Current Neuropharmacology最新文献

{"title":"Separation of Channels Subserving Approach and Avoidance/Escape at the Level of the Basal Ganglia and Related Brainstem Structures.","authors":"Véronique Coizet, Racha Al Tannir, Arnaud Pautrat, Paul G Overton","doi":"10.2174/1570159X21666230818154903","DOIUrl":"10.2174/1570159X21666230818154903","url":null,"abstract":"<p><p>The basal ganglia have the key function of directing our behavior in the context of events from our environment and/or our internal state. This function relies on afferents targeting the main input structures of the basal ganglia, entering bids for action selection at the level of the striatum or signals for behavioral interruption at the level of the subthalamic nucleus, with behavioral reselection facilitated by dopamine signaling. Numerous experiments have studied action selection in relation to inputs from the cerebral cortex. However, less is known about the anatomical and functional link between the basal ganglia and the brainstem. In this review, we describe how brainstem structures also project to the main input structures of the basal ganglia, namely the striatum, the subthalamic nucleus and midbrain dopaminergic neurons, in the context of approach and avoidance (including escape from threat), two fundamental, mutually exclusive behavioral choices in an animal's repertoire in which the brainstem is strongly involved. We focus on three particularly well-described loci involved in approach and avoidance, namely the superior colliculus, the parabrachial nucleus and the periaqueductal grey nucleus. We consider what is known about how these structures are related to the basal ganglia, focusing on their projections toward the striatum, dopaminergic neurons and subthalamic nucleus, and explore the functional consequences of those interactions.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":"1473-1490"},"PeriodicalIF":4.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11097992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10375174","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":"Childhood Trauma and Self-harm in Youths with Bipolar Disorders.","authors":"Delfina Janiri, Michelangelo Di Luzio, Silvia Montanari, Daniele Hirsch, Alessio Simonetti, Lorenzo Moccia, Eliana Conte, Ilaria Contaldo, Chiara Veredice, Eugenio Mercuri, Gabriele Sani","doi":"10.2174/1570159X21666230213155249","DOIUrl":"10.2174/1570159X21666230213155249","url":null,"abstract":"<p><strong>Background: </strong>Bipolar disorders (BD) in youth are associated with a high risk of self-harm behaviors. Childhood trauma (CT) is a relevant environmental stressor that is related to both BD diagnosis and self-harm in adulthood. It is not yet established whether CT may impact self-harm risk in youth. Therefore, the aim of this study was to investigate the distribution patterns of CT in youth BD with and without self-harm.</p><p><strong>Methods: </strong>We assessed 273 participants (aged 13-25 years), 96 youths with BD according to DSM-5 criteria and 177 healthy controls (HC). History of CT was obtained using the Childhood Trauma Questionnaire (CTQ). The association between CT and self-harm was tested using multivariate statistical models.</p><p><strong>Results: </strong>Over 45% of participants with BD reported lifetime self-harm. The BD Self-harm group reported more emotional abuse, emotional neglect, sexual abuse, and physical abuse than HC. The BD No-Self-harm group reported more emotional abuse than HC. The BD Self-harm group reported more emotional abuse and neglect than the BD No-Self-harm group. The BD Self-harm group also reported separated parents, hospitalizations, smoking, use of antiepileptics, antipsychotics and lithium. Emotional abuse was an independent predictor of self-harm in youths with BD.</p><p><strong>Conclusion: </strong>Findings support the importance of assessing CT, in particular emotional abuse, in youth with BD at risk for self-harm.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":"152-158"},"PeriodicalIF":4.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10716889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10705556","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":"Subcortical Contribution to the Role of the Basal Ganglia in Action Selection.","authors":"Veronique Coizet, Frederic Ambroggi","doi":"10.2174/1570159X2209240229143211","DOIUrl":"10.2174/1570159X2209240229143211","url":null,"abstract":"","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":"22 9","pages":"1417-1418"},"PeriodicalIF":4.