ACS Chemical Neuroscience最新文献

{"title":"Aromatic Amino Acid Hydroxylases as Off-Targets of Histone Deacetylase Inhibitors.","authors":"Anne Baumann, Niklas Papenkordt, Dina Robaa, Peter D Szigetvari, Anja Vogelmann, Franz Bracher, Wolfgang Sippl, Manfred Jung, Jan Haavik","doi":"10.1021/acschemneuro.4c00346","DOIUrl":"10.1021/acschemneuro.4c00346","url":null,"abstract":"<p><p>The aromatic amino acid hydroxylases (AAAHs) phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylases 1 and 2 are structurally related enzymes that contain an active site iron atom and depend on tetrahydrobiopterin (BH₄) as cosubstrate. Due to their important roles in synthesis of serotonin, dopamine, noradrenaline, and adrenaline and their involvement in cardiovascular, neurological, and endocrine disorders, AAAHs have been targeted by substrate analogs, iron chelators, and allosteric ligands. Phenylalanine hydroxylase is also off-target of the histone deacetylase (HDAC) inhibitor panobinostat. To systematically explore the binding of HDAC inhibitors to AAAHs, we screened a library of 307 HDAC inhibitors and structural analogs against tryptophan hydroxylase 1 using a fluorescence-based thermal stability assay, followed by activity assays. Selected hits were enzymatically tested against all four purified human AAAHs. Cellular thermal shift assay was performed for phenylalanine hydroxylase. We show that panobinostat and structurally related compounds such as TB57, which similarly to panobinostat also contains a cinnamoyl hydroxamate, bind to human AAAHs and inhibit these enzymes with high selectivity within the class (panobinostat inhibition (IC₅₀): phenylalanine hydroxylase (18 nM) > tyrosine hydroxylase (450 nM) > tryptophan hydroxylase 1 (1960 nM). This study shows that panobinostat and related hydroxamic acid type HDAC inhibitors inhibit all AAAHs at therapeutically relevant concentrations. Our results warrant further investigations of the off-target relevance of HDAC inhibitors intended for clinical use and provide directions for new dual HDAC/AAAH and selective AAAH inhibitors. These findings may also provide a new mechanistic link between regulation of histone modification, AAAH function, and monoaminergic neurotransmission.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4143-4155"},"PeriodicalIF":4.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dexmedetomidine Attenuates Neuroinflammation-Mediated Hippocampal Neurogenesis Impairment in Sepsis-Associated Encephalopathy Mice through Central α2A-Adrenoceptor.","authors":"Xinlong Zhang, Yue Feng, Yi Zhong, Rui Ding, Yaoyi Guo, Fan Jiang, Yan Xing, Hongwei Shi, Hongguang Bao, Yanna Si","doi":"10.1021/acschemneuro.4c00486","DOIUrl":"10.1021/acschemneuro.4c00486","url":null,"abstract":"<p><p>Sepsis-associated encephalopathy (SAE), one of the common complications of sepsis, is associated with higher ICU mortality, prolonged hospitalization, and long-term cognitive decline. Sepsis can induce neuroinflammation, which negatively affects hippocampal neurogenesis. Dexmedetomidine has been shown to protect against SAE. However, the potential mechanism remains unclear. In this study, we added lipopolysaccharide (LPS)-stimulated astrocytes-conditioned media (LPS-CM) to neural stem cells (NSCs) culture, which were pretreated with dexmedetomidine in the presence or absence of the α2-adrenoceptor antagonist yohimbine or the α2A-adrenoceptor antagonist BRL-44408. LPS-CM impaired the neurogenesis of NSCs, characterized by decreased proliferation, enhanced gliogenesis, and declined viability. Dexmedetomidine alleviated LPS-CM-induced impairment of neurogenesis in a dose-dependent manner. Yohimbine, as well as BRL-44408, reversed the effects of dexmedetomidine. We established a mouse model of SAE via cecal ligation and perforation (CLP). CLP-induced astrocyte-related neuroinflammation and hippocampal neurogenesis deficits, accompanied by learning and memory decline, which were reversed by dexmedetomidine. The effect of dexmedetomidine was blocked by BRL-44408. Collectively, our findings support the conclusion that dexmedetomidine can protect against SAE, likely mediated by the combination of inhibiting neuroinflammation via the astrocytic α2A-adrenoceptor with attenuating neuroinflammation-induced hippocampal neurogenesis deficits via NSCs α2A-adrenoceptor.