ACS Chemical Neuroscience最新文献

Vascular cognitive impairment (VCI) significantly contributes to dementia; however, the precise metabolic mechanisms underlying its region-specific pathological progression remain poorly understood. We hypothesized that spatially resolved metabolomics could uncover detailed spatiotemporal metabolic disruptions and key therapeutic windows. Using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), we systematically mapped metabolite alterations in hippocampal subregions (CA1, CA3, dentate gyrus) and cortical areas of a rat model of chronic cerebral hypoperfusion (2-VO) at early (7 days), intermediate (28 days), and late (56 days) stages. MALDI-MSI enabled region-resolved visualization of lipid, energy, and inflammatory metabolic signatures at a spatial resolution of 20 μm, allowing comparative analysis of spatiotemporal metabolic trajectories across disease progression. Our analysis revealed distinct temporal patterns: early depletion of membrane lipids and cholinergic precursors primarily in CA1 and DG, midphase ceramide accumulation and glycolytic shift notably in CA3 at day 28, and widespread mitochondrial dysfunction with necroptotic signaling by day 56. Critical metabolic putative markers─including PC(15:0/16:0), CerP(d18:1/18:0), and LysoPA(0:0/18:1)─delineated disease stages, establishing day 28 as a pivotal therapeutic intervention window. These findings provide novel mechanistic insights and metabolic targets for therapeutic strategies in VCI.

Amyloid polymorphism can reflect Alzheimer’s disease (AD) stages. This paper demonstrates that amyloid β (Aβ) peptides, primarily Aβ-40 and Aβ-42 (implicated in AD pathology), present in cerebrospinal fluid (CSF), can be differentiated, and their morphology studied in detail using fluorescence-based super-resolution and atomic force microscopy (AFM). An inhibitory effect of Aβ-40 on Aβ-42 protein aggregation, marked by Aβ-40 oligomers colocalizing along the Aβ-42 fibril backbone, was resolved at the single-particle level. Molecular dynamics simulations revealed that coaggregation is modulated by the ionic environment in CSF, where calcium ions form bridges between Glu residues of Aβ-40 and Aβ-42, known to stabilize the fibril structure. This ion-mediated tethering compacts Aβ-40 and kinetically traps the fibril–oligomer interface, thus reducing fibril elongation. The isoform-specific imaging method further allowed us to distinguish Aβ-40 and Aβ-42 aggregates from oligomers to mature fibrils in the CSF of AD patients, and the nanoscopic differences in aggregate sizes were quantified from the AFM topographs. Such a protein characterization approach, which is not limited by analyte size or shape and is capable of fingerprinting Aβ aggregates in CSF, could be used in clinical settings to monitor the progression of Alzheimer’s disease and related pathologies.

The thousand and one (TAO) kinases, TAOK1, TAOK2, and TAOK3, have garnered great interest for their role in, and therapeutic potential for, breast cancer, neurodegeneration in human tauopathies, and a large number of neurodevelopmental disorders (NDDs). However, only one pan-TAO kinase inhibitor, referred to as compound 43, has been employed to pharmacologically validate this important family of kinases despite a poor pharmacokinetic(PK) profile and off-target liabilities. In order to understand the isoenzyme-specific role of TAOKs in NDDs and in regulating tau pathology, isoenzyme-selective inhibitors and activators are required. Here, we report on an iterative medicinal chemistry exercise to expand the chemical space around compound 43, which resulted in the first TAOK1 selective inhibitor VU6083859 (TAOK1 IC₅₀ = 158 nM; TAOK2/TAOK1 = 22; TAOK3/TAOK1 > 63; selective versus the Cerep 360 kinase panel) and quite unexpectedly, by virtue of a ‘magic methyl,’ a pan-TAOK activator, VU6080195 (TAOK1 EC₅₀ = 270 nM, TAOK2 EC₅₀ = 1,376 nM, TAOK3 EC₅₀ = 503 nM; note: the des-methyl congener is a TAOK1-preferring inhibitor). Both new kinase ligands showed modest rat PK, central nervous system (CNS) penetration (K_ps > 0.15) and therefore provide a foundation to further optimize this chemotype to probe and validate the role(s) of TAO kinase modulation in the CNS.