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11097989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141283276","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":"<i>In Silico</i> Prediction of Quercetin Analogs for Targeting Death-Associated Protein Kinase 1 (DAPK1) Against Alzheimer's Disease.","authors":"Yilu Sun, Jia Zhao, Yizhu Lu, Fung Yin Ngo, Bo Shuai, Zhang-Jin Zhang, Yibin Feng, Jianhui Rong","doi":"10.2174/1570159X22666240515090434","DOIUrl":"10.2174/1570159X22666240515090434","url":null,"abstract":"<p><p>Alzheimer's Disease (AD) is a progressive neurodegenerative disorder that greatly affects the health and life quality of the elderly population. Existing drugs mainly alleviate symptoms but fail to halt disease progression, underscoring the urgent need for the development of novel drugs. Based on the neuroprotective effects of flavonoid quercetin in AD, this study was designed to identify potential AD-related targets for quercetin and perform <i>in silico</i> prediction of promising analogs for the treatment of AD. Database mining suggested death-associated protein kinase 1 (DAPK1) as the most promising AD-related target for quercetin among seven protein candidates. To achieve better biological effects for the treatment of AD, we devised a series of quercetin analogs as ligands for DAPK1, and molecular docking analyses, absorption, distribution, metabolism, and excretion (ADME) predictions, as well as molecular dynamics (MD) simulations, were performed. The energy for drug-protein interaction was predicted and ranked. As a result, quercetin-A1a and quercetin-A1a1 out of 19 quercetin analogs exhibited the lowest interaction energy for binding to DAPK1 than quercetin, and they had similar dynamics performance with quercetin. In addition, quercetin-A1a and quercetin-A1a1 were predicted to have better water solubility. Thus, quercetin-A1a and quercetin-A1a1 could be promising agents for the treatment of AD. Our findings paved the way for further experimental studies and the development of novel drugs.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":"2353-2367"},"PeriodicalIF":4.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11451310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140944446","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":"Inhibitory Pedunculopontine Neurons Gate Dopamine-Mediated Motor Actions of Unsigned Valence.","authors":"Sirin Zhang, Juan Mena-Segovia, Nadine K Gut","doi":"10.2174/1570159X21666230911103520","DOIUrl":"10.2174/1570159X21666230911103520","url":null,"abstract":"<p><strong>Background: </strong>The pedunculopontine nucleus (PPN) maintains a bidirectional connectivity with the basal ganglia that supports their shared roles in the selection and execution of motor actions. Previous studies identified a role for PPN neurons in goal-directed behavior, but the cellular substrates underlying this function have not been elucidated. We recently revealed the existence of a monosynaptic GABAergic input from the PPN that inhibits dopamine neurons of the substantia nigra. Activation of this pathway interferes with the execution of learned motor sequences when the actions are rewarded, even though the inhibition of dopamine neurons did not shift the value of the action, hence suggesting executive control over the gating of behavior.</p><p><strong>Objective: </strong>To test the attributes of the inhibition of dopamine neurons by the PPN in the context of goal-directed behavior regardless of whether the outcome is positively or negatively reinforced.</p><p><strong>Methods: </strong>We delivered optogenetic stimulation to PPN GABAergic axon terminals in the substantia nigra during a battery of behavioral tasks with positive and negative valence.</p><p><strong>Results: </strong>Inhibition of dopamine neurons by PPN optogenetic activation during an appetitive task impaired the initiation and overall execution of the behavioral sequence without affecting the consumption of reward. During an active avoidance task, the same activation impaired the ability of mice to avoid a foot shock, but their escape response was unaffected. In addition, responses to potential threats were significantly attenuated.</p><p><strong>Conclusion: </strong>Our results show that PPN GABAergic neurons modulate learned, goal-directed behavior of unsigned valence without affecting overall motor behavior.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":"1540-1550"},"PeriodicalIF":4.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11097985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10572624","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":"Future Directions for Developing Non-dopaminergic Strategies for the Treatment of Parkinson's Disease.","authors":"Daniel J van Wamelen, Valentina Leta, K Ray Chaudhuri, Peter Jenner","doi":"10.2174/1570159X21666230731110709","DOIUrl":"10.2174/1570159X21666230731110709","url":null,"abstract":"<p><p>The symptomatic treatment of Parkinson's disease (PD) has been dominated by the use of dopaminergic medication, but significant unmet need remains, much of which is related to non-motor symptoms and the involvement of non-dopaminergic transmitter systems. As such, little has