ACS Chemical Neuroscience最新文献

{"title":"LRRK2 Inhibitors as Promising Treatment for Parkinson's Disease.","authors":"Shuoyan Tan, Huanxiang Liu, Xiaojun Yao","doi":"10.1021/acschemneuro.4c00657","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00657","url":null,"abstract":"<p><p>Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorders, with current treatments offering only temporary symptomatic relief. There is an urgent need for the development of novel therapeutic approaches. Abnormal increases in LRRK2 kinase activity have been identified in both sporadic and familial PD patients, suggesting that inhibiting LRRK2 kinase activity presents a promising avenue for the pursuit of effective PD treatment strategies. In this Viewpoint, we discuss the exciting new insights regarding the development of LRRK2 kinase inhibitors as a treatment for Parkinson's disease.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563515","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":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","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":"AI-Enabled Ultra-large Virtual Screening Identifies Potential Inhibitors of Choline Acetyltransferase for Theranostic Purposes.","authors":"Anurag T K Baidya, Abhinav Kumar Goswami, Bhanuranjan Das, Taher Darreh-Shori, Rajnish Kumar","doi":"10.1021/acschemneuro.4c00361","DOIUrl":"10.1021/acschemneuro.4c00361","url":null,"abstract":"<p><p>Alzheimer's disease (AD) and related dementias are among the primary neurological disorders and call for the urgent need for early-stage diagnosis to gain an upper edge in therapeutic intervention and increase the overall success rate. Choline acetyltransferase (ChAT) is the key acetylcholine (ACh) biosynthesizing enzyme and a legitimate target for the development of biomarkers for early-stage diagnosis and monitoring of therapeutic responses. It is also a theranostic target for tackling colon and lung cancers, where overexpression of non-neuronal ChAT leads to the production of acetylcholine, which acts as an autocrine growth factor for cancer cells. Theranostics is a hybrid of diagnostics and therapeutics that can be used to locate cancer cells using radiotracers and kill them without affecting other healthy tissues. Traditional virtual screening protocols have a lot of limitations; given the current rate of chemical database expansion exceeding billions, much faster screening protocols are required. Deep docking (DD) is one such platform that leverages the power of deep neural network (DNN)-based virtual screening, empowering researchers to dock billions of molecules in a speedy, yet explicit manner. Here, we have screened 1.3 billion compounds library from the ZINC20 database, identifying the best-performing hits. With each iteration run where the first iteration gave ∼116 million hits, the second iteration gave ∼3.7 million hits, and the final third iteration gave 168,447 hits from which further refinement gave us the top 5 compounds as potential ChAT inhibitors. The discovery of novel ChAT inhibitors will enable researchers to develop new probes that can be used as novel theranostic agents against cancer and as early-stage diagnostics for the onset of AD, for timely therapeutic intervention to halt the further progression of AD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556531","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":"Fluoxetine Ameliorates Cognitive Deficits in High-Fat Diet Mice by Regulating BDNF Expression.","authors":"Xiang Zuo, ZiKun Zhu, MengYu Liu, Qili Zhao, XinYu Li, Xin Zhao, XiZeng Feng","doi":"10.1021/acschemneuro.4c00540","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00540","url":null,"abstract":"<p><p>High-fat diet (HFD) induced obesity is associated with depression-related behavioral and neurogenic changes and may lead to cognitive impairment. Fluoxetine (FXT), the most commonly used antidepressant, may alleviate depressive symptoms by increasing neurogenesis, but the potential efficacy of FXT for HFD-induced cognitive deficits is unclear. In this study, we established an obese HFD mouse model by feeding three-week-old male C57BL/6N mice with a chronic HFD for 18 weeks, then assessed adipose tissue morphology by magnetic resonance imaging and histopathology, assessed cognitive function by Morris water maze and novel object recognition tests, and detected DCX⁺ and BrdU⁺ expression in the hippocampal dentate gyrus (DG) region by immunofluorescence bioassay. Western blot detected brain-derived neurotrophic factor (BDNF) levels and <i>CREB-BDNF</i> pathway-related genes were assayed by Quantitative RT-PCR. The results of the study showed that HFD contributes to obesity and cognitive deficits, and more importantly, it also reduces BDNF expression and neurogenesis levels in the hippocampus. Subsequently, we found that treatment with FXT (10 mg/kg/day) ameliorated chronic HFD-induced cognitive deficits and increased the expression of Nestin, BrdU⁺, and DCX⁺ in the DG, restored BDNF expression in the hippocampus and increased the expression of genes related to <i>CREB</i>, <i>BDNF</i>, <i>NGF</i>, and <i>MAPK1</i>. In conclusion, our data elucidated that FXT ameliorates cognitive deficits and reduces chronic HFD-induced neurogenesis by restoring BDNF expression and <i>CREB-BDNF</i> signaling, this provides a good basis and scientific significance for future research on the clinical treatment of obesity.