ACS Chemical Neuroscience最新文献_第4页

HINT1 Inhibitors as Selective Modulators of MOR-NMDAR Cross-Regulation and Non-Opioid Analgesia.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-02-19 Epub Date: 2025-02-06 DOI: 10.1021/acschemneuro.4c00564

Maxwell Dillenburg, Cristina D Peterson, Rafal Dolot, Kostana Ligori, Kelley F Kitto, George L Wilcox, Carolyn A Fairbanks, Carston R Wagner

{"title":"HINT1 Inhibitors as Selective Modulators of MOR-NMDAR Cross-Regulation and Non-Opioid Analgesia.","authors":"Maxwell Dillenburg, Cristina D Peterson, Rafal Dolot, Kostana Ligori, Kelley F Kitto, George L Wilcox, Carolyn A Fairbanks, Carston R Wagner","doi":"10.1021/acschemneuro.4c00564","DOIUrl":"10.1021/acschemneuro.4c00564","url":null,"abstract":"Human histidine triad nucleotide-binding protein 1 (HINT1) has recently become a protein of interest due to its involvement in several CNS processes, including neuroplasticity and the development of several neuropsychiatric disorders. Crucially, HINT1 behaves as a mediator for cross-regulation of the mu-opioid receptor (MOR) and N-methyl-d-aspartate receptor (NMDAR). Active site inhibition of HINT1 using small-molecule inhibitors has been demonstrated to have a significant impact on this cross-regulatory relationship in vivo. Herein, we describe the development of a series of ethenoadenosine HINT1 inhibitors to further evaluate the effect of HINT1 inhibition on morphine's blockade of NMDA-evoked behaviors, the development of acute endomorphin-2 tolerance, and analgesia. X-ray crystallographic analysis and HINT1 binding experiments demonstrate that modifications to the inhibitor nucleobase greatly impact the inhibitor binding interactions with HINT1. Our results reveal a complex structure-activity relationship for HINT1 inhibitors, in which minor modifications to the ethenoadenosine scaffold resulted in dramatic changes to their activity in these assays modeling MOR-NMDAR interaction. Specifically, we observed the ability of HINT1 inhibitors to selectively affect individual pathways of MOR-NMDAR crosstalk. Furthermore, we observed that a carbamate ethenoadenosine inhibitor of HINT1 can induce analgesia while not affecting opioid tolerance. Additionally, although past studies have indicated that the loss of HINT1 expression can result in the downregulation of p53, we have shown that the inhibition of HINT1 has no effect on either the expression of HINT1 or p53. These studies highlight the critical role of HINT1 in MOR-NMDAR crosstalk and demonstrate the intriguing potential of using HINT1 active-site inhibitors as tools to probe its role in these biochemical pathways and its potential as a novel pain target.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"604-618"},"PeriodicalIF":4.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254076","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}

引用次数: 0

Therapeutic Potential of Arimoclomol Nanomicelles: In Vitro Impact on Alzheimer's and Parkinson's Pathology and Correlation with In Vivo Inflammatory Response.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-02-19 Epub Date: 2025-02-05 DOI: 10.1021/acschemneuro.4c00734

Isabelle Xavier-de-Britto, Natália Cristina Gomes-da-Silva, Marilia Amável Gomes Soares, Cristian Follmer, David Dabkiewicz, Luciana Magalhães Rebelo Alencar, Celso Sant'Anna, Tatiana Paula Teixeira Ferreira, Patrícia Machado Rodrigues E Silva Martins, Eduardo Ricci-Junior, Pierre Basílio Almeida Fechine, Ralph Santos-Oliveira