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4185-4201"},"PeriodicalIF":4.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural Insights into Dopamine Receptor-Ligand Interactions: From Agonists to Antagonists.","authors":"Emmanuel D Barbosa, Yuanyuan Ma, Heather E Clift, Linda J Olson, Lan Zhu, Wei Liu","doi":"10.1021/acschemneuro.4c00295","DOIUrl":"10.1021/acschemneuro.4c00295","url":null,"abstract":"<p><p>This study explores the intricacies of dopamine receptor-ligand interactions, focusing on the D1R and D5R subtypes. Using molecular modeling techniques, we investigated the binding of the pan-agonist rotigotine, revealing a universal binding mode at the orthosteric binding pocket. Additionally, we analyze the stability of antagonist-receptor complexes with SKF83566 and SCH23390. By examining the impact of specific mutations on ligand-receptor interactions through computational simulations and thermostability assays, we gain insights into binding stability. Our research also delves into the structural and energetic aspects of antagonist binding to D1R and D5R in their inactive states. These findings enhance our understanding of dopamine receptor pharmacology and hold promise for drug development in central nervous system disorders, opening doors to future research and innovation in this field.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4123-4131"},"PeriodicalIF":4.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and In Vitro and In Vivo Characterization of KAC-50.1 as a Potential α-Synuclein PET Radioligand.","authors":"Dinahlee Saturnino Guarino, Patricia Miranda Azpiazu, Dan Sunnemark, Charles S Elmore, Jonas Bergare, Markus Artelsmair, Gunnar Nordvall, Anton Forsberg Morén, Zhisheng Jia, Miguel Cortes-Gonzalez, Robert H Mach, Kyle C Wilcox, Sjoerd Finnema, Magnus Schou, Andrea Varrone","doi":"10.1021/acschemneuro.4c00493","DOIUrl":"10.1021/acschemneuro.4c00493","url":null,"abstract":"<p><p>The accumulation of aggregated α-synuclein (α-syn) is a pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Here within, we report the in vitro characterization targeting site 2 of α-syn fibrils and in vivo evaluation of NHPs of KAC-50.1 as a potential α-syn positron emission tomography (PET) radioligand. Preclinical studies were performed using a multidimensional approach of post-mortem brain imaging techniques, radioligand binding, and biochemical studies. These experiments were followed by PET imaging in cynomolgus monkeys using [¹¹C]KAC-50.1. [3H]KAC-50.1 displayed a KD of 35 nM toward site 2 in recombinant α-syn fibrils. Specific binding of [3H]KAC-50.1 was observed in brain tissues with abundant α-syn pathology but also in AD, PSP, and CBD cases, indicating binding to amyloid β (Aβ) and tau pathology. PET studies showed a rapid entrance of [¹¹C]KAC-50.1 into the brain and relatively rapid washout from cortical brain regions, with slower washout in subcortical regions. [3H]KAC-50.1 is a ligand that binds to fibrillar α-syn but shows limited selectivity for α-syn versus Aβ and tau fibrils. PET studies in NHPs indicate that [¹¹C]KAC-50.1, despite reversible kinetic properties, displays retention in white matter. Altogether, the in vitro and in vivo properties do not support further development of [¹¹C]KAC-50.1 as a PET imaging agent.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4210-4219"},"PeriodicalIF":4.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-Interactions of Aβ Peptides Implicated in Alzheimer’s Disease Shape Amyloid Oligomer Structures and Aggregation","authors":"Tanja Habeck,&nbsp;Silvana Smilla Zurmühl,&nbsp;António J. Figueira,&nbsp;Edvaldo Vasconcelos Soares Maciel,&nbsp;Cláudio M. Gomes and Frederik Lermyte*,&nbsp;","doi":"10.1021/acschemneuro.4c0049210.1021/acschemneuro.4c00492","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00492https://doi.org/10.1021/acschemneuro.4c00492","url":null,"abstract":"<p >A defining hallmark of Alzheimer’s disease (AD) is the synaptic aggregation of the amyloid β (Aβ) peptide. <i>In