharm.2024.110266","url":null,"abstract":"<div><div>Perioperative neurocognitive disorders (PND) is one of the most common postoperative complications, which can lead to a harmful impact on self-dependence, longer hospital stays, increased medical costs, morbidity, and mortality amongst older adults. Microglia can modulate synapse elimination involved in the complement component protein 1q (C1q) pathway to induce cognitive dysfunction, which is significantly improved by short chain fatty acids (SCFAs) treatment. Here we investigate the effects of SCFAs treatment on PND via mediating C1q complement pathway. High-throughput sequencing of 16S rDNA from fecal samples of male SD rats was applied to assess the changes in gut microbiota. Fecal microbiota transplantation (FMT) was performed to investigate whether gut microbiota from PND rats could alter cognitive impairment. The blood from the rat tail vein was collected to measure the SCFAs concentrations. Hippocampal and brain tissue samples were obtained to perform Western blots, Golgi and immunofluorescence staining. Primary microglia treated with SCFAs or Histone deacetylase inhibitor were cultured to measure microglial activation states and the expression of acetylated histone. The 16S rDNA sequencing results showed that PND rats had the significant changes in the species diversity of the gut microbiota and the metabolite of specifc species. Gut microbiota from PND rats could alter spatial learning and memory, and meanwhile, the changed SCFAs concentrations in plasma were involved. The synapse elimination in PND rats was strikingly reversed by SCFAs treatment involved in modulation complement C1q via suppressing neuroinflammation. This suggests that a link between gut microbiota dysbiosis and cognitive function impairment is involved in synapse elimination via mediating complement C1q pathway. SCFAs treatment can alleviate PND, the mechanisms of which may be associated with regulating complement C1q pathway.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"265 ","pages":"Article 110266"},"PeriodicalIF":4.6,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142838316","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":"Insights into the neurobiology of weight loss after bariatric surgery and GLP-1R agonists","authors":"Tyler M. Cook,&nbsp;Kelly N.Z. Fuller,&nbsp;Darleen A. Sandoval","doi":"10.1016/j.neuropharm.2024.110269","DOIUrl":"10.1016/j.neuropharm.2024.110269","url":null,"abstract":"<div><div>Obesity and its related complications are growing in prevalence worldwide, with increasing impact to individuals and healthcare systems alike. Currently, the leading treatment approaches for effective and sustained weight loss are bariatric surgery and gut peptide therapeutics. At a high level, both treatment strategies work by hijacking gut-brain axis signaling to reduce food intake. However, we predict that each modality has distinct neuronal mechanisms that are responsible for their success and complications. This review compares the neurobiology of feeding behavior between these two weight loss strategies via a discussion of both clinical and pre-clinical data. The most compelling evidence points to signaling within the hindbrain, hypothalamus, and reward circuits contributing to weight loss. Considerations for treatment, including differing complications between the two treatment approaches, will also be discussed. Based on the data, we pose the hypothesis that these two interventions are acting via distinct mechanisms to induce weight loss. Both interventions have variable degrees of weight loss across the patient population, thus, understanding these distinct mechanisms could help drive individualized medicine to optimize weight loss.</div><div>This article is part of the Special Issue on \"Food intake and feeding states\".