{"title":"Therapeutic Potential of Arimoclomol Nanomicelles: In Vitro Impact on Alzheimer's and Parkinson's Pathology and Correlation with In Vivo Inflammatory Response.","authors":"Isabelle Xavier-de-Britto, Natália Cristina Gomes-da-Silva, Marilia Amável Gomes Soares, Cristian Follmer, David Dabkiewicz, Luciana Magalhães Rebelo Alencar, Celso Sant'Anna, Tatiana Paula Teixeira Ferreira, Patrícia Machado Rodrigues E Silva Martins, Eduardo Ricci-Junior, Pierre Basílio Almeida Fechine, Ralph Santos-Oliveira","doi":"10.1021/acschemneuro.4c00734","DOIUrl":"10.1021/acschemneuro.4c00734","url":null,"abstract":"This study investigates the potential of arimoclomol-loaded nanomicelles for the treatment of neurodegenerative diseases like Alzheimer's and Parkinson's, as well as their anti-inflammatory properties. Arimoclomol, a coinducer of heat shock proteins (HSPs), has shown clinical promise in mitigating protein misfolding, a hallmark of these diseases. In this work, arimoclomol nanomicelles significantly reduced the aggregation of β-amyloid (Aβ1-42) and α-synuclein (α-syn), key pathological proteins in Alzheimer's and Parkinson's. Additionally, the nanomicelles demonstrated potent anti-inflammatory effects, reducing leukocyte and neutrophil counts in an acute inflammation model. These results suggest that arimoclomol nanomicelles could enhance clinical outcomes by targeting both neurodegenerative and inflammatory processes, offering a promising therapeutic strategy for long-term disease management.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"699-710"},"PeriodicalIF":4.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843614/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187540","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}

引用次数: 0

Microglial Autophagic Dysregulation in Traumatic Brain Injury: Molecular Insights and Therapeutic Avenues.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-02-19 Epub Date: 2025-02-07 DOI: 10.1021/acschemneuro.4c00617

Nargis Bano, Sameera Khan, Shakir Ahamad, Nawab John Dar, Hamad H Alanazi, Aamir Nazir, Shahnawaz Ali Bhat

{"title":"Microglial Autophagic Dysregulation in Traumatic Brain Injury: Molecular Insights and Therapeutic Avenues.","authors":"Nargis Bano, Sameera Khan, Shakir Ahamad, Nawab John Dar, Hamad H Alanazi, Aamir Nazir, Shahnawaz Ali Bhat","doi":"10.1021/acschemneuro.4c00617","DOIUrl":"10.1021/acschemneuro.4c00617","url":null,"abstract":"Traumatic brain injury (TBI) is a complex and multifaceted condition that can result in cognitive and behavioral impairments. One aspect of TBI that has received increasing attention in recent years is the role of microglia, the brain-resident immune cells, in the pathophysiology of the injury. Specifically, increasing evidence suggests that dysfunction in microglial autophagy, the process by which cells degrade and recycle their own damaged components, may contribute to the development and progression of TBI-related impairments. Here, we unravel the pathways by which microglia autophagic dysregulation predisposes the brain to secondary damage and neurological deficits following TBI. An overview of the role of autophagic dysregulation in perpetuation and worsening of the inflammatory response, neuroinflammation, and neuronal cell death in TBI follows. Further, we have evaluated several signaling pathways and processes that contribute to autophagy dysfunction-mediated inflammation, neurodegeneration, and poor outcome in TBI. Additionally, a discussion on the small molecule therapeutics employed to modulate these pathways and mechanisms to treat TBI have been presented. However, additional research is required to fully understand the processes behind these underlying pathways and uncover potential therapeutic targets for restoring microglial autophagic failure in TBI.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"543-562"},"PeriodicalIF":4.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373428","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}

引用次数: 0

Dual GLP-1 and GIP Agonist Tirzepatide Exerted Neuroprotective Action in a Parkinson's Disease Rat Model.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-02-18 DOI: 10.1021/acschemneuro.4c00729

Prashant Delvadia, Vipin Dhote, Avinash Singh Mandloi, Ritu Soni, Jigna Shah

{"title":"Dual GLP-1 and GIP Agonist Tirzepatide Exerted Neuroprotective Action in a Parkinson's Disease Rat Model.","authors":"Prashant Delvadia, Vipin Dhote, Avinash Singh Mandloi, Ritu Soni, Jigna Shah","doi":"10.1021/acschemneuro.4c00729","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00729","url":null,"abstract":"Parkinson's disease (PD) is an age-related progressive disorder that leads to dopaminergic loss and subsequent motor dysfunction. Current therapies mainly deal with symptomatic effects, and hence, therapies targeting progressive neurodegeneration need to developed. In this study, tirzepatide, a coagonist of glucagon like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, exhibited a neuroprotective effect in preliminary studies. This study aims to evaluate the effect of tirzepatide, in comparison with exendin-4, in a rat model of PD. The effect of tirzepatide (50 and 100 nmol/kg, s.c.) and exendin-4 (8 μg/kg, s.c.) on behavioral functions, oxidative markers, inflammatory markers, dopamine level, and alpha-synuclein expression were studied against a rotenone (2 mg/kg)-induced toxicity model in rats. Tirzepatide prevented rotenone-induced motor deficits. Additionally, it significantly inhibited the rotenone-induced increase in proinflammatory cytokines TNF-α and IL-6. Furthermore, it upregulated striatal dopamine levels. It alleviated oxidative stress and alpha-synuclein aggregation. Both doses of tirzepatide exert neuroprotective effects in a PD rat model. Furthermore, the effect is dose-dependent, and a 100 nmol/kg dose of tirzepatide was found to be more effective.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439312","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}