changed in the past decades that has led to milestone advances in therapy and significantly improved treatment paradigms and patient outcomes, particularly in relation to symptoms unresponsive to levodopa. This review has looked at how pharmacological approaches to treatment are likely to develop in the near and distant future and will focus on two areas: 1) novel non-dopaminergic pharmacological strategies to control motor symptoms; and 2) novel non-dopaminergic approaches for the treatment of non-motor symptoms. The overall objective of this review is to use a 'crystal ball' approach to the future of drug discovery in PD and move away from the more traditional dopamine-based treatments. Here, we discuss promising non-dopaminergic and 'dirty drugs' that have the potential to become new key players in the field of Parkinson's disease treatment.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":"1606-1620"},"PeriodicalIF":4.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11284721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9914224","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":"Neurotensin and Neurotensin Receptors in Stress-related Disorders: Pathophysiology & Novel Drug Targets.","authors":"Grigorios Kyriatzis, Michel Khrestchatisky, Lotfi Ferhat, Ekaterini Alexiou Chatzaki","doi":"10.2174/1570159X21666230803101629","DOIUrl":"10.2174/1570159X21666230803101629","url":null,"abstract":"<p><p>Neurotensin (NT) is a 13-amino acid neuropeptide widely distributed in the CNS that has been involved in the pathophysiology of many neural and psychiatric disorders. There are three known neurotensin receptors (NTSRs), which mediate multiple actions, and form the neurotensinergic system in conjunction with NT. NTSR1 is the main mediator of NT, displaying effects in both the CNS and the periphery, while NTSR2 is mainly expressed in the brain and NTSR3 has a broader expression pattern. In this review, we bring together up-to-date studies showing an involvement of the neurotensinergic system in different aspects of the stress response and the main stress-related disorders, such as depression and anxiety, post-traumatic stress disorder (PTSD) and its associated symptoms, such as fear memory and maternal separation, ethanol addiction, and substance abuse. Emphasis is put on gene, mRNA, and protein alterations of NT and NTSRs, as well as behavioral and pharmacological studies, leading to evidence-based suggestions on the implicated regulating mechanisms as well as their therapeutic exploitation. Stress responses and anxiety involve mainly NTSR1, but also NTSR2 and NTSR3. NTSR1 and NTSR3 are primarily implicated in depression, while NTSR2 and secondarily NTSR1 in PTSD. NTSR1 is interrelated with substance and drug abuse and NTSR2 with fear memory, while all NTSRs seem to be implicated in ethanol consumption. Some of the actions of NT and NTSRs in these pathological settings may be driven through interactions between NT and corticotrophin releasing factor (CRF) in their regulatory contribution, as well as by NT's pro-inflammatory mediating actions.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":"916-934"},"PeriodicalIF":4.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10845085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9927506","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":"Cool the Inflamed Brain: A Novel Anti-inflammatory Strategy for the Treatment of Major Depressive Disorder.","authors":"Wen-Jun Su, Ting Hu, Chun-Lei Jiang","doi":"10.2174/1570159X21666230809112028","DOIUrl":"10.2174/1570159X21666230809112028","url":null,"abstract":"<p><strong>Background: </strong>Abundant evidence suggests that inflammatory cytokines contribute to the symptoms of major depressive disorder (MDD) by altering neurotransmission, neuroplasticity, and neuroendocrine processes. Given the unsatisfactory response and remission of monoaminergic antidepressants, anti-inflammatory therapy is proposed as a feasible way to augment the antidepressant effect. Recently, there have been emerging studies investigating the efficiency and efficacy of anti-inflammatory agents in the treatment of MDD and depressive symptoms comorbid with somatic diseases.</p><p><strong>Methods: </strong>In this narrative review, prospective clinical trials focusing on anti-inflammatory treatment for depression have been comprehensively searched and screened. Based on the included studies, we summarize the rationale for the anti-inflammatory therapy of depression and discuss the utilities and confusions regarding the anti-inflammatory strategy for MDD.</p><p><strong>Results: </strong>This review included over 45 eligible trials. For ease of discussion, we have grouped them into six categories based on their mechanism of action, and added some other anti-inflammatory modalities, including Chinese herbal medicine and non-drug therapy. Pooled results suggest that anti-inflammatory therapy is effective in improving depressive symptoms, whether used as monotherapy or add-on therapy. However, there remain confusions in the application of anti-inflammatory therapy for MDD.