The human amylin, hAM, also known as the human islet amyloid polypeptide (hIAPP), fibrils are identified as a substantial risk element in type 2 diabetes (T2D). Thus, targeting hAM fibrillation could significantly influence the prevention and treatment of T2D. In this work, a library of computationally designed peptides based on the hAM amyloidogenic sequence NFGAILSS, an effective inhibitor of hAM fibrillation, has been generated, which is further evaluated for its ability to effectively attenuate hAM fibrillation. Notably, MM-PBSA analysis identified two new peptides, QYGPILSS (ΔG_binding = −37.66 ± 3.96 kcal/mol) and NWGPILSS (ΔG_binding = −33.10 ± 6.19 kcal/mol), displaying significantly higher binding affinity to hAM as compared to NFGAILSS (ΔG_binding = −21.03 ± 6.56 kcal/mol). Importantly, among the designed peptides, QYGPILSS preserves the helix conformation of hAM to the maximum extent and prevents the conformational transformation of hAM to an aggregation-competent β-sheet conformation, which is further corroborated using CD studies. Furthermore, the thioflavin T (ThT) fluorescence assay depicted no self-fibrillation of QYGPILSS and a maximum inhibitory effect among the synthesized peptides (QYGPILSS inhibition efficiency = 77%, IC₅₀ = 5.51 ± 0.81 μM) against hAM fibrillation, consistent with the computational findings. Notably, DLS and TEM analyses confirmed the modulation in hAM fibrillation upon the incorporation of QYGPILSS. Remarkably, QYGPILSS efficiently rescued human embryonic kidney (HEK293) cells against hAM-induced cytotoxicity by enhancing cell viability in the range of 47.5–81.6% as compared to 35.8% (hAM alone). Remarkably, this study highlights the synergistic effect of three key mutations (N → Q, F → Y, and A → P) in the amyloidogenic fragment of hAM (NFGAILSS) in yielding a new potent inhibitor (QYGPILSS) of hAM fibrillation.

The escalating number of Alzheimer’s disease (AD) cases and the limitations of current therapies pose a significant threat to human health, necessitating the discovery of novel drugs with innovative modes of action. To address this challenge, we pursued multitarget ligand strategy with the expectation of improved disease management. Continuing our efforts to discover new multitarget agents for AD, we decorated the planar 6-Cl-2-OCH₃-9-aminoacridine core with basic heterocyclic or benzyl side chains as polar and hydrophobic structural features, respectively. All the compounds inhibited acetylcholinesterase, and in several cases also inhibited butyrylcholinesterase, with potencies comparable to or exceeding those of reference drugs. Exploring activity against MAO isoforms, heterocyclic derivatives 2, 5, 6, 9, 11, and 12 proved to be selective MAO-A inhibitors, while the 3,4-dichlorobenzyl derivative 20 provided balanced inhibition of both MAO-A and MAO-B enzymes. Favorable predicted blood-brain barrier permeability and low toxicity toward SH-SY5Y neuronal cells were also observed. Intriguingly, compounds 4, 12 and 20 altered the aggregation morphology of the neurotoxic Aβ₄₂ peptide, revealing distinct inhibition profiles likely reflecting the different nature of the side chain. Based on these findings, the planar 6-Cl-2-OCH₃-9-aminoacridine ring emerges as a valuable scaffold for future development of multitargeted anti-AD agents.