</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"265 ","pages":"Article 110269"},"PeriodicalIF":4.6,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829529","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":"Subanesthetic propofol alleviates chronic stress-induced anxiety by enhancing VTADA neurons’ activity","authors":"Shaolei Jiang ,&nbsp;Dengyun Ge ,&nbsp;Bo Song ,&nbsp;Xiaofei Deng ,&nbsp;Zhongdong Liu ,&nbsp;Jian He ,&nbsp;Jing Sun ,&nbsp;Zhi Zhu ,&nbsp;Zhiqiang Meng ,&nbsp;Yingjie Zhu","doi":"10.1016/j.neuropharm.2024.110264","DOIUrl":"10.1016/j.neuropharm.2024.110264","url":null,"abstract":"<div><div>Anxiety, a common mental disorder, imposes significant clinical and economic burdens. Previous studies indicate that propofol has anxiolytic effects at anesthetic doses. However, the risks associated with general anesthesia limit its application in anxiety treatment. The feasibility of using subanesthetic doses of propofol to alleviate chronic stress-induced anxiety and the underlying neural mechanisms remain unknown. Here, we found that subanesthetic dose (20 mg/kg and 40 mg/kg) of propofol alleviated anxiety-like behaviors induced by chronic unpredictable mild stress (CUMS) in mice, and the anxiolytic effects were maintained for at least 6 h. <em>In vivo</em> calcium imaging study showed that propofol significantly enhanced Ca²⁺ signals in ventral tegmental area dopaminergic (VTA^DA) neurons. Whole-cell patch-clamp recordings confirmed that subanesthetic propofol increased the excitability of VTA^DA neurons while inhibiting VTA GABAergic (VTA^GABA) neurons. Propofol suppressed spontaneous inhibitory postsynaptic currents (sIPSCs) in VTA^DA neurons, accompanied by a decline in the ability of GABAergic neurons to transmit inhibitory signals. These findings suggests that a subanesthetic dose of propofol enhances the excitability of VTA^DA neurons through disinhibition, demonstrating its potential for the treatment of CUMS-associated anxiety-like behaviors.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"265 ","pages":"Article 110264"},"PeriodicalIF":4.6,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829530","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":"Neural circuits and therapeutic mechanisms of empathic pain","authors":"Zonghan Yang ,&nbsp;Li Xie ,&nbsp;Bingyuan Zhang ,&nbsp;Suwan Hu ,&nbsp;Cunming Liu ,&nbsp;Zifeng Wu ,&nbsp;Chun Yang","doi":"10.1016/j.neuropharm.2024.110268","DOIUrl":"10.1016/j.neuropharm.2024.110268","url":null,"abstract":"<div><div>Empathy is the capacity to understand and share the experiences of others. This ability fosters connections between individuals, enriching the fabric of our shared world. One notable example is empathy for the pain of others. Such experiences facilitate the identification of potential dangers, both for oneself and for others. Neuroimaging studies have helped to pinpoint brain regions that modulate empathic pain. Recently, there has also been a surge in studies exploring the neural mechanisms of empathic pain in rodent models. Neuropsychiatric disorders such as autism, psychosis, and schizophrenia often exhibit empathy deficits. Targeting the modulation of empathic pain holds potential for alleviating core symptoms in these patients. Interestingly, empathy research may also benefit pain management, leading to new approaches for understanding the negative emotions associated with pain. This review summarizes recent advances in neuroimaging for the study of empathic pain, outlines the underlying neurocircuit mechanisms, describes therapeutic strategies, and explores promising avenues for future research.</div><div>This article is part of the Special Issue on \"Empathic Pain\".</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"265 ","pages":"Article 110268"},"PeriodicalIF":4.6,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824380","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":"Acute kappa opioid receptor blocking disrupts the pro-cognitive effect of cannabidiol in neuropathic rats","authors":"Serena Boccella ,&nbsp;Antimo Fusco ,&nbsp;Federica Ricciardi ,&nbsp;Andrea Maria Morace ,&nbsp;Roozbe Bonsale ,&nbsp;Michela Perrone ,&nbsp;Ida Marabese ,&nbsp;Danilo De Gregorio ,&nbsp;Carmela Belardo ,&nbsp;Luca Posa ,&nbsp;Laura Rullo ,&nbsp;Fabiana Piscitelli ,&nbsp;Vincenzo di Marzo ,&nbsp;Alessandro Nicois ,&nbsp;Brenda Marfella ,&nbsp;Luigia Cristino ,&nbsp;Livio Luongo ,&nbsp;Francesca Guida ,&nbsp;Sanzio Candeletti ,&nbsp;Gabriella Gobbi ,&nbsp;Sabatino Maione","doi":"10.1016/j.neuropharm.2024.110265","DOIUrl":"10.1016/j.neuropharm.2024.110265","url":null,"abstract":"<div><div>Cannabidiol has been shown to ameliorate neuropathic pain and its affective components. Previous studies highlighted the pharmacological interaction between the CBD and opioid system, particularly the MOR, but the understanding of the interaction between CBD and kappa opioid receptor (KOR), physiologically stimulated by the endogenous opioid dynorphin, remains elusive. We assessed the pharmacological interactions between CBD and nor-BNI, a selective