ACS Chemical Neuroscience最新文献

{"title":"Targeting 5-HT7 Receptor with Biased Ligands to Alleviate Pain and Spinal Neuroinflammation","authors":"Fahima Madouri,&nbsp;Cyril Guimpied,&nbsp;Enora Pigeon,&nbsp;Nadège Hervouet,&nbsp;David Gosset,&nbsp;Pascal Auzou,&nbsp;Mélanie Kremer,&nbsp;Quentin Leboulleux,&nbsp;Marie-Aude Hiebel,&nbsp;Julie Le Bescont,&nbsp;Gérald Guillaumet,&nbsp;Franck Suzenet,&nbsp;Patrick Baril,&nbsp;Raphaël Serreau and Séverine Morisset-Lopez*,&nbsp;","doi":"10.1021/acschemneuro.5c00982","DOIUrl":"10.1021/acschemneuro.5c00982","url":null,"abstract":"<p >The serotonin 5-HT₇ receptor (5-HT₇R), a member of the rhodopsin-like family of G protein-coupled receptors (GPCRs), is highly expressed in the central nervous system (CNS) and represents a promising target for treating CNS disorders such as sleep disturbances, migraine, neuropsychiatric conditions, and neuropathic pain. Because of its therapeutic potential, extensive efforts have focused on developing selective 5-HT₇R ligands. In the last decades, biased signaling has emerged as a key concept in GPCR pharmacology as biased ligands can stabilize specific active states of the receptor and trigger selective activation of downstream signaling pathways. In this context, we recently identified two biased 5-HT₇R ligands, Serodolin and MOA51, from different chemical series. Here, we aimed to compare the pharmacological and safety profiles of these ligands and assess their effect on pain-related behaviors and spinal neuroinflammation. In inflammatory pain models (acid acetic writhing, formalin, and CFA tests), both Serodolin and MOA51 effectively attenuated pain responses to a similar extent. Furthermore, in neuropathic pain models, spinal nerve injury (SNI) and the Cuff model, both ligands reversed mechanical allodynia. Interestingly, unlike pregabalin, a clinically used reference drug, neither Serodolin nor MOA51, induced apparent development of tolerance after 10 consecutive days of administration. Treatment with these 5-HT₇R ligands also reduced spinal microglial activity and attenuated neuronal hyperactivity in the spinal cord. Altogether, these findings highlight the potential of 5-HT₇R-biased ligands as promising analgesic candidates capable of modulating neuroinflammatory processes and mitigating both inflammatory and neuropathic pain.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 12","pages":"2331–2347"},"PeriodicalIF":4.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148051075","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":"Acid-Sensing Ion Channels: Gatekeepers of Chronic Pain","authors":"Adinath Markad,&nbsp;Taiba Nafis,&nbsp;Ashutosh Kumar Dubey and Vinod Tiwari*,&nbsp;","doi":"10.1021/acschemneuro.6c00054","DOIUrl":"10.1021/acschemneuro.6c00054","url":null,"abstract":"<p >Chronic pain typically develops in situations such as tissue injury, inflammation, and ischemia, where extracellular acidity increases in the altered microenvironment. Acid-sensing ion channels (ASICs) are proton-gated membrane proteins that enable sensory neurons to detect these pH changes and convert them into electrical signals. Emerging evidence suggests that specific ASIC subtypes, particularly ASIC1a and ASIC3, contribute to nociceptive signaling, peripheral sensitization, and neuroinflammatory responses. Recent structural studies have bettered our understanding of ASIC architecture and gating mechanisms, while functional studies have revealed their interactions with multiple intracellular signaling pathways involved in pain modulation. This review summarizes current understanding of ASIC structure, activation mechanisms, and their role in inflammation-associated pain pathways. We also discuss emerging pharmacological strategies aimed at altering ASIC activity. A clearer understanding of ASIC-mediated signaling may help identify new therapeutic approaches for the management of chronic pain and related neurological disorders.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 12","pages":"2262–2277"},"PeriodicalIF":4.