Alzheimer’s disease (AD) is a neurodegenerative disorder and the predominant cause of dementia, characterized by amyloid β (Aβ) plaques and tau tangles that disrupt neurons in memory-related brain regions. This study explores the therapeutic potential of santonin using integrated in silico, in vitro, and in vivo approaches. Molecular docking identified santonin as a promising acetylcholinesterase, NOD-like receptor family, pyrin domain-containing 3 (NLRP3), brain-derived neurotrophic factor (BDNF), and nuclear factor kappa B (NF-κB) ligand with significant binding affinities and supportive interaction scores supported by molecular dynamics simulations with significant multitarget therapeutic relevance. In vitro assays demonstrated that santonin has measurable inhibition of cholinesterase enzymes, showing significant effects on butyrylcholinesterase and acetylcholinesterase enzymes. Behavioral analysis revealed that santonin produced dose-dependent improvements in memory and exploratory behaviors, indicating significant neuroprotective effects against streptozotocin (STZ)-induced impairments. Histological analysis showed that santonin preserved neuronal architecture, enhanced neuronal density, and reduced Aβ deposition in STZ-treated brains using hematoxylin and eosin, Congo red, and Nissl analysis. These effects were evident in the cortical and hippocampal regions. Santonin exhibited strong antioxidant effects, mitigating induced enzyme depletion and oxidative marker elevation. Santonin effectively mitigated STZ-induced Aβ buildup and provided protective effects. Santonin modulated marker expression in STZ-treated brains by reducing the amyloid precursor protein, Tau, toll-like receptor 4, NLRP3, discs large MAGUK scaffold protein 4, and BDNF. Santonin reduces neuroinflammation and neurotrophic signaling in the early stages of AD, which suggests that it may be used as a treatment. However, more research is needed to confirm its effectiveness.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss and α-synuclein pathology, yet the role of autophagy in PD and its translational relevance remain incompletely defined. Here, we integrated GEO transcriptomic data sets (GSE7621, GSE20141, and GSE20163) to identify autophagy-related biomarkers and to delineate their biological context. Differentially expressed genes (DEGs) were intersected with autophagy genes curated in the Human Autophagy Database to derive autophagy-related DEGs, followed by Gene Ontology and KEGG analyses. Biomarkers were prioritized using three complementary machine-learning approaches and validated in an independent cohort (GSE49036), with a nomogram constructed for PD risk estimation. We further profiled biomarker-associated programs using gene set enrichment analysis, ceRNA network inference, and immune-cell infiltration assessment, and evaluated expression changes in an MPTP-induced PD mouse model. We identified 2177 DEGs across discovery data sets, and intersection with 232 autophagy genes yielded 29 autophagy-related DEGs. Machine-learning analyses nominated six hub genes (PEX14, VEGFA, BECN1, LAMP1, CXCR4, and ATF6), among which external validation robustly supported PEX14 and LAMP1. Enrichment analyses linked these markers to immune and inflammation pathways, including cytokine–cytokine receptor interaction, antigen processing and presentation, and hematopoietic cell lineage, and suggested concomitant shifts in immune infiltration. Consistently, MPTP-treated mice exhibited decreased PEX14 and increased LAMP1 expression. Together, our findings identify PEX14 and LAMP1 as autophagy-related biomarkers in PD, connecting autophagy with immune-related signaling and supporting their potential utility for biomarker-based PD risk prediction and therapeutic stratification.

Psychedelics are a diverse class of psychoactive compounds that profoundly alter perception, cognition, and emotional states. Recently, classical serotonergic agents, such as psilocybin and lysergic acid diethylamide (LSD), along with atypical agents such as methylenedioxymethamphetamine (MDMA, ecstasy) and ibogaine, have attracted renewed attention due to their rapid and sustained clinical effects in psychiatric disorders. Preclinical and clinical studies indicate that serotonergic psychedelics acutely modulate glutamatergic and GABAergic transmission, enhance neuroplasticity, and reorganize brain network connectivity. However, a unified mechanistic framework linking these effects to enduring clinical outcomes remains elusive. Here, we propose a neurodevelopmental hypothesis in which psychedelics restore excitation/inhibition (E/I) balance, a fundamental property of both neurodevelopment and adult brain function. Acutely, psychedelics shift E/I dynamics through serotonergic and nonserotonergic mechanisms, creating a transient state of heightened plasticity similar to developmental sensitive periods. This permissive window facilitates the long-term reorganization of excitatory and inhibitory circuits with GABAergic interneurons as key mediators. By integrating established pharmacological effects with developmental principles, our dual-phase model links initial network excitability with subsequent neuroplasticity and circuit stabilization, providing a coherent framework for the rapid onset and sustained efficacy of psychedelic interventions across psychiatric disorders.