vivo</i>, Aβ production results in a diverse mixture of variants, of which Aβ40, Aβ42, and Aβ43 are profusely present in the AD brain, and their relative abundance is recognized to play a role in disease onset and progression. Nonetheless, the occurrence of Aβ40, Aβ42, and Aβ43 hetero-oligomerization and the subsequent effects on Aβ aggregation remain elusive and were investigated here. Using thioflavin-T (ThT)-monitored aggregation assays and native mass spectrometry coupled to ion mobility analysis (IM-MS), we first show that all Aβ peptides are aggregation-competent and self-assemble into homo-oligomers with distinct conformational populations, which are more pronounced between Aβ40 than the longer variants. ThT assays were then conducted on binary mixtures of Aβ variants, revealing that Aβ42 and Aβ43 aggregate independently from Aβ40 but significantly speed up Aβ40 fibrillation. Aβ42 and Aβ43 were observed to aggregate concurrently and mutually accelerate fibril formation, which likely involves hetero-oligomerization. Accordingly, native MS analysis revealed pairwise oligomerization between all variants, with the formation of heterodimers and heterotrimers. Interestingly, IM-MS indicates that hetero-oligomers containing longer Aβ variants are enriched in conformers with lower collision cross-sections when compared to their homo-oligomer counterparts. This suggests that Aβ42 and Aβ43 are capable of remodeling the oligomer structure toward a higher compaction level. Altogether, our findings provide a mechanistic description for the hetero-oligomerization of Aβ variants implicated in AD, contributing to rationalizing their <i>in vivo</i> proteotoxic interplay.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"15 23","pages":"4295–4304 4295–4304"},"PeriodicalIF":4.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142761282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging Frontiers in Conformational Exploration of Disordered Proteins: Integrating Autoencoder and Molecular Simulations","authors":"Jiyuan Zeng,&nbsp;Zhongyuan Yang,&nbsp;Yiming Tang* and Guanghong Wei*,&nbsp;","doi":"10.1021/acschemneuro.4c0067010.1021/acschemneuro.4c00670","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00670https://doi.org/10.1021/acschemneuro.4c00670","url":null,"abstract":"<p >Intrinsically disordered proteins (IDPs) are closely associated with a number of neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. Due to the highly dynamic nature of IDPs, their structural determination and conformational exploration pose significant challenges for both experimental and computational research. Recently, the integration of machine learning with molecular dynamics (MD) simulations has emerged as a promising methodology for efficiently exploring the conformation spaces of IDPs. In this viewpoint, we briefly review recently developed autoencoder-based models designed to enhance the conformational exploration of IDPs through embedding and latent sampling. We highlight the capability of autoencoders in expanding the conformations sampled by MD simulations and discuss their limitations due to the non-Gaussian latent space distribution and the limited conformational diversity of training conformations. Potential strategies to overcome these limitations are also discussed.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"15 23","pages":"4241–4244 4241–4244"},"PeriodicalIF":4.1,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathological Mutations D169G and P112H Electrostatically Aggravate the Amyloidogenicity of the Functional Domain of TDP-43","authors":"Meenakshi Pillai,&nbsp;Anjali D. Patil,&nbsp;Atanu Das* and Santosh Kumar Jha*,&nbsp;","doi":"10.1021/acschemneuro.4c0037210.1021/acschemneuro.4c00372","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00372https://doi.org/10.1021/acschemneuro.4c00372","url":null,"abstract":"<p >Aggregation of TDP-43 is linked to the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Notably, electrostatic point mutations such as D169G and P112H, located within the highly conserved functional tandem RNA recognition motif (RRM) domains of the TDP-43 protein (TDP-43^tRRM), have been identified