引用次数: 0

Anterior Cingulate Cortex-Anterior Insular Cortex Circuit Mediates Hyperalgesia in Adolescent Mice Experiencing Early Life Stress.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-02-17 DOI: 10.1021/acschemneuro.4c00884

Meng Li, Kefang Liu, Mingyu Xu, Zhaoyi Chen, Lu Yu, Jingquan Zhang, Chunyan Wang, Cheng Long, Jinxiang Jiang

{"title":"Anterior Cingulate Cortex-Anterior Insular Cortex Circuit Mediates Hyperalgesia in Adolescent Mice Experiencing Early Life Stress.","authors":"Meng Li, Kefang Liu, Mingyu Xu, Zhaoyi Chen, Lu Yu, Jingquan Zhang, Chunyan Wang, Cheng Long, Jinxiang Jiang","doi":"10.1021/acschemneuro.4c00884","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00884","url":null,"abstract":"Understanding neurobiological mechanisms underlying changes in behavior and neural activity caused by early life stress (ELS) is essential for improving these adverse outcomes in individuals. ELS incited by exposure to maternal separation (MS) can be defined as a form of social pain, but little is known about the neural mechanism in adolescents with ELS-induced pain sensitization. Employing an MS-induced ELS paradigm in mice, we reported here that both male and female MS mice aged 1-2 months exhibited mechanical and thermal hyperalgesia using paw-withdrawal and hot/cold plate tests. The increased high gamma (γhigh) oscillations accompanied by the activation of parvalbumin-positive interneurons (PVINs) in the anterior insular cortex (AIC), but not the anterior cingulate cortex (ACC), were shown in MS mice. Moreover, ACC-driven AIC connectivity was enhanced in MS mice, characterized by amplified phase coherence in the delta (δ) and theta (θ) bands and an escalation in the coupling of the ACC θ phase and AIC γ amplitude. Chemogenetic inactivation of AIC PVINs relieved hyperalgesia and altered the ACC-AIC connectivity in MS mice. The observed increase in δ-θ synchronization and PVIN activation in the ACC-AIC circuit indicates this pathway is a therapeutic target for ELS-induced hyperalgesia.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143431902","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}

引用次数: 0

Do Neurochemicals Reflect Psychophysiological Dimensions in Behaviors? A Transdisciplinary Perspective Based on Analogy with Maslow's Needs Pyramid.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-02-17 DOI: 10.1021/acschemneuro.4c00566

Sandrine Parrot

{"title":"Do Neurochemicals Reflect Psychophysiological Dimensions in Behaviors? A Transdisciplinary Perspective Based on Analogy with Maslow's Needs Pyramid.","authors":"Sandrine Parrot","doi":"10.1021/acschemneuro.4c00566","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00566","url":null,"abstract":"All behaviors, including motivated behaviors, result from integration of information in the brain via nerve impulses, with two main means of communication: electrical gap-junctions and chemical signaling. The latter enables information transfer between brain cells through release of biochemical messengers, such as neurotransmitters. Neurochemical studies generate plentiful biochemical data, with many variables per individual, since there are many methods to quantify neurotransmitters, precursors and metabolites. The number of variables can be far higher using other concomitant techniques to monitor behavioral parameters on the same subject of study. Surprisingly, while many quantitative variables are obtained, data analysis and discussion focus on just a few or only on the neurotransmitter known to be involved in the behavior, and the other biochemical data are, at best, regarded as less important for scientific interpretation. The present article aims to provide novel transdisciplinary arguments that all neurochemical data can be regarded as items of psychophysiological dimensions, just as questionnaire items identify modified behaviors or disorders using latent classes. A first proof of concept on nonmotivated and motivated behaviors using a multivariate data-mining approach is presented.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439305","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}

引用次数: 0

UPF 648, a Selective KMO Inhibitor, Attenuates Psychomotor and Cognitive Impairment in Chronic Kidney Disease.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-02-17 DOI: 10.1021/acschemneuro.4c00844

