ACS Chemical Neuroscience最新文献

Melatonin, the pineal gland hormone, is produced in various extrapineal tissues as well, and its reduction has been reported in sporadic Alzheimer’s disease (AD). The exact reason for tissue melatonin synthesis, despite the pineal source of melatonin, is not well understood, although the melatonin decline in the biological fluids of AD patients is a reasonable justification for melatonin therapy in cognitive impairment. However, the effectiveness of melatonin administration in AD patients was insignificant. Additionally, there is evidence of alterations in local melatonin synthesis in pathological situations, and little is known regarding its physiological or pathological modulators. Recently, the decline in the hippocampal enzyme of melatonin synthesis has been reported in amyloid-β neurotoxicity. It has been shown that reduced hippocampal melatonin synthesis by siRNA has been associated with cognitive decline. This review has included AD studies that noticed the impacts of melatonin prescription on memory and cognitive function in both animal research and randomized controlled trials, while also reviewing the available data regarding the alterations in brain tissue melatonin synthesis. This review highlights the role of brain (extrapineal) tissue melatonin synthesis in cognitive function in AD pathophysiology. Understanding the induction pattern of extrapineal melatonin synthesis, dosing optimization of exogenous administration, noting gender-specific differences, and clarifying microbiota–melatonin interactions point toward new approaches that may enhance the effectiveness of melatonin-based interventions for preventing or delaying AD progression.

Intracerebral hemorrhage (ICH) is a cerebrovascular event associated with a high fatality rate, leading to a considerable health and economic burden. Tanshinone IIA (Tan IIA), a promising compound used to treat coronary artery disease, has recently been shown to exert significant neuroprotective effects. Therefore, whether Tan IIA can alleviate NETosis induced by LPS after ICH remains unclear. For this purpose, we explored the effects of Tan IIA on collagenase-induced ICH with peripheral inflammation and its potential mechanisms using an after-ICH infection animal model (male C57BL/6J mice) treated with Tan IIA for 5 days, starting at 2 months of age. Further analysis demonstrated that Tan IIA-treated ICH mice with peripheral inflammation exhibited improved motor and sensory dysfunction compared with untreated groups. Administration of Tan IIA in ICH mice with peripheral inflammation alleviated neuropathological alterations of the corpus striatum, including NETosis inhibition, glial inactivation, and inflammasome activity attenuation, and significantly decreased levels of PAD4 and H3 Cit in the corpus striatum of ICH mice with peripheral inflammation. In vitro investigations showed that Tan IIA suppressed neuroinflammation in LPS-stimulated glial cells by inhibiting the NLRP3/caspase-1 signaling pathway. Further molecular docking predicted that Tan IIA directly interacted with the NLRP3 protein. Collectively, these findings strongly indicate that Tan IIA is an effective compound for mitigating hemiplegia symptoms, NETosis, and neuroinflammation in the collagenase-induced ICH model with peripheral inflammation, primarily through the dual actions of inhibiting NET formation and suppressing the NLRP3/caspase-1 pathway.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with compromised prognosis and treatment. Current research has shown that along with genetic factors, maternal health, environmental exposures, and epigenetic modifiers play a critical pathogenic role. Emerging scientific evidence reveals the significant impact of increased advanced glycation end products (AGEs) in impairing pediatric brain development that may contribute to ASD by inducing neuroinflammation and oxidative stress through activation of the receptor for AGEs (RAGE) signaling in neuronal cells. Accumulation of AGEs has been shown to disrupt the blood–brain barrier (BBB) integrity, which is crucial for protecting the developing brain from harmful substances, as well as interfering with the vascular function and blood flow, affecting brain maturation, and inducing neuroendocrine dysregulation. In this review, we describe the impact of AGEs on pediatric brain development and synaptic plasticity, critical for learning and memory, as well as their input in exacerbating neuroinflammation through microglia activation, contributing to the development of autism-related neuropathology. We further discuss the diagnostic and patients’ stratification potential of specific AGE types as well as current interventions to reduce their exposure and tissue accumulation, mitigating their harmful effects to support a better neurodevelopmental outcome in children.

Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder characterized by hyperandrogenism, has been increasingly associated with a high risk of autism spectrum disorder (ASD) in offspring. The emerging interaction between reproductive endocrinology and neurodevelopmental biology suggests that excessive androgen exposure during gestation may perturb neurotrophic signaling and impair neural circuit formation. Brain-derived neurotrophic factor (BDNF) acts through tropomyosin receptor kinase B receptor to activate downstream phosphoinositide 3-kinase/protein kinase B and extracellular signal-regulated kinase/mitogen-activated protein kinase pathways, both of which are fundamental to neuronal survival and synaptogenesis. Disruption of these signaling cascades under hyperandrogenic conditions may lead to altered neuroarchitecture, impaired synaptic connectivity, and ASD-like behavioral phenotypes. Clinical and experimental studies also implicate aberrant BDNF expression in ovarian dysfunction, oocyte maturation deficits, and placental steroidogenic imbalance, highlighting a shared endocrine-neurodevelopmental axis in PCOS. Moreover, androgen excess may induce epigenetic modifications and post translational alterations of BDNF or tropomyosin receptor kinases B receptors, further compromising downstream signaling. These molecular events can dysregulate the transcriptional control of multiple synaptic and neurodevelopmental genes, thereby promoting atypical neuronal circuit formation. Understanding the interaction between BDNF signaling and androgen excess provides a mechanistic framework to explain how maternal endocrine imbalance influences neurodevelopment of offspring. This review integrates multidisciplinary findings spanning clinical cohorts, animal models, and molecular studies to delineate how androgen-BDNF interactions amplified by epigenetic, transcriptional, and post translational dysregulation underpin key neurodevelopmental disruptions observed in ASD. Furthermore, it emphasizes the translational potential of targeting BDNF-related pathways as early biomarkers or therapeutic entry points to mitigate the intergenerational neurodevelopmental consequences of PCOS.

The comorbidity of chronic pain and attention deficit complicates treatment, as each condition intensifies the other through mechanisms that are not well understood. The locus coeruleus (LC) integrates a variety of somatosensory and emotional inputs and has been implicated in both chronic pain and attention deficit disorders. We hypothesized that the LC and its projections may contribute to the pathophysiology of comorbid chronic pain and attention deficit. We found that in male mice with chronic sciatic nerve constriction injury (CCI), LC neurons were easily activated by mechanical and thermal stimuli. Chemogenetic activation of LC neurons improved hypersensitivity and attention deficit-like behaviors in naive mice, while inhibition of these neurons exacerbated hypersensitivity and attention deficit-like behaviors in CCI mice. Through neuronal tracing, chemogenetics, optogenetics, and electrophysiology, we discovered a monosynaptic dopaminergic pathway from the locus coeruleus to the thalamic reticular nucleus, influencing pain modulation in naive mice. In CCI mice, both projections were enhanced, and activation of these pathways resulted in analgesic and anti-attention deficit-like effects. This study suggests that LC, particularly the LC-thalamic reticular circuit, is crucial in the regulation of comorbid chronic pain and attention deficit.

Deep generative models have emerged as powerful computational engines for de novo molecular design, enabling efficient exploration of a vast chemical space that remains inaccessible to traditional experimental approaches. This review provides a comprehensive survey of machine learning-driven molecular generation, systematically organizing the field across three foundational pillars: molecular representations, model architectures, and evaluation frameworks. We present a detailed taxonomy of state-of-the-art generative models, including Variational Autoencoders (VAEs), Generative Adversarial Networks (GANs), Recurrent Neural Networks (RNNs), Transformers, Diffusion Models, Normalizing Flows, and Hybrid Architectures, analyzing their underlying mechanisms, comparative strengths, and inherent limitations. Critically, we depart from purely descriptive surveys by systematically examining algorithmic failure modes and practical deployment challenges across model families. We discuss core applications spanning distribution learning and goal-directed generation. Special attention is given to challenging therapeutic domains such as Central Nervous System (CNS) drug discovery, where stringent constraints like blood–brain barrier (BBB) permeability and neurotoxicity mitigation demand multiparameter optimization. We critically evaluate the gap between computational benchmarks and practical medicinal chemistry, addressing synthetic feasibility and experimental validation. Subsequently, we highlight persistent theoretical, computational, and empirical challenges that currently limit widespread deployment, and outline promising future opportunities, including physics-informed architectures, large language models, and autonomous laboratories. This review aims to provide actionable insights for both machine learning researchers and medicinal chemists engaged in next-generation drug discovery.

Perspectives surrounding Cannabis use have transformed over the past decade. This shift in perspective has been noted in pregnant populations in Canada and the US, where various investigations report that the use of Cannabis in pregnancy is increasingly commonplace. There is some evidence indicating that Δ9-tetrahydrocannabinol (THC), the main intoxicating phytocannabinoid found within Cannabis flower, may influence the biochemical composition of lipids within the developing fetal brain. The aim of this study was to apply multimodal biospectroscopic imaging techniques, X-ray fluorescence imaging (XFI) and Fourier transform mid-infrared spectromicroscopy (FTIR), to investigate the biochemical and biomolecular changes underlying the distinct behavioral phenotypes identified previously. XFI was used to investigate the presence of metal, nonmetal, and alkali dysregulation, while FTIR provided information on neurochemical dysbiosis within the brains of offspring exposed to THC (3 mg/kg; i.p.) or vehicle (VEH). The THC offspring exhibited decreased copper (Cu) concentrations within the perimeter of their corpus callosum, as identified by XFI. FTIR hyperspectral data from the brain revealed noteworthy changes in peaks associated with lipid methylene (CH_2as), carbohydrates, and peak ratios identifying changes in the lipid structure and the relative content of lipids, cholesterol esters, and cholesterols to saturated fatty acids. These changes were particularly evident in the hippocampus, where THC offspring exhibited increased CH_2as, lipid esters, phosphate, protein, and unsaturation levels of lipids. The biochemical changes seen in the FTIR spectra were modest, with THC offspring showing an increase in the number of structural changes of lipids in the corpus callosum and an increase in protein in the lateral ventricle. This study supports the usefulness of these techniques to detect subtle changes in biomolecular composition within brain tissues exposed to gestational THC. These results contribute to the growing body of knowledge unraveling the complex effects of THC on fetal neurodevelopmental trajectories.