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148154581","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":"Targeted Mutations Activate Allosteric Modulation of α5-Containing Nicotinic Acetylcholine Receptors","authors":"Christopher B. Marotta*,&nbsp;Henry A. Lester and Dennis A. Dougherty,&nbsp;","doi":"10.1021/acschemneuro.6c00267","DOIUrl":"10.1021/acschemneuro.6c00267","url":null,"abstract":"<p >Nicotinic acetylcholine receptors play vital roles in neuronal communication. The α5 subunit is unique, in that it assembles only into the auxiliary position (the “5th” subunit of the pentamer) of a functional receptor, yet it can have a substantial effect on a receptor’s physiological response. In addition, it is expressed in reward and aversive pathways, highlighting its importance in nicotine dependence. The novel α5−α4 interface seems well positioned for selective small molecule binding, yet no agonist activation has been observed. Here, we mutate the α5 subunit to mimic the α4 residues at the agonist binding site. Although no direct activation is observed from several agonists (acetylcholine, nicotine, and cytisine), we were able to modulate the receptor signal response through the introduction of NS9283, a positive allosteric modulator.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 12","pages":"2324–2330"},"PeriodicalIF":4.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.6c00267","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148160947","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":"Caffeic Acid Ameliorates l-Methionine-Induced Hyperhomocysteinemia, Leading to Decreased Adult Neurogenesis and Oxidative Stress Status in Adult Rats","authors":"Oabnithi Dornlakorn,&nbsp;Apiwat Sirichoat,&nbsp;Wanassanan Pannangrong,&nbsp;Nataya Sritawan,&nbsp;Anusara Aranarochana,&nbsp;Ram Prajit,&nbsp;Peter Wigmore and Jariya Umka Welbat*,&nbsp;","doi":"10.1021/acschemneuro.6c00206","DOIUrl":"10.1021/acschemneuro.6c00206","url":null,"abstract":"<p >Chronic <span>l</span>-methionine (<span>l</span>-met) treatment induces hyperhomocysteinemia, which impairs neurogenesis and memory by increasing oxidative stress. Caffeic acid (CA) possesses antioxidant properties that reduce brain oxidative damage and promote neurogenesis. This study investigated the neuroprotective effects of caffeic acid against the impact of <span>l</span>-met on hippocampal neurogenesis. Forty male Sprague–Dawley rats were randomly assigned to four groups (<i>n</i> = 10 per group): Control, <span>l</span>-met, CA, and CA+<span>l</span>-met. Rats received daily oral gavage of <span>l</span>-met (1.7 g/kg) and/or CA (40 mg/kg) for 28 days. The results demonstrated that CA ameliorated <span>l</span>-met-induced decreases in DCX and Sox-2-positive cells in the SGZ of the dentate gyrus, as shown by immunofluorescence staining. CA also reversed the <span>l</span>-met-induced decreases in hippocampal protein expression of Nrf2, Sox-2, and BDNF, as determined by Western blotting. Furthermore, CA alleviated <span>l</span>-met-induced oxidative damage and decreased antioxidant enzyme activity in the prefrontal cortex (PF) and hippocampus. These findings demonstrate CA’s ability to counteract neurotoxicity induced by <span>l</span>-methionine.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 12","pages":"2379–2388"},"PeriodicalIF":4.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.6c00206","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148100670","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":"Structural Basis of Frizzled-Wnt in Recognition of Aβ Unveils Mechanism of Aβ-Mediated Disruption","authors":"Jinfei Mei*,&nbsp;Ruhua Zha,&nbsp;Yuqin Qiu,&nbsp;Zhaoxian Du,&nbsp;Sitian Liang,&nbsp;Liangquan Sheng and Yumei Hou*,&nbsp;","doi":"10.1021/acschemneuro.5c01028","DOIUrl":"10.1021/acschemneuro.5c01028","url":null,"abstract":"<p >Although previous studies have confirmed that Aβ oligomers (AβO) can bind to Frizzled and inhibit Wnt signaling, the molecule details and the impact of AβO structural heterogeneity remain unclear. This study utilized molecular dynamics simulation, combined with free energy, RMSF and other calculations, to systematically explore the interaction molecule details of different histidine conformational forms (ε→δ) of AβO with the Fz-Wnt complex. The results indicated that AβO could induce significant conformational perturbations in both the dissociative Fz-CRD domain and the full Fz-Wnt complex. Notably, Aβ42 exhibited a stronger perturbing effect than Aβ40. Free energy calculations further revealed that the binding affinity of Aβ42 was significantly higher than that of Aβ40, with the FW-(εδδ)42 complex showing the strongest binding (Δ<i>G</i>* = −13.33 