Aparajita Ghosh, Neeraja Rayanki, Abhijeet R Joshi, Onkar P Kulkarni

{"title":"UPF 648, a Selective KMO Inhibitor, Attenuates Psychomotor and Cognitive Impairment in Chronic Kidney Disease.","authors":"Aparajita Ghosh, Neeraja Rayanki, Abhijeet R Joshi, Onkar P Kulkarni","doi":"10.1021/acschemneuro.4c00844","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00844","url":null,"abstract":"Kynurenine-3-monooxygenase (KMO), a key enzyme in the kynurenine pathway (KP) of tryptophan metabolism, converts kynurenine into the neurotoxic intermediate quinolinic acid (QA). QA, an N-methyl-d-aspartate (NMDA) receptor agonist, increases glutamate release and inhibits its reuptake, resulting in excitotoxic cell death in the hippocampus and striatum. Plasma metabolomics study exhibited KP metabolites as the most altered pathway in patients with chronic kidney disease (CKD). Recently, QA was linked to the kidney-brain axis as one of the major neurotoxins responsible for cognitive impairment in advanced CKD stages. Various preclinical models are being tested to explore different intermediates of KP that can be targeted to ameliorate the central nervous system (CNS) complications of CKD. In this study, an adenine-induced CKD model was developed in C57BL/6 mice, where UPF 648, a selective KMO inhibitor, was administered to observe the changes in KP metabolites in the hippocampus. Treatment with UPF 648 did not alter kidney function or morphology in CKD. KMO inhibition led to decreased plasma QA levels and reduced levels of pro-inflammatory cytokine interleukin-1-β (IL-1β). UPF 648 treatment in CKD ameliorated the characteristic symptoms of motor dysfunction, anxiety, depression, and hippocampus-dependent memory. Important markers for neuronal survival and plasticity through the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TRKB)-cAMP-responsive element binding protein 1 (CREB1) pathway were upregulated in the hippocampus after KMO inhibition. In conclusion, KMO inhibition can be an exciting target to attenuate the neuropsychiatric burden of advanced stages in CKD.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439315","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}

引用次数: 0

Corilagin Attenuates Neuronal Apoptosis and Ferroptosis of Parkinson's Disease through Regulating the TLR4/Src/NOX2 Signaling Pathway. 柯里拉京通过调节TLR4/Src/NOX2信号通路减轻帕金森病的神经元凋亡和铁凋亡

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-02-14 DOI: 10.1021/acschemneuro.5c00035

Yu Lei, Jiabin Zhou, Dongyuan Xu, Songshan Chai, Nanxiang Xiong

{"title":"Corilagin Attenuates Neuronal Apoptosis and Ferroptosis of Parkinson's Disease through Regulating the TLR4/Src/NOX2 Signaling Pathway.","authors":"Yu Lei, Jiabin Zhou, Dongyuan Xu, Songshan Chai, Nanxiang Xiong","doi":"10.1021/acschemneuro.5c00035","DOIUrl":"10.1021/acschemneuro.5c00035","url":null,"abstract":"Corilagin has shown neuroprotective potential in various neurological disorders, but its effects in Parkinson's disease (PD) have not been fully explored. In this study, we investigated the therapeutic impact and underlying mechanism of corilagin on PD using MPTP-induced mice and MPP+-treated N2a cells. Behavioral tests and immunohistochemical analysis demonstrated that corilagin significantly reduced MPTP-induced loss of TH-positive neurons in the substantia nigra. In vitro, corilagin improved cell viability, decreased MPP+-induced apoptosis, and mitigated the associated oxidative stress by lowering intracellular ROS levels and preserving mitochondrial membrane potential. Moreover, corilagin reversed MPP+-induced iron accumulation and lipid peroxidation in N2a cells. Mechanistically, Western blotting revealed that the protective effects of corilagin are linked to the TLR4/Src/NOX2 signaling pathway. The TLR4 agonist RS 09 impaired the neuroprotective effects of corilagin, further supporting its role in modulating ferroptosis via this pathway. These findings suggest that corilagin could be a promising therapeutic agent for PD by targeting the TLR4/Src/NOX2 signaling axis to inhibit ferroptosis.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412288","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}

引用次数: 0

Effects of Transmembrane Phenylalanine Residues on γ-Secretase-Mediated Notch-1 Proteolysis. 跨膜苯丙氨酸残基对γ-分泌酶介导的 Notch-1 蛋白质解构的影响

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-02-14 DOI: 10.1021/acschemneuro.4c00790