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542768","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":"Cholesterol Accelerates Aggregation of α-Synuclein Simultaneously Increasing the Toxicity of Amyloid Fibrils","authors":"Mikhail Matveyenka,&nbsp;Abid Ali,&nbsp;Charles L. Mitchell,&nbsp;Harris C. Brown and Dmitry Kurouski*,&nbsp;","doi":"10.1021/acschemneuro.4c0050110.1021/acschemneuro.4c00501","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00501https://doi.org/10.1021/acschemneuro.4c00501","url":null,"abstract":"<p >A hallmark of Parkinson disease (PD) is a progressive degeneration of neurons in the substantia nigra pars compacta, hypothalamus, and thalamus. Although the exact etiology of irreversible neuronal degeneration is unclear, a growing body of experimental evidence indicates that PD could be triggered by the abrupt aggregation of α-synuclein (α-Syn), a small membrane protein that is responsible for cell vesicle trafficking. Phospholipids uniquely alter the rate of α-Syn aggregation and, consequently, change the cytotoxicity of α-Syn oligomers and fibrils. However, the role of cholesterol in the aggregation of α-Syn remains unclear. In this study, we used <i>Caenorhabditis elegans</i> that overexpressed α-Syn to investigate the effect of low (15%), normal (30%), and high (60%) concentrations of cholesterol on α-Syn aggregation. We found that an increase in the concentration of cholesterol in diets substantially shortened the lifespan of <i>C. elegans</i>. Using biophysical methods, we also investigated the extent to which large unilamellar vesicles (LUVs) with low, normal, and high concentrations of cholesterol altered the rate of α-Syn aggregation. We found that only lipid membranes with a 60% concentration of cholesterol substantially accelerated the rate of protein aggregation. Cell assays revealed that α-Syn fibrils formed in the presence of LUVs with different concentrations of cholesterol exerted very similar levels of cytotoxicity to rat dopaminergic neurons. These results suggest that changes in the concentration of cholesterol in the plasma membrane, which in turn could be caused by nutritional preferences, could accelerate the onset and progression of PD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00501","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585624","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":"DNA-Mediated Formation of Phase-Separated Coacervates of the Nucleic Acid-Binding Domain of TAR DNA-Binding Protein (TDP-43) Prevents Its Amyloid-Like Misfolding.","authors":"Divya Patni, Anjali D Patil, Mona S Kirmire, Anjali Jha, Santosh Kumar Jha","doi":"10.1021/acschemneuro.4c00117","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00117","url":null,"abstract":"<p><p>Sequestration of protein molecules and nucleic acids to stress granules is one of the most promising strategies that cells employ to protect themselves from stress. In vitro, studies suggest that the nucleic acid-binding domain of TDP-43 (TDP-43^tRRM) undergoes amyloid-like aggregation to β-sheet-rich structures in low pH stress. In contrast, we observed that the TDP-43^tRRM undergoes complex coacervation in the presence of ssDNA to a dense and light phase, preventing its amyloid-like aggregation. The soluble light phase consists of monomeric native-like TDP-43^tRRM. The microscopic data suggest that the dense phase consists of spherical coacervates with limited internal dynamics. We performed multiparametric analysis by employing various biophysical techniques and found that complex coacervation depends on the concentration and ratio of the participating biomolecules and is driven by multivalent interactions. The modulation of these forces due to environmental conditions or disease mutations regulates the extent of coacervation, and the weakening of interactions between TDP-43^tRRM and ssDNA leads to amyloid-like aggregation of TDP-43^tRRM. Our results highlight a competition among the native state, amyloid-like aggregates, and complex coacervates tuned by various environmental factors. Together, our results illuminate an alternate function of TDP-43^tRRM in response to pH stress in the presence of the ssDNA.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542767","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":"Transcranial Alternating Current Stimulation: A Novel Neuromodulatory Treatment for Anxiety and Related Disorders","authors":"Yahui Chen,&nbsp;Bicheng Gao and Yuqi You*,&nbsp;","doi":"10.1021/acschemneuro.4c0064210.1021/acschemneuro.4c00642","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00642https://doi.org/10.1021/acschemneuro.4c00642","url":null,"abstract":"<p >Given the high prevalence and socioeconomic burden of anxiety disorders, there is an urgent need for effective, fast-acting, cost-efficient treatment alternatives to traditional psychotherapy. Transcranial alternating current stimulation (tACS), a noninvasive brain stimulation technique that modulates endogenous brain oscillations via the application of sinusoidal currents to the scalp, emerges as a promising neuromodulatory treatment. We reviewed oscillatory neuropsychopathology in anxiety, examined current evidence of tACS interventions for anxiety and related disorders, and proposed novel simulation targets and protocols. We emphasize the need for rigorously designed clinical trials to systematically investigate the neuropsychological effects of different tACS protocols on diverse populations with pathological anxiety.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585983","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":"Ultrasound Neuromodulation for Sleep and Neurological Disorder Therapy: A Path to Clinical Translation","authors":"Hanming Zheng,&nbsp;Jiaru He,&nbsp;Greta S. P. Mok* and Zhihai Qiu*,&nbsp;","doi":"10.1021/acschemneuro.4c0068710.1021/acschemneuro.4c00687","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00687https://doi.org/10.1021/acschemneuro.4c00687","url":null,"abstract":"<p >Ultrasound neuromodulation is a promising noninvasive technique capable of penetrating the skull and precisely targeting deep brain regions with millimeter accuracy. Recent studies have demonstrated that transcranial ultrasound stimulation (TUS) of sleep-related brain areas can induce sleep in mice and even trigger a reversible, hibernation-like state without causing damage. Beyond its utility in preclinical models of central nervous system diseases, such as epilepsy, tremors, Alzheimer’s disease, and depression, TUS holds significant potential for clinical translation. Given that many neurological disorders, including Alzheimer’s and Parkinson’s disease, are associated with sleep abnormalities, leveraging clinical TUS applications for these diseases also creates a pathway for translating this technology to sleep modulation in human use. These findings highlight the potential for ultrasound neuromodulation to advance neuroscience research and clinical applications in sleep control.