</p><p><strong>Conclusion: </strong>Based on current clinical evidence, anti-inflammatory therapy is a promisingly effective treatment for depression. This study proposes a novel strategy for clinical diagnosis, disease classification, personalized treatment, and prognostic prediction of depression. Inflammatory biomarkers are recommended to be assessed at the first admission of MDD patients, and anti-inflammatory therapy are recommended to be included in the clinical practice guidelines for diagnosis and treatment. Those patients with high levels of baseline inflammation (e.g., CRP > 3 mg/L) may benefit from adjunctive anti-inflammatory therapy.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":"810-842"},"PeriodicalIF":4.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10845090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9967181","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":"Recombinant Antibody Fragments for Neurological Disorders: An Update.","authors":"Karen Manoutcharian, Goar Gevorkian","doi":"10.2174/1570159X21666230830142554","DOIUrl":"10.2174/1570159X21666230830142554","url":null,"abstract":"<p><p>Recombinant antibody fragments are promising alternatives to full-length immunoglobulins, creating big opportunities for the pharmaceutical industry. Nowadays, antibody fragments such as antigen-binding fragments (Fab), single-chain fragment variable (scFv), single-domain antibodies (sdAbs), and bispecific antibodies (bsAbs) are being evaluated as diagnostics or therapeutics in preclinical models and in clinical trials. Immunotherapy approaches, including passive transfer of protective antibodies, have shown therapeutic efficacy in several animal models of Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), Huntington's disease (HD), transmissible spongiform encephalopathies (TSEs) and multiple sclerosis (MS). There are various antibodies approved by the Food and Drug Administration (FDA) for treating multiple sclerosis and two amyloid beta-specific humanized antibodies, Aducanumab and Lecanemab, for AD. Our previous review summarized data on recombinant antibodies evaluated in pre-clinical models for immunotherapy of neurodegenerative diseases. Here, we explore recent studies in this fascinating research field, give an update on new preventive and therapeutic applications of recombinant antibody fragments for neurological disorders and discuss the potential of antibody fragments for developing novel approaches for crossing the blood-brain barrier (BBB) and targeting cells and molecules of interest in the brain.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":"2157-2167"},"PeriodicalIF":4.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11337690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10104295","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":"The Seeking Proxies for Internal States (SPIS) Model of OCD - A Comprehensive Review of Current Findings and Implications for Future Directions.","authors":"Amit Lazarov, Nira Liberman, Reuven Dar","doi":"10.2174/1570159X21666230920165403","DOIUrl":"10.2174/1570159X21666230920165403","url":null,"abstract":"<p><p>The Seeking Proxies for Internal States (SPIS) model of obsessive-compulsive disorder (OCD) explains symptoms of OCD as stemming from attenuated access to internal states, which is compensated for by using proxies, which are indices of these states that are more discernible or less ambiguous. Internal states in the SPIS model are subjective states that are not accessible to others, encompassing physiological states, motivations, preferences, memories, and emotions. Compensatory proxies in OCD include fixed rules and rituals as well as seeking and relying on external information. In the present review, we outline the SPIS model and describe its basic tenets. We then use the SPIS conceptualization to explain two pivotal OCD-related phenomena - obsessive doubt and compulsive rituals. Next, we provide a detailed overview of current empirical evidence supporting the SPIS in several domains, including physiological states, emotions, sense of understanding, decision-making, and sense of agency. We conclude by discussing possible neural correlates of the difficulty in accessing internal states, focusing on the anterior insular cortex (AIC) and highlighting potential clinical implications of the model to the treatment of OCD.</p>","PeriodicalId":10905,"journal":{"name":"Current Neuropharmacology","volume":" ","pages":"1807-1825"},"PeriodicalIF":4.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11284725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50161050","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}