Shweta R Malvankar, Michael S Wolfe

{"title":"Effects of Transmembrane Phenylalanine Residues on γ-Secretase-Mediated Notch-1 Proteolysis.","authors":"Shweta R Malvankar, Michael S Wolfe","doi":"10.1021/acschemneuro.4c00790","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00790","url":null,"abstract":"γ-Secretase is a presenilin-containing intramembrane aspartyl protease complex that cleaves within the transmembrane domain (TMD) of nearly 150 substrates, with the amyloid precursor protein (APP) being the most well studied. APP cleavage by γ-secretase generates amyloid β-peptides (Aβ) that pathologically deposit in Alzheimer's disease. The APP TMD substrate undergoes initial endoproteolysis (ε-cleavage) followed by processive carboxypeptidase trimming of long Aβ intermediates in ∼tripeptide intervals. Although γ-secretase cleavage of Notch1 is essential in developmental biology and is altered in many cancers, the processing of this cell-surface receptor is relatively understudied. Only one sequence specificity rule is known for γ-secretase substrate processing: Aromatic residues such as phenylalanine are not tolerated in the P2' position with respect to any processing event on the APP TMD. Here we show using biochemical and mass spectrometry (MS) techniques that this specificity rule holds for Notch1 as well. Analysis of products from the reactions of a purified enzyme complex and Notch1 TMD substrate variants revealed that P2' Phe relative to ε-site cleavage reduced proteolysis and shifted initial cleavage N-terminally by one residue. Double Phe mutation near the ε site resulted in reduced proteolysis with shifting to two major initial cleavage sites, one N-terminally and one C-terminally, both of which avoid Phe in the P2' position. Additionally, three natural Phe residues were mutated to the corresponding residues in the APP TMD, which led to increased ε proteolysis. Thus, Phe residues can affect the enzyme reaction rate as well as cleavage site specificity in the Notch1 TMD.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412289","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}

引用次数: 0

Neuroprotective Effect of Withaferin Derivatives toward MPP⁺ and 6-OHDA Toxicity to Dopaminergic Neurons.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-02-13 DOI: 10.1021/acschemneuro.4c00655

Valeria Parrales, Guillaume Arcile, Louise Laserre, Sébastien Normant, Géraldine Le Goff, Christian Da Costa Noble, Jamal Ouazzani, Noelle Callizot, Stéphane Haïk, Chérif Rabhi, Nicolas Bizat

{"title":"Neuroprotective Effect of Withaferin Derivatives toward MPP+ and 6-OHDA Toxicity to Dopaminergic Neurons.","authors":"Valeria Parrales, Guillaume Arcile, Louise Laserre, Sébastien Normant, Géraldine Le Goff, Christian Da Costa Noble, Jamal Ouazzani, Noelle Callizot, Stéphane Haïk, Chérif Rabhi, Nicolas Bizat","doi":"10.1021/acschemneuro.4c00655","DOIUrl":"10.1021/acschemneuro.4c00655","url":null,"abstract":"Parkinson's disease is a neurodegenerative proteinopathy that primarily affects mesencephalic dopaminergic neurons. This dopaminergic depletion can be phenotypically reproduced in various experimental models through the administration of two neurotoxins: N-methyl-4-phenylpyridinium (MPP+) and 6-hydroxydopamine (6-OHDA). The mechanisms underlying the cell death processes induced by these toxins remain a subject of debate. In this context, studies suggest that oxidative-stress-related processes may contribute to the dysfunction and death of dopaminergic neurons. Therefore, investigating pharmacological compounds that can counteract these processes remains crucial for developing therapeutic strategies targeting these neuropathological mechanisms. Withania somnifera (L.) Dunal, commonly known as ashwagandha, is a plant whose roots are used in Ayurvedic medicine to treat various ailments, including those affecting the central nervous system. The active compound Withaferin-A (WFA), a steroid lactone from the withanolide group, is reported to possess antioxidant properties. In this study, we explored the potential neuroprotective effects of WFA and two of its molecular derivatives, cr-591 and cr-777, which contain, respectively, an additional cysteine or glutathione chemical group, known for their antiradical properties. We demonstrated that WFA and its two derivatives, cr-591 and cr-777, protect the integrity and function of dopaminergic neurons exposed to the neurotoxins MPP+ and 6-OHDA both in vitro, using primary mesencephalic neuron cultures from rodents, and in vivo, using the nematode Caenorhabditis elegans.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412302","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}

引用次数: 0