in diseased patients as well. In this study, we address how the electrostatic mutations alter both the native state stability and aggregation propensity of TDP-43^tRRM. The mutants D169G and P112H show increased chemical stability compared to the TDP-43^tRRM at physiological pH. However, at low pH, both the mutants undergo a conformational change to form amyloid-like fibrils, though with variable rates─the P112H mutant being substantially faster than the other two sequences (TDP-43^tRRM and D169G mutant) showing comparable rates. Moreover, among the three sequences, only the P112H mutant undergoes a strong ionic strength-dependent aggregability trend. These observations signify the substantial contribution of the excess charge of the P112H mutant to its unique aggregation process. Complementary simulated observables with atomistic resolution assign the experimentally observed sequence-, pH-, and ionic strength-dependent aggregability pattern to the degree of thermal lability of the mutation site-containing RRM1 domain and its extent of dynamical anticorrelation with the RRM2 domain whose combination eventually dictate the extent of generation of aggregation-prone partially unfolded conformational ensembles. Our choice of a specific charge-modulated pathogenic mutation-based experiment-simulation-combination approach unravels the otherwise hidden residue-wise contribution to the individual steps of this extremely complicated multistep aggregation process.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"15 23","pages":"4267–4283 4267–4283"},"PeriodicalIF":4.1,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142761267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering the Monomeric and Dimeric Conformational Landscapes of the Full-Length TDP-43 and the Impact of the C-Terminal Domain","authors":"Vaishnavi Tammara,&nbsp;Abhilasha A. Doke,&nbsp;Santosh Kumar Jha* and Atanu Das*,&nbsp;","doi":"10.1021/acschemneuro.4c0055710.1021/acschemneuro.4c00557","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00557https://doi.org/10.1021/acschemneuro.4c00557","url":null,"abstract":"<p >The aberrant aggregation of TAR DNA-binding protein 43 kDa (TDP-43) in cells leads to the pathogenesis of multiple fatal neurodegenerative diseases. Decoding the proposed initial transition between its functional dimeric and aggregation-prone monomeric states can potentially design a viable therapeutic strategy, which is presently limited by the lack of structural detail of the full-length TDP-43. To achieve a complete understanding of such a delicate phase space, we employed a multiscale simulation approach that unearths numerous crucial features, broadly summarized in two categories: (1) state-independent features that involve inherent chain collapsibility, rugged polymorphic landscape dictated by the terminal domains, high β-sheet propensity, structural integrity preserved by backbone-based intrachain hydrogen bonds and electrostatic forces, the prominence of the C-terminal domain in the intrachain cross-domain interfaces, and equal participation of hydrophobic and hydrophilic (charged and polar) residues in cross-domain interfaces; and (2) dimerization-modulated characteristics that encompass slower collapsing dynamics, restricted polymorphic landscape, the dominance of side chains in interchain hydrogen bonds, the appearance of the N-terminal domain in the dimer interface, and the prominence of hydrophilic (specifically polar) residues in interchain homo- and cross-domain interfaces. In our work, the ill-known C-terminal domain appears as the most crucial structure-dictating domain, which preferably populates a compact conformation with a high β-sheet propensity in its isolated state stabilized by intrabackbone hydrogen bonds, and these signatures are comparatively faded in its integrated form. Validation of our simulated observables by a complementary spectroscopic approach on multiple counts ensures the robustness of the computationally predicted features of the TDP-43 aggregation landscape.