CNS & neurological disorders drug targets最新文献

{"title":"In Silico and ADMET Studies of Spiro-Quinazoline Compounds as Acetylcholine Esterase Inhibitors Against Alzheimer's Disease.","authors":"Abdulelah Aljuaid, Osama Abdulaziz, Mamdouh Allahyani, Mazen Almehmadi, Abdullah Yahya Abdullah Alzahrani, Shivani Verma, Mohd Yusuf, Mohammad Asif","doi":"10.2174/0118715273315412241009092249","DOIUrl":"https://doi.org/10.2174/0118715273315412241009092249","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is a prevalent neurodegenerative condition characterized by progressive cognitive decline and memory impairment resulting from the degeneration and death of brain neurons. Acetylcholinesterase (AChE) inhibitors are used in primary pharmacotherapy for numerous neurodegenerative conditions, providing their capacity to modulate acetylcholine levels crucial for cognitive function. Recently, quinazoline derivatives have emerged as a compelling model for neurodegenerative disease treatment, showcasing promising pharmacological features. Their unique structural features and pharmacokinetic profiles have sparked interest in their potential efficacy and safety across diverse neurodegenerative disorders. The exposure of quinazoline derivatives as a potential therapeutic way underscores the imperative for continued research exploration. Their multifaceted mechanisms of action and ability to target various pathways implicated in neurodegeneration offer exciting prospects for developing novel, effective, and well-tolerated treatments. Further investigations into their pharmacological activities and precise therapeutic roles are essential to advance our understanding of neurodegenerative disease pathophysiology and promote the development of modern therapeutic strategies to address this critical medical challenge.</p><p><strong>Methods: </strong>Quinazoline derivatives have gained eminent acetylcholinesterase (AChE) inhibitory activity. Their ability to effectively modulate AChE activity makes them promising candidates for treating neurological disorders, particularly Alzheimer's disease (AD). Their intricate molecular structures confer selectivity and affinity for AChE, offering potential for the development of novel therapeutic agents targeting cholinergic pathways. Hence, in this study, we designed, synthesized, and characterized a series of spiro[cycloalakane-1,2'-quinazoline derivatives (1-6) to assess their possible AChE inhibiting ability using docking into the active sites.</p><p><strong>Results: </strong>The AChE inhibitory potential of spiro[cycloalkane-1,2'-quinazoline derivatives (1-6) was explored via docking studies of the AChE active site. The findings revealed significant inhibitory activity and highlighted the promising nature of these derivatives.</p><p><strong>Conclusion: </strong>The synthesized spiro[cycloalkane-1,2'-quinazoline derivatives (1-6) exhibited their notable potential as AChE inhibitors. The observed significant inhibitory activity suggested that these derivatives warrant further exploration as candidates for developing therapeutic agents in AChE inhibitory pathways. This study emphasizes the relevance of quinazoline derivatives in searching for novel treatments for neurological disorders, particularly associated with cholinergic dysfunction, and they could be a useful alternative therapeutic agent.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Insight into Medicinal Chemistry and SAR Studies of Cholinesterase and BACE-1 Inhibitors for Alzheimer's Disease.","authors":"Abhimannu Shome, Keshav Taruneshwar Jha, Chahat, Viney Chawla, Pooja A Chawla","doi":"10.2174/0118715273315191241002115155","DOIUrl":"https://doi.org/10.2174/0118715273315191241002115155","url":null,"abstract":"<p><p>Alzheimer's Disease (AD) is a serious neurodegenerative condition that predominantly impacts the cholinergic neurons of the entorhinal cortex and hippocampal regions, playing a critical role in learning, navigation, and brain processing. This paper aims to discuss the three main hypotheses of Alzheimer's disease, focusing on neurotoxicity and neurodegeneration caused by mitochondrial dysfunction and ROS production, particularly analyzing the susceptibility differences between genders. Our comprehensive review focuses on significant findings from the past five years, particularly on Cholinesterase (ChE) and BACE-1 inhibitors. Researchers have conducted a detailed analysis of in vitro, in silico, and in vivo