kcal/mol). At the residue level, hydrophobic residues (F4, L17, F19, M35, V40) serve as the core region driving AβO binding, whereas charged residues (D1, E3, R5, K16) modulate the interaction in different histidine tautomeric forms. Importantly, through analysis of how the “clasp” structure of Fz-Wnt was affected by AβO, the “unlocking” mechanism of AβO was revealed: The binding of AβO can cause a two-way size change of the clasp interface ranging from −0.35 nm (contraction) to +0.43 nm (expansion). In summary, this study for the first time reveals that histidine tautomerism regulates the binding affinity of Aβ-Fz and clarifies an allosteric “clamping-unlock” mechanism that goes beyond simple competitive inhibition, providing novel insights at the molecule level into AβO interfering with Wnt signal transduction.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 11","pages":"2086–2095"},"PeriodicalIF":3.9,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148012495","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":"Advances in Real-Time Electrochemical Monitoring of Neurotransmitter Dynamics in Drosophila","authors":"Linfeng Meng,&nbsp;Wendong Liu,&nbsp;Yadong Niu,&nbsp;Xinchen Lv,&nbsp;Tongbo Jin,&nbsp;Guanran Wang,&nbsp;Zhongqin Sun,&nbsp;Yong-Ming Wang,&nbsp;Ya Yang* and Ying Wang*,&nbsp;","doi":"10.1021/acschemneuro.5c00960","DOIUrl":"10.1021/acschemneuro.5c00960","url":null,"abstract":"<p ><i>Drosophila melanogaster</i> is a genetically tractable model organism with a compact yet functionally rich nervous system, making it ideal for investigating neural mechanisms and modeling neurological diseases. However, its small brain size poses challenges for real-time measurement of neurotransmitter dynamics. Recent advances in electrochemical methodologies, particularly fast-scan cyclic voltammetry (FSCV) and amperometry with carbon fiber microelectrodes, enable high spatiotemporal resolution measurements <i>in vivo</i>. The integration of electrochemistry with optogenetic tools further enhances experimental precision, allowing causal interrogation of neurotransmission. This review summarizes recent advances in electrochemical methodologies for monitoring neurotransmitter dynamics in <i>Drosophila</i>. FSCV has facilitated real-time, chemically selective quantitative analysis of dopamine and serotonin in defined brain regions, providing new insights into their roles in behavior and neurodegeneration, as well as their modulation by antidepressants and ketamine. Amperometry provides complementary capabilities, allowing detection of exocytic release events and quantification of vesicular neurotransmitter content. Amperometric studies have shown that octopamine primarily undergoes partial release at the neuromuscular junction, whereas serotonin in the ventral nerve cord exhibits both partial release and, notably, full vesicular release events. Looking forward, convergence with advanced imaging technologies promises multidimensional views of neurotransmitter signaling and may uncover novel therapeutic targets for neurological diseases. This review highlights key methodological innovations and their applications in <i>Drosophila</i>, underscoring its unique value in bridging molecular neuroscience, behavior, and translational research.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 11","pages":"2037–2048"},"PeriodicalIF":3.9,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147924501","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":"Visualizing Biomolecules within Living Microglia in Complex Environments Using a Clickable Small Fluorogenic Compound","authors":"Wonju Kim,&nbsp;Yeongran Hwang,&nbsp;Xiao Liu,&nbsp;Minkyo Jung,&nbsp;Dongwan Ko,&nbsp;Srikanta Sahu,&nbsp;Moonseok Choi,&nbsp;Do-Geun Kim,&nbsp;Ji-Young Mun*,&nbsp;Young-Tae Chang* and Beomsue Kim*,&nbsp;","doi":"10.1021/acschemneuro.6c00070","DOIUrl":"10.1021/acschemneuro.6c00070","url":null,"abstract":"<p >Microglia, the brain’s resident macrophages, are key players in neurodegenerative disease progression. While understanding how microglial organelles and biomolecules dynamically respond to physiological and pathological cues is essential for developing therapeutic strategies, current tools lack the specificity required to visualize these processes in complex, physiologically relevant environments. Here, we present CDr20-CO1, a dual-functional