The prevalence of neurodegenerative diseases and mental health disorders has been increasing over the past few decades. While genetic and lifestyle factors are important to the etiology of these illnesses, the pathogenic role of environmental factors, especially toxicants such as pesticides encountered over the life span, is receiving increased attention. As an environmental factor, organophosphates pose a constant threat to human health due to their widespread use as pesticides, their deployment by rogue militaries, and their use in terrorist attacks. The standard organophosphate-antidotal regimen provides modest efficacy against lethality, although morbidity remains high, and there is little evidence that it attenuates long-term neurobehavioral sequelae. Here we show that a novel intranasally administered treatment strategy with specific gangliosides can prevent the organophosphate-related alterations in important neurotrophin pathways that are involved in cognition and depression. We found that a single exposure to the organophosphate diisopropylfluorophosphate (DFP) in mice leads to persistent decreases in the neurotrophins NGF and BDNF and their receptors, TrkA and TrkB. Moreover, 7 days of repeated intranasal administration of gangliosides GM1 or GD3 24 h after the DFP injection prevented the neurotrophin receptor alterations. As NGF and BDNF signaling are involved in cognitive function and depression symptoms, respectively, intranasal administration of GM1 or GD3 may offer a preventative strategy against organophosphate-related alterations in these brain functions. Our study thus supports the potential of a novel therapeutic strategy for neurological and psychiatric deficits associated with a class of poisons that endangers millions of people worldwide.

This review aims to evaluate the pharmacological properties, mechanistic selectivity, and early clinical development of zalsupindole, highlighting its potential as a next-generation psychiatric therapeutic. This review was conducted using a structured literature search strategy across PubMed, Google Scholar, ClinicalTrials.gov, and the official Web sites of regulatory bodies and pharmaceutical developers. Searches included combinations of keywords such as “zalsupindole,” “DLX-001,” “AAZ-A-154,” “non-hallucinogenic psychoplastogen,” “5-HT₂A receptor,” “biased agonism,” “neuroplasticity,” and “Delix Therapeutics.” The inclusion criteria encompassed English-language publications between January 2019 and October 2025. Peer-reviewed articles, preclinical studies, clinical trial data, patents, regulatory documents, and officially released press materials were considered. Sources were excluded if they lacked relevance to zalsupindole’s pharmacology, therapeutic positioning, or clinical development pathway. To ensure transparency, all sources have been categorized in-text according to type: Peer-reviewed literature is cited directly and forms the scientific backbone of the review. Gray literature, including press releases, conference posters, patents, and corporate briefings, is clearly identified and used only to provide supplementary context where peer-reviewed data are unavailable. No original research was conducted as part of this review. Peer-reviewed in vitro and in vivo studies confirm that zalsupindole promotes neuritogenesis and dendritic spine growth via 5-HT₂-dependent mechanisms; ketanserin abolishes these effects, and rapamycin-based inhibition studies suggest potential mTOR pathway participation in zalsupindole-induced plasticity. The compound demonstrates rapid brain penetration in rats, with no measurable 5-HT₂B agonism, no glutamate surge, and no head-twitch response, suggesting strong neuroplastic effects without hallucinogenic activity. In the forced swim test and VMAT2-deficient mouse models, single doses produced rapid and durable antidepressant-like effects. In Phase 1 clinical trials, oral zalsupindole was well tolerated across a dose range of 2–360 mg, with no reports of psychotomimetic effects. Pharmacokinetic assessments showed linear absorption/CNS penetration. EEG-based biomarkers revealed dose-dependent increases in power spectra associated with synaptic potentiation. The development of zalsupindole marks a significant step forward in neuropsychiatry. Its unique 5-HT₂A receptor biasing and safety profile position it as a potential treatment for mood disorders. Pending future results, zalsupindole could contribute to evolving treatment strategies in psychiatry.