data, incorporating extensive Structure-Activity Relationship (SAR) studies. The reviewed papers have been sourced from platforms, such as Google Scholar, Semantic Scholar, and ClinicalTrials.gov, and have been selected based on their AChE and BACE-1 inhibitory activity and structural motif similarity. The review identifies the most effective compounds targeting ChE and BACE-1, highlighting acridine, dihydropyridine, and thiazole-coumarin hybrids for ChE inhibition, and oxadiazole, benzofuran, and dihydropyrimidinone for BACE-1 inhibition. This demonstrates a diverse array of potent heterocyclic hybrids. The review presents a varied compilation of scaffolds showing promise in treating Alzheimer's disease, highlighting the potential of specific compounds against ChE and BACE-1. Given the critical insights derived from our analysis, we posit that this compilation will substantially contribute to the ongoing efforts to combat neurodegeneration and prolong dementia, underscoring the importance of continuous research in this domain.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142483130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BBBper: A Machine Learning-based Online Tool for Blood-Brain Barrier (BBB) Permeability Prediction.","authors":"Pawan Kumar, Vandana Saini, Dinesh Gupta, Pooja A Chawla, Ajit Kumar","doi":"10.2174/0118715273328174241007060331","DOIUrl":"https://doi.org/10.2174/0118715273328174241007060331","url":null,"abstract":"<p><strong>Aims: </strong>Neuronal disorders have affected more than 15% of the world's population, signifying the importance of continued design and development of drugs that can cross the Blood-Brain Barrier (BBB).</p><p><strong>Background: </strong>BBB limits the permeability of external compounds by 98% to maintain and regulate brain homeostasis. Hence, BBB permeability prediction is vital to predict the activity of a drug-like substance.</p><p><strong>Objective: </strong>Here, we report about developing BBBper (Blood-Brain Barrier permeability prediction) using machine learning tool.</p><p><strong>Method: </strong>A supervised machine learning-based online tool, based on physicochemical parameters to predict the BBB permeability of given chemical compounds was developed. The user-end webpage was developed in HTML and linked with back-end server by a python script to run user queries and results.</p><p><strong>Result: </strong>BBBper uses a random forest algorithm at the back end, showing 97% accuracy on the external dataset, compared to 70-92% accuracy of currently available web-based BBB permeability prediction tools.</p><p><strong>Conclusion: </strong>The BBBper web tool is freely available at http://bbbper.mdu.ac.in.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142483131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Navigating into the Paradigm of Nose-to-brain Delivery of Nanotherapeutics and their Repurposing as Nanotheranostics for Neurodegenerative Diseases.","authors":"Asad Ali, Nasr A Emad, Niha Sultana, Ayesha Waheed, Mohd Aqil, Yasmin Sultana, Mohd Mujeeb","doi":"10.2174/0118715273319597240927044906","DOIUrl":"https://doi.org/10.2174/0118715273319597240927044906","url":null,"abstract":"<p><p>Repurposing drugs for neurodegenerative diseases using the nose-to-brain route of administration is an intriguing concept with potential benefits. The nose-to-brain route involves delivering drugs directly to the brain via the olfactory or trigeminal pathways, bypassing the blood-brain barrier, which can improve drug efficacy and reduce systemic side effects. Treatment of numerous neurodegenerative diseases such as Multiple sclerosis, Amyotrophic lateral sclerosis, Huntington's, Alzheimer's, and Parkinson's diseases has been attempted using this route of administration. These drugs may include neuroprotective agents, anti-inflammatory drugs, antioxidants, or diseasemodifying therapies. Nanotheranostics, which integrates therapeutic and diagnostic functions in a nanosystem, improves treatment precision and efficacy. Repurposing nanotherapeutics as nanotheranostics for neurodegenerative diseases through the nose-to-brain route of administration holds great potential for both diagnosis and treatment. This review highlights the various mechanisms engaged in transporting nanocarriers from nose-to-brain and the proposed fate of these nanocarriers using different live imaging techniques. Additionally, the discussion covers the recent combinatorial therapeutic approaches and theranostic applications of various nanocarriers used for neurodegenerative diseases through the nose-to-brain. Toxicity to the CNS and nasal mucosa and regulatory considerations about these delivery systems are also deliberated. Overall, repurposed nanoparticles designed as nanotheranostic agents offer a versatile platform for precise diagnosis, targeted therapy, and personalized management of neurodegenerative diseases, holding great promise for improving patient care and advancing our understanding of these complex disorders.