fluorescent probe designed for live-cell imaging of microglial biomolecules. CDr20-CO1 combines selective enzymatic activation by the microglia-specific enzyme UGT1A7C with a bio-orthogonal clickable moiety for conjugation to azide-tagged biomolecules. Using this system, we successfully visualized microglial lysosomes, phospholipids, and newly synthesized proteins in live heterogeneous brain cell cultures. Notably, this probe revealed that microglia in mixed cultures exhibited attenuated lysosomal remodeling and phosphatidylcholine metabolism in response to inflammatory stimuli compared to isolated microglia, primarily through direct cell–cell contact with neighboring glial cells, with an additional contribution from their secreted factors, underscoring the influence of the cellular microenvironment. Furthermore, CDr20-CO1 enabled in vivo labeling of microglial targets in intact live mouse embryos, demonstrating its robust tissue permeability and physiological applicability. This versatile platform provides a powerful tool for tracking microglial organelles and biomolecules in real time, offering new insights into microglial functions in health and disease.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 11","pages":"2108–2121"},"PeriodicalIF":3.9,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147961312","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":"Design and Synthesis of Indole-Based Imidazo[1,2-a]pyridine Derivatives as Antiseizure Candidates: Evaluation in Chemically Induced Seizure Models and In Vitro Antioxidant Assays","authors":"Tarfah Al-Warhi,&nbsp;Mahmoud S. Elkotamy*,&nbsp;Mahmoud Abdelrahman Alkabbani,&nbsp;Zainab M. Elsayed,&nbsp;Mohamed D. Morsy,&nbsp;Mostafa M. Elbadawi and Wagdy M. Eldehna*,&nbsp;","doi":"10.1021/acschemneuro.5c01012","DOIUrl":"10.1021/acschemneuro.5c01012","url":null,"abstract":"<p >This study presents the design and synthesis of a targeted series of indole-based derivatives and their assessment as potential antiseizure candidates. The antiseizure activity of the synthesized compounds was evaluated using two chemically induced seizure models, pentylenetetrazole (PTZ) and pilocarpine, to assess their capacity to suppress acute seizure activity <i>in vivo</i>. Several compounds showed dose-specific protection against seizures in both models, supporting acute antiseizure activity under the tested screening conditions. The radical-scavenging properties of the active compounds were evaluated using the DPPH assay as a cell-free chemical measure of radical-quenching capacity. Three lead candidates (<b>9b</b>, <b>9e</b>, and <b>9h</b>) were prioritized because they combined favorable dose-specific antiseizure outcomes with DPPH radical-scavenging activity. However, the DPPH findings are interpreted here as evidence of chemical radical-scavenging properties rather than direct proof of a biological antioxidant mechanism underlying the observed antiseizure effects. The findings indicate that the synthesized indole derivatives are promising antiseizure candidates and warrant further preclinical and mechanistic studies, including direct biological evaluation of redox-related pathways in seizure control.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 11","pages":"2071–2085"},"PeriodicalIF":3.9,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147947129","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":"Discovery of Small-Molecule Inhibitors of the KCNQ1/Kv7.1 Potassium Channel with Virtual Screening and Functional Validation in Electrophysiological Assays and KCNQ1-Knockout Neural Stem Cells","authors":"Kazi Asraful Alam,&nbsp;Josep Martí-Solans,&nbsp;Dorothea Schall,&nbsp;Sumit Kumar,&nbsp;Shahid Muhammad Iqbal,&nbsp;Knut Teigen,&nbsp;Simone Berkel,&nbsp;Daniela Mauceri,&nbsp;Bengt Erik Haug,&nbsp;Sara I. Liin,&nbsp;Timothy Lynagh,&nbsp;Aurora Martinez* and Jan Haavik*,&nbsp;","doi":"10.1021/acschemneuro.6c00197","DOIUrl":"10.1021/acschemneuro.6c00197","url":null,"abstract":"<p >Voltage-gated potassium channel KCNQ1 (Kv7.1) plays a critical role in electrical excitability in the heart, gut, and brain. Together with the auxiliary subunit KCNE1, KCNQ1 generates a slow delayed rectifier current (<i>I</i>_<i>Ks</i>) that is essential for cardiac repolarization. Mutations and dysregulation of this channel are found in channelopathies leading to sudden death, long-QT syndrome, atrial