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585780","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":"Element Changes Occurring in Brain Point at the White Matter Abnormalities in Rats Exposed to the Ketogenic Diet During Prenatal Life","authors":"Marzena Rugieł,&nbsp;Zuzanna Setkowicz,&nbsp;Mateusz Czyzycki,&nbsp;Rolf Simon,&nbsp;Tilo Baumbach and Joanna Chwiej*,&nbsp;","doi":"10.1021/acschemneuro.4c0028310.1021/acschemneuro.4c00283","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00283https://doi.org/10.1021/acschemneuro.4c00283","url":null,"abstract":"<p >A large number of clinical studies demonstrate that the ketogenic diet (KD) may be an effective approach to the reduction of epileptic seizures in children and adults. Such dietary therapy could also help pregnant women with epilepsy, especially since most antiseizure drugs have teratogenic action. However, there is a lack of medical data, considering the safety of using KD during gestation for the progeny. Therefore, we examined the influence of KD used prenatally in rats on the elemental composition of the selected brain regions in their offspring. For this purpose, synchrotron radiation-induced X-ray fluorescence (SR-XRF) microscopy was utilized, and elements such as P, S, K, Ca, Fe, and Zn were determined. Moreover, to verify whether the possible effects of KD are temporary or long-term, different stages of animal postnatal development were taken into account in our experiment. The obtained results confirmed the great applicability of SR-XRF microscopy to track the element changes occurring in the brain during postnatal development as well as those induced by prenatal exposure to the high-fat diet. The topographic analysis of the brains taken from offspring of mothers fed with KD during pregnancy and appropriate control individuals showed a potential influence of such dietary treatment on the brain levels of elements such as P and S. In the oldest progeny, a significant reduction of the surface of brain areas characterized by an increased P and S content, which histologically/morphologically correspond to white matter structures, was noticed. In turn, quantitative elemental analysis showed significantly decreased levels of Fe in the striatum and white matter of 30-day-old rats exposed prenatally to KD. This effect was temporary and was not noticed in adult animals. The observed abnormalities may be related to the changes in the accumulation of sphingomyelin and sulfatides and may testify about disturbances in the structure and integrity of the myelin, present in the white matter.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00283","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585665","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":"Hypoxanthine Produces Rapid Antidepressant Effects by Suppressing Inflammation in Serum and Hippocampus","authors":"Lei Wu,&nbsp;Jianhuai Chen,&nbsp;Qiao Yu,&nbsp;Chao Lu* and Yachun Shu*,&nbsp;","doi":"10.1021/acschemneuro.4c0034510.1021/acschemneuro.4c00345","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00345https://doi.org/10.1021/acschemneuro.4c00345","url":null,"abstract":"<p >The occurrence and development of depression are closely related to disorders of the brain and peripheral substances. Abnormal metabolites in the blood affect the signal regulation function of the nerve center, which is one of the key factors for depression episodes. This study was focused on metabolites in serum and the mechanism of its antidepressant in the hippocampus. In the present study, serum metabolites in patients with depression were screened by metabolomic techniques. Various depressive mouse models and behavioral tests were used to assess its antidepressant effects. The expressions of inflammatory signaling were detected by using Western blot, ELISA, and immunofluorescence. We found that the metabolite hypoxanthine in the serum of patients with depression was significantly reduced, and the same result was also found in two mouse models of depression such as chronic unpredictable mild stress (CUMS) and social defeat stress (SD). By administering different doses of hypoxanthine (5, 10, 15 mg/kg), we found that only 15 mg/kg was able to significantly reduce the latency and increase food consumption in the novelty suppressed-feeding test (NSF), which was also able to reverse the depressive phenotypes of mice in the CUMS model after a single administration at 2 h later. Hypoxanthine obviously reduced the expressions of inflammation in serum and downregulated the expressions of MAPK and NLRP3-related pathways in the hippocampus in CUMS mice. Moreover, hypoxanthine also suppressed the activations of glial cells including GFAP and IBA-1 in hippocampal CA1, CA3, and dentate gyrus (DG). To sum up, hypoxanthine exerted antidepressant effect relying on the inhibition of peripheral and hippocampal inflammations by regulating MAPK, NLRP3-related pathways, and glial cells. This was the first time that we have found a disordered metabolite in patients with depression and further systematically demonstrated its efficacy and potential mechanism of antidepressants, providing new ideas for antidepressant drug development.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585531","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}