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"15 23","pages":"4305–4321 4305–4321"},"PeriodicalIF":4.1,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142761077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rimota-Gd: Paramagnetic Probe for In Vivo MRI Studies of the Cannabinoid 1 Receptor Distribution in the Mouse Brain","authors":"Qi Ouyang,&nbsp;Fei Zhao,&nbsp;Jingjing Ye,&nbsp;Mengyang Xu,&nbsp;Suyun Pu,&nbsp;Wenxue Hui,&nbsp;Xinyan Gao,&nbsp;Xiaochuan Zha,&nbsp;Hao Chen,&nbsp;Zhiming Wang,&nbsp;Fei Li,&nbsp;Zonghua Luo*,&nbsp;Kurt Wüthrich and Garth J. Thompson*,&nbsp;","doi":"10.1021/acschemneuro.4c0025910.1021/acschemneuro.4c00259","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00259https://doi.org/10.1021/acschemneuro.4c00259","url":null,"abstract":"<p >The cannabinoid 1 receptor (CB1) is highly expressed in the central nervous system, where its physiological functions include the regulation of energy balance, pain, and addiction. Herein, we develop and validate a technique to use magnetic resonance imaging (MRI) to investigate the distribution of CB1 across mouse brains with high spatial resolution, expanding previously described in vitro studies and in vivo studies with positron emission tomography (PET). To support the MRI investigations, we developed a ligand that is specific for in vivo neuroimaging of CB1. By chemically conjugating the CB1 antagonist rimonabant acid to a gadolinium chelator, we obtained the paramagnetic probe Rimota-Gd. The specificity of binding of rimonabant acid to CB1 and the relaxation enhancement by the paramagnetic gadolinium permit MRI-based localization of CB1. We used Rimota-Gd to investigate the spatial distribution of CB1 across the mouse brain and compared the results with an investigation using the PET radioligand [¹⁸F]MK-9470. Rimota-Gd opens the door for in vivo MRI imaging of CB1 and provides a roadmap for the study of other receptors by whole-brain images with high spatial and temporal resolution.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"15 23","pages":"4258–4266 4258–4266"},"PeriodicalIF":4.1,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142761059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unlocking the Potential of Oxymatrine: A Comprehensive Review of Its Neuroprotective Mechanisms and Therapeutic Prospects in Neurological Disorders","authors":"Yogita Dhurandhar,&nbsp;Shubham Tomar,&nbsp;Ashmita Das,&nbsp;As Pee Singh,&nbsp;Jeevan Lal Prajapati,&nbsp;Surendra H. Bodakhe and Kamta P. Namdeo*,&nbsp;","doi":"10.1021/acschemneuro.4c0033810.1021/acschemneuro.4c00338","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00338https://doi.org/10.1021/acschemneuro.4c00338","url":null,"abstract":"<p ><i>Sophora flavescens</i>, the source of oxymatrine, is gaining popularity due to its potential in neuroprotection and treatment of various neurological conditions like epilepsy, depression, Parkinson’s, Alzheimer’s and multiple sclerosis. Its natural occurrence and promising preliminary research highlight its ability to reduce nerve cell damage and inflammation, attributed to its antiapoptotic, antioxidant and anti-inflammatory properties. However, challenges like solubility, potential adverse effects and limited bioavailability hinder its full therapeutic utilization. Current strategies, including formulation optimization and innovative drug delivery systems, aim to enhance its efficacy and safety. Despite its potential, further research is necessary to overcome these obstacles and maximize its clinical effectiveness. Conclusively, oxymatrine demonstrates distinct neuroprotective properties, offering unique advantages over other agents currently being studied or used in clinical practice for neurological disorders. nevertheless, additional study is necessary to surmount current obstacles and maximize its effectiveness for clinical settings. This study provides a comprehensive overview of oxymatrine’s neuroprotective mechanisms and therapeutic potential while emphasizing the need for continued investigation and development for practical clinical application.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"15 23","pages":"4245–4257 4245–4257"},"PeriodicalIF":4.1,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142761076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}