KOR antagonist in a rat neuropathic pain model. We show an increase in dynorphin peptide and its KOR receptors in the hippocampus’ dentate gyrus (DG) of neuropathic rats showing allodynia, and memory deficits. Consistent with these findings, neuropathic pain was associated with long-term potentiation (LTP) impairment in the entorhinal cortex-DG, also referred to as the lateral perforant pathway (LPP). Moreover, a downregulation of the endocannabinoid 2-AG and an upregulation of the cannabinoid CB1 receptors in the DG were detected in neuropathic pain animals. Either an acute KOR antagonist administration or one-week CBD treatment normalized dynorphin levels and improved affective symptoms, LTP and receptor expression, whereas only CBD showed an anti-allodynic effect. In addition, CBD normalized the SNI-induced changes in neuroplasticity as well as endocannabinoid and GABA levels in the DG. Noteworthy, the acute blockade of the KOR carried out after CBD repeated administration causes the re-installment of some neuropathic condition symptoms.</div><div>As a whole, these original results indicate a critical relationship between the adaptive changes in the hippocampus produced by CBD and the need to maintain the recovered physiological dynorphin tone to preserve the therapeutic effect of CBD in neuropathic rats.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"266 ","pages":"Article 110265"},"PeriodicalIF":4.6,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824378","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":"Heat shock proteins in chronic pain: From molecular chaperones to pain modulators","authors":"Nivedita Verma,&nbsp;Deepak Chouhan,&nbsp;Allani Meghana,&nbsp;Vinod Tiwari","doi":"10.1016/j.neuropharm.2024.110263","DOIUrl":"10.1016/j.neuropharm.2024.110263","url":null,"abstract":"<div><div>Chronic pain is the most prevalent and complex clinical disorder,affecting approximately 30% of people globally. Various intricate alterations in nociceptive pathways responsible for chronic pain are linked to long-term tissue damage or injury to the peripheral or central nervous systems. These include remolding in the phenotype of cells and fluctuations in the expression of proteins such as ion channels, neurotransmitters, and receptors. Heat shock proteins are important molecular chaperone proteins in cell responses to stress, including inflammation, neurodegeneration, and pain signaling. They play a key role in activating glial and endothelial cells and in the production of inflammatory mediators and excitatory amino acids in both peripheral and central nervous systems. In particular, they contribute to central sensitization and hyperactivation within the dorsal horn of the spinal cord. The expression of some HSPs plays a remarkable role in upregulating pain response by acting as scavengers of ROS, controlling inflammatory cytokines. Different HSPs act by different mechanisms and several important pathways have been implicated in targeting HSPs for the treatment of neuropathic pain including p38-mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases (ERKs), brain-derived neurotrophic factors (BDNF). We summarize the role of HSPs in various preclinical and clinical studies and the crosstalk of HSPs with various nociceptors and other pain models. We also highlighted some artificial intelligence tools and machine learning-assisted drug discovery methods for rapid screening of HSPs in various diseases. Focusing on HSPs could lead to the development of new therapeutics that modulate pain responses and enhance our understanding of pain in various pathological conditions and neurological disorders.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"266 ","pages":"Article 110263"},"PeriodicalIF":4.6,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818677","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":"Decreased voluntary alcohol intake and ventral striatal epigenetic and transcriptional remodeling in male Acss2 KO mice","authors":"Gabor Egervari ,&nbsp;Greg Donahue ,&nbsp;Natalia A.Quijano Cardé ,&nbsp;Desi C. Alexander ,&nbsp;Connor Hogan ,&nbsp;Jessica K. Shaw ,&nbsp;Erica M. Periandri ,&nbsp;Vanessa Fleites ,&nbsp;Mariella De Biasi ,&nbsp;Shelley L. Berger","doi":"10.1016/j.neuropharm.2024.110258","DOIUrl":"10.1016/j.neuropharm.2024.110258","url":null,"abstract":"<div><div>Metabolic-epigenetic interactions are emerging as key pathways in regulating alcohol-related transcriptional