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142483133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the Potential of Herbal Compounds as Autophagy Modulators in Alzheimer's Disease: A Comprehensive Review.","authors":"Ekta Yadav, Ashok Kumar Mandal, Ajay Kumar Sah, Sandesh Poudel, Prateek Pathak, Habibullah Khalilullah, Mariusz Jaremko, Abdul-Hamid Emwas, Pankajkumar Yadav, Amita Verma","doi":"10.2174/0118715273298025240905130205","DOIUrl":"https://doi.org/10.2174/0118715273298025240905130205","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive neurodegenerative disorder that causes atrophy of brain cells, leading to their death, and has become a leading cause of death in aging populations worldwide. AD is characterized by β-amyloid (Aβ) deposition and tau phosphorylation in neural tissues, but the precise pathophysiology of the disease is still obscure. Autophagy is an evolutionarily targeted mechanism that is necessary for the elimination of neuronal and glial misfolded proteins as well as proteins. It also plays an essential role in synaptic plasticity. The aberrant autophagy primarily influences the process of aging and neurodegeneration. Autophagy significantly influences how Aβ and tau function physiologically, therefore, atypical autophagy is expected to perform an important role in Aβ deposition and tau phosphorylation characteristic in the development of AD. Bioactive phytoconstituents could majorly contribute as a natural yet effective alternative approach to slow down the progression of neurodegeneration and promote the active aging process in elderly patients. Over the recent years, it is well evidenced that different secondary metabolites including polyphenols, alkaloids, terpenes, and phenols exhibited neuroprotective effects, and attenuated brain damage, and cognitive impairment in vitro as well as in vivo. Additionally, the underlying mechanism of action shared by them is the regulation of competent autophagy via the removal of aggregated protein and mitochondrial dysfunction. The present article is structured as a reference for researchers keen to investigate and assess the new natural compound-mediated therapeutic approach for AD treatment through the modulation of autophagy.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142303471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging Treatments for Subarachnoid Hemorrhage.","authors":"Matthew C Findlay, Mrinmoy Kundu, Jayson R Nelson, Kyril L Cole, Candace Winterton, Samuel Tenhoeve, Brandon Lucke-Wold","doi":"10.2174/0118715273279212240130065713","DOIUrl":"10.2174/0118715273279212240130065713","url":null,"abstract":"<p><p>The current landscape of therapeutic strategies for subarachnoid hemorrhage (SAH), a significant adverse neurological event commonly resulting from the rupture of intracranial aneurysms, is rapidly evolving. Through an in-depth exploration of the natural history of SAH, historical treatment approaches, and emerging management modalities, the present work aims to provide a broad overview of the shifting paradigms in SAH care. By synthesizing the historical management protocols with contemporary therapeutic advancements, patient-specific treatment plans can be individualized and optimized to deliver outstanding care for the best possible SAH-related outcomes.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":"1345-1356"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139974991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacogenetics of Carbamazepine: A Systematic Review on CYP3A4 and CYP3A5 Polymorphisms.","authors":"Rachda Riffi, Wefa Boughrara, Amina Chentouf, Wassila Ilias, Narimene Malika Taieb Brahim, Amel Alioua Berrebbah, Fatma Belhoucine","doi":"10.2174/0118715273298953240529100325","DOIUrl":"10.2174/0118715273298953240529100325","url":null,"abstract":"<p><strong>Background and objective: </strong>The association between carbamazepine (CBZ) metabolism and resistance in epilepsy and the genetic polymorphisms of CYP3A5 (rs776746 and rs15524) and CYP3A4 (rs2242480, rs2740574, rs35599367, rs12721627, and rs28371759) has been the subject of previous investigations with controversial results. Hence, we conducted a systematic review to assess the potential link between these polymorphisms and CBZ metabolism and resistance.