fibrillation, epilepsy, deafness, diabetes, and neuropsychiatric disorders. Although KCNQ1 and related potassium channels are promising therapeutic targets, there are few potent, selective, and therapeutically safe inhibitors and activators available for these proteins. A virtual screening of 36,374 compounds was conducted against KCNQ1, followed by <i>in silico</i> analyses that identified eight potential ligand candidates for experimental evaluation using human KCNQ1 coexpressed with KCNE1 in <i>Xenopus laevis</i> oocytes. Electrophysiological recordings showed that the benzodiazepine-based ligand Zinc13732787 was a potent inhibitor of the channel complex, without affecting KCNQ2/KCNQ3. Based on virtual screening and molecular docking, the 1-(3-chlorophenyl)-urea substituent on the benzodiazepine core is important for selective inhibition of KCNQ1/KCNE1, as further supported by structure-activity relationship and stereochemical exploration of Zinc13732787. Furthermore, low concentrations of Zinc13732787 reduced neurite outgrowth in human neuronal stem cells (NSCs), mirroring the phenotype observed in homozygous <i>KCNQ1</i>-knockout cells. Importantly, Zinc13732787 did not affect NSC proliferation, nor did it induce cytotoxicity. In homozygous <i>KCNQ1</i>-knockout NSCs, compound Zinc13732787 had no effect on neurite outgrowth, indicating high target specificity. These findings suggest that this compound is a valuable tool for investigating the physiological and pathological roles of KCNQ1 across various tissues. Additionally, it could be used as a precursor for novel antiarrhythmic agents as well as for epilepsy and neuropsychiatric conditions.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 11","pages":"2203–2218"},"PeriodicalIF":3.9,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.6c00197","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147979539","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":"Molecular, Biochemical, and Epigenetic Mechanisms Involved in Environmental Neurotoxicants Exposure Induced Premature Brain Aging with Central Focus on Pesticides Role","authors":"Poulin M.,&nbsp; and ,&nbsp;RamaRao Golime*,&nbsp;","doi":"10.1021/acschemneuro.5c00771","DOIUrl":"10.1021/acschemneuro.5c00771","url":null,"abstract":"<p >Environmental neurotoxicants are widely used in various industries, including agriculture and public health sectors, and are known to cause harmful effects to humans through environmental and occupational exposures. Neurotoxicants are increasingly recognized as significant contributors to premature brain aging and neurodegenerative disorders. This review delineates the literature on neurotoxicant-induced comprehensive biochemical and molecular pathways leading to brain aging by consolidating the mechanistic insights with a main focus on pesticides. Exposome research combines environmental monitoring with integrative multiomics technologies such as exposomics, proteomics, and adductomics to map the real impact of neurotoxicants in neurodegenerative disorders. We discussed the intersecting molecular genetic pathways, including genomic instability, telomere attrition, epigenetic remodeling, including aberrant DNA methylation and microRNA deregulation, and biochemical pathways, including mitochondrial dysfunction, oxidative stress, impaired proteostasis, and autophagic disruption across the lifespan. These complex and often intergenerational mechanisms can be contextualized within the exposome framework to emphasize the cumulative environmental exposures that shape premature brain aging. Neurotoxicant exposure interferes with critical neuroprotective pathways, induces systemic metabolic dysregulation, neuroinflammation, and neurodegeneration, and disturbs the gut-brain axis, further amplifying neuronal vulnerability. A mechanistic understanding is important for toxicity screening and regulatory frameworks to mitigate the long-term consequences of neurotoxic insults. This review highlights the importance of eco-friendly alternatives such as integrated pest management strategies to reduce pesticide burdens on humans and environmental health for sustainable development.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 11","pages":"2015–2036"},"PeriodicalIF":3.9,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147979457","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}