Alzheimer’s disease (AD) presents a critical therapeutic gap, necessitating novel multitarget strategies. Excitotoxicity via NMDA receptor overactivation and oxidative stress is a key driver of Tau hyperphosphorylation and neuronal loss. While the tripeptide Gly-Pro-Glu (GPE) derived from IGF-1 exhibits NMDA receptor antagonism, its clinical potential is limited by poor blood–brain barrier penetration and rapid hydrolysis. Herein, we rationally designed three novel GPE-derived oligopeptide conjugates (SAC-PE, SPE, and SAR-SPE) by replacing the N-terminal glycine with antioxidant moieties ((S)-allyl-l-cysteine or thioproline derivatives) while preserving the active C-terminal Pro-Glu (PE) dipeptide core. This design aimed to confer dual-targeting capabilities against both excitotoxicity and oxidative stress. Among them, SAC-PE demonstrated superior properties, including the highest calculated lipophilicity and excellent cellular safety. In Aβ_1–42-stimulated HT-22 hippocampal neurons, SAC-PE effectively scavenged reactive oxygen species (ROS), released endogenous H₂S, and significantly reduced p-Tau and p-CaMKII levels while upregulating the expression of the neurotrophic factor BDNF, synaptic proteins (SYN, PSD-95) and the antioxidant regulator Nrf2, outperforming GPE. In AD model mice, SAC-PE administration robustly improved cognitive deficits in Morris water maze (MWM), novel object recognition, and passive avoidance tests. Molecular and histological analyses confirmed its superior efficacy in reducing hippocampal p-Tau and p-CaMKII levels, enhancing Nrf2 expression, and preventing neuronal loss compared with GPE. These findings establish SAC-PE as a promising dual-targeting therapeutic candidate that synergistically inhibits excitotoxicity and oxidative stress, offering a novel strategic approach for AD modification.

Transferrin-functionalized chitosan nanoparticles (TfCZNP) were developed for the intranasal delivery of Cariprazine to enhance brain targeting and minimize systemic exposure. The optimized nanoparticles exhibited favorable physicochemical properties (size, 207 nm; PDI, 0.403; zeta potential, +34.1 mV) with confirmed transferrin conjugation (gel electrophoresis, surface plasmon resonance, and FTIR spectroscopy) and uniform morphology (TEM). TfCZNP showed sustained in vitro release, improved ex vivo nasal permeation, and excellent biocompatibility. Gamma-scintigraphy revealed preferential brain accumulation (44 ± 4%) with a minimal systemic distribution. Pharmacokinetics demonstrated higher brain exposure (C_max 132.35 ± 7.79 ng/mL; AUC_0–24h 498.67 ng·h/mL) and favorable targeting indices (DTE 6.26, DTI 6.04, direct transport percentage 90.69%) versus controls. Behavioral studies in ketamine-induced schizophrenia models confirmed the normalization of locomotor activity, anxiolytic effects, and reduced catalepsy. These findings establish TfCZNP as a safe, effective nose-to-brain delivery platform that enhances Cariprazine’s therapeutic potential in neuropsychiatric disorders.

The human dopamine transporter (DAT) is a presynaptic transmembrane protein that facilitates the reuptake of synaptically released dopamine. Several lines of evidence indicate that DAT dysfunction is linked to neuropsychiatric disorders. Moreover, the lateral membrane diffusion and clustering propensity of DAT are emergent properties that may factor into functional dopamine signaling. The disorder-associated DAT missense mutant A559V undergoes anomalous dopamine efflux (ADE) and increased lateral mobility and diffuse localization. The D2 dopamine autoreceptor short isoform (D2S), a popular antipsychotic target, signaling augments ADE in DAT A559V and may form stable DAT-D2S complexes. Using quantum dot (Qdot)-based single-molecule localization microscopy, we investigated the effect of D2S antagonism on DAT and DAT A559V membrane mobility in transfected HEK-293 cells. Single-color Qdot-DAT tracking shows phenotypic rescue of DAT A559V mobility upon D2S antagonism, while aberrant DAT A559V mobility is insensitive to ADE-linked CaMKII activity. Using two-color Qdot tracking of both the transporter and receptor, we report the first DAT-D2S colocalization lifetime in live cells. We show an increased propensity for both transporter types to colocalize with D2S, without impacting D2S diffusion speed under D2S antagonism. Downregulating D2S activity may stabilize DAT coconfinement in D2S microdomains on the cell surface.