</p><p><strong>Methods: </strong>Identifying relevant studies was carried out by searching PubMed, Scopus, PharmGKB, EPIGAD, and PHARMAADME databases up until June 2023. The studies included in our analysis investigated the connection between CYP3A5 (rs776746 and rs15524) and CYP3A4 (rs2242480, rs2740574, rs35599367, rs12721627, and rs28371759) polymorphisms and CBZ metabolism and resistance.</p><p><strong>Results: </strong>This review included a total of 23 studies and more than 2177 epilepsy patients. It was found that the CYP3A4 (rs12721627 and rs28371759) polymorphisms are associated with reduced catalytic activity, whereas the CYP3A4 (rs2740574) polymorphism is linked to lower levels of CBZ-diol and decreased activity. It was also observed that the CYP3A5 (rs776746) polymorphism influences the dose-adjusted plasma levels of CBZ.</p><p><strong>Conclusion: </strong>Although these findings highlight the impact of genetic variations in the CYP3A4 and CYP3A5 genes on CBZ pharmacokinetics and pharmacodynamics, further studies across diverse populations are essential to enhance personalized epilepsy therapy in clinical settings.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":"1463-1473"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141302259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T Lymphocyte Interferon-gamma Response to Anaplasmataceae-related Major Surface Proteins and Ankyrin A in Fibromyalgia.","authors":"Basant K Puri, Rosemarie Preyer, Gary S Lee, Armin Schwarzbach","doi":"10.2174/0118715273274091231207101522","DOIUrl":"10.2174/0118715273274091231207101522","url":null,"abstract":"<p><strong>Background: </strong>The aetiology of fibromyalgia is unknown; its symptoms may be related to a T-lymphocyte-mediated response to infectious organisms.</p><p><strong>Objectives: </strong>First, to test the hypothesis that fibromyalgia is associated with increased interferon (IFN)-γ-secreting T-lymphocytes after stimulation with Anaplasmataceae-related major surface proteins (MSPs) and the macromolecular translocation type IV secretion system effector ankyrin repeat domain-containing protein A (AnkA). Second, to ascertain the relationship in fibromyalgia between (i) the IFN-γ-secreting T-lymphocyte response to stimulation with Anaplasmataceae-related MSPs and AnkA, and (ii) co-infection by <i>Borrelia</i> and <i>Yersinia</i> spp., and antinuclear antibodies.</p><p><strong>Methods: </strong>Using a case-control design, patients fulfilling the American College of Rheumatology revised criteria for fibromyalgia, and controls, underwent the following blinded assessments: (i) enzyme- linked immune absorbent spot (ELISpot) IFN-γ release assay of T-lymphocyte reactivity to Anaplasmataceae-related MSPs and AnkA; (ii) ELISpot IFN-γ release assays of T-lymphocyte reactivity to three <i>Borrelia</i> antigens, namely<i> Borrelia burgdorferi</i> full antigen (B31); peptide mix (from <i>Borrelia burgdorferi</i> sensu stricto, <i>Borrelia afzelii, Borrelia garinii</i>); and <i>Borrelia burgdorferi</i> lymphocyte function-associated antigen-1; (iii) immunoglobulin (Ig) A assay by enzyme-linked immunosorbent assay (ELISA) of antibodies to <i>Yersinia</i> spp.; (iv) IgG (ELISA) antibodies to <i>Yersinia</i> spp.; (v) serum antinuclear antibodies (immunofluorescence).</p><p><strong>Results: </strong>The groups were age- and sex-matched. The mean (standard error) value of IFN-γ release for the fibromyalgia group was 1.52 (0.26), compared with 1.00 (0.22) for the controls. Generalised linear modelling (p<0.001) of IFN-γ release in the fibromyalgia patients showed significant main effects of all three indices of <i>Borrelia</i> infection and of antinuclear antibodies.</p><p><strong>Conclusion: </strong>Anaplasmataceae may play an aetiological role in fibromyalgia.