changes in the brain. Recently, we have shown that this is mediated by the metabolic enzyme Acetyl-CoA synthetase 2 (Acss2), which is nuclear and chromatin-bound in neurons. Mice lacking ACSS2 fail to deposit alcohol-derived acetate onto histones in the brain and show no conditioned place preference for ethanol reward. Here, we further explored the role of this pathway during voluntary alcohol intake. We found that Acss2 KO mice consume significantly less alcohol in a model of binge drinking, an effect primarily driven by males. Genome-wide transcriptional profiling of 7 key brain regions implicated in alcohol and drug use revealed that, following drinking, Acss2 KO mice exhibit blunted gene expression in the ventral striatum. Similarly to the behavioral differences, transcriptional dysregulation was more pronounced in male mice. Further, we found that the gene expression changes were associated with depletion of ventral striatal histone acetylation (H3K27ac) in Acss2 KO mice compared to WT. Taken together, our data suggest that ACSS2 plays an important role in orchestrating ventral striatal epigenetic and transcriptional changes during voluntary alcohol drinking, especially in males. Consequently, targeting this pathway could be a promising new therapeutic avenue.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"265 ","pages":"Article 110258"},"PeriodicalIF":4.6,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801760","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":"Metformin activates the PI3K/AKT/BDNF axis to attenuate postoperative cognitive dysfunction","authors":"Qing Wu ,&nbsp;Xiao-Yu Jia ,&nbsp;Shi-Hua Zhang ,&nbsp;Yun-Zhe Wu ,&nbsp;Long-Sheng Xu ,&nbsp;Jun-Gang Han ,&nbsp;Wei Yu ,&nbsp;Qing-He Zhou","doi":"10.1016/j.neuropharm.2024.110262","DOIUrl":"10.1016/j.neuropharm.2024.110262","url":null,"abstract":"<div><div>Postoperative cognitive dysfunction (POCD) is a prevalent neurocognitive complication of anesthesia and surgery. Metformin, a widely used antidiabetic drug, has neuroprotective properties and improves cognitive impairment and memory deficits. However, the mechanisms underlying its action in improving cognitive dysfunction after anesthesia and surgery remain unclear. This study aimed to explore the effects of metformin on POCD and the underlying mechanisms at play. We established an in vivo POCD model using isoflurane inhalation anesthesia with exploratory laparotomy. We found that pretreatment with metformin significantly improved cognitive function and anxiety-like behaviors in mice. Additionally, metformin attenuated the impairment of synaptic plasticity induced by POCD and restored levels of synaptic proteins and dendritic density in the hippocampus. Furthermore, metformin attenuated neuroinflammation by downregulating the expression of interleukin (IL)-6, IL-1β, and tumor necrosis factor-α, and reducing neuronal apoptosis. It also activates the PI3K/AKT signaling pathway, resulting in increased expression of brain-derived neurotrophic factor (BDNF). Finally, the PI3K inhibitor, LY294002, reversed the effects of metformin on the levels of PI3K, AKT phosphorylation, and BDNF in vitro cultured HT-22 cells. Additionally, in an in vivo model of POCD, it was observed that cognitive function in mice was significantly suppressed by treatment with the PI3K inhibitor LY294002. These results reveal that metformin may alleviate POCD by modulating the PI3K/AKT/BDNF axis. Our study may provide a novel strategy for preventing and treating POCD with this medication.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"265 ","pages":"Article 110262"},"PeriodicalIF":4.6,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813696","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":"Corrigendum to “Neuroprotective effects of ginsenoside Rg1 through the Wnt/β-catenin signaling pathway in both in vivo and in vitro models of Parkinson's disease” [Neuropharmacology 101 (2016) 480–489 NEUROPHARM-D-15-00626]","authors":"Tingting Zhou ,&nbsp;Guo Zu ,&nbsp;Xiaogang Zhang ,&nbsp;Xi Wang ,&nbsp;Shao Li ,&nbsp;Xiaoyang Gong ,&nbsp;Zhanhua Liang ,&nbsp;Jie Zhao","doi":"10.1016/j.neuropharm.2024.110260","DOIUrl":"10.1016/j.neuropharm.2024.110260","url":null,"abstract":"","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"265 ","pages":"Article 110260"},"PeriodicalIF":4.6,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813714","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}