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":"1392-1399"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139907112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effectiveness of Transcranial Magnetic Stimulation in Treating Apraxia.","authors":"Asma AlRuwaili, Rida Fatima, Amal Hussain, Mohammad Uzair, Turki Abualait, Kaleem Imdad, Shahid Bashir","doi":"10.2174/0118715273249412231010171926","DOIUrl":"10.2174/0118715273249412231010171926","url":null,"abstract":"<p><p>Apraxia can be detected when engaging in mental motor envisioning exercises. The nonverbal skills of manufacturing, representation, strategizing, arithmetic, visual sensitivity, and motor skills are all related to apraxia. Limb apraxia also negatively affects communication gestures and linguistic skills. The impairment of brain regions related to motion patterns is the primary cause of apraxia. People with apraxia may struggle to complete a variety of tasks because they are unable to focus on various movements. Apraxia can result from injury to the premotor cortex since it has a role in the left hemisphere-dependent selection of movements. Cognitive and complicated motor system deficits are hallmarks of the corticobasal syndrome. Apraxia of the limbs and visuospatial abnormalities are typical clinical types. TMS was used to study these problems; however, no research was done on the relationship between TMS parameters and clinical types. It is possible for changes in brain activity to last a long time when repetitive TMS (rTMS) is utilized. Electromyography shows that noninvasive TMS of the motor cortex causes target muscle spasms (MEP). The human motor cortex is a part of the cerebral cortex that is involved in the organization, management, and execution of voluntary movements. TMS and other neuroimaging techniques are frequently used to identify changes in this region. Cortical motor excitability varies among different diagnoses; therefore, it is important to determine the effectiveness of TMS. Therefore, this study aims to review the causes and neurophysiological simulation of apraxia along with the principles and effects of TMS on apraxia.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":"1030-1039"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41242191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amelioration of Neurochemical Alteration and Memory and Depressive Behavior in Sepsis by Allopurinol, a Tryptophan 2,3-Dioxygenase Inhibitor.","authors":"Kiuanne Lino Lobo Metzker, Khiany Mathias, Richard Simon Machado, Sandra Bonfante, Larissa Joaquim, Marina Goulart da Silva, Guilherme Cabreira Daros, Elisa Mitkus Flores Lins, Fernanda Belle, Carolina Giassi Alano, Rafaela Tezza Matiola, Isabela da Silva Lemos, Lucinéia Gainski Danielski, Fernanda Frederico Gava, Rafael Mariano de Bitencourt, Franciane Bobinski, Emilio Luiz Streck, Gislaine Zilli Reus, Fabricia Petronilho","doi":"10.2174/0118715273282363240415045927","DOIUrl":"10.2174/0118715273282363240415045927","url":null,"abstract":"<p><strong>Background: </strong>In response to inflammation and other stressors, tryptophan is catalyzed by Tryptophan 2,3-Dioxygenase (TDO), which leads to activation of the kynurenine pathway. Sepsis is a serious condition in which the body responds improperly to an infection, and the brain is the inflammation target in this condition.</p><p><strong>Objective: </strong>This study aimed to determine if the induction of TDO contributes to the permeability of the Blood-Brain Barrier (BBB), mortality, neuroinflammation, oxidative stress, and mitochondrial dysfunction, besides long-term behavioral alterations in a preclinical model of sepsis.</p><p><strong>Methods: </strong>Male Wistar rats with two months of age were submitted to the sepsis model using Cecal Ligation and Perforation (CLP). The rats received allopurinol (Allo, 20 mg/kg, gavage), a TDO inhibitor, or a vehicle once a day for seven days.</p><p><strong>Results: </strong>Sepsis induction increased BBB permeability, IL-6 level, neutrophil infiltrate, nitric oxide formation, and oxidative stress, resulting in energy impairment in 24h after CLP and Allo administration restored these parameters. Regarding memory, Allo restored short-term memory impairment and decreased depressive behavior. However, no change in survival rate was verified.</p><p><strong>Conclusion: </strong>In summary, TDO inhibition effectively prevented depressive behavior and memory impairment 10 days after CLP by reducing acute BBB permeability, neuroinflammation, oxidative stress, and mitochondrial alteration.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":"1499-1515"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140873845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}