ACS Chemical Neuroscience最新文献

Oxidative stress and neuroinflammation can synergistically accelerate dopaminergic neuronal degeneration in Parkinson's disease (PD). Small extracellular vesicles derived from mesenchymal stem cells (MSC-sEVs) inhibit Nox4/ROS production by delivering specific miRNAs, regulate the EGR1/NOX4/p38MAPK axis to exert antioxidant effects, and can enhance antioxidant capacity by activating the Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Additionally, at the same time, neuroinflammation can be alleviated by inhibiting the Sp1 signal and regulating pro-inflammatory/anti-inflammatory factors. MSC-sEVs can penetrate the blood-brain barrier, improve movement disorders, and relieve neuronal damage in PD models, providing a new anti-inflammatory and antioxidant strategy for PD treatment.

The application of terahertz waves in the field of neurological disease research has gradually attracted attention in recent years. Prior studies have indicated that terahertz waves are capable of alleviating the symptoms of Alzheimer's disease (AD) in mice, yet the underlying relevant mechanisms remain unclear. This study explores the therapeutic potential of terahertz (THz) radiation on AD using a transgenic Caenorhabditis elegans model expressing human tau protein. The nematodes were subjected to 0.1 THz radiation at varying power levels, and its impact on locomotion, tau protein aggregation, and associative learning was evaluated. Results indicate that 0.1 THz irradiation significantly improved the locomotor performance and associative learning of the tau transgenic nematodes, reduced tau aggregation, and increased the expression of SKN-1 and DAF-16. Molecular dynamics simulation revealed that THz waves inhibited the structural stability of tau protofibrils by reducing the protein compactness, altering the secondary structure, reducing hydrogen bond formation, and changing the hydrophobic interaction. Overall, this study demonstrates the potential of low-frequency THz radiation as a nonpharmacological therapy for AD, highlighting its ability to modulate neuronal function and alleviate disease symptoms.

The relationship between alterations in brain microstructure and dysbiosis of gut microbiota in Alzheimer's disease (AD) has garnered increasing attention, although the functional implications of these changes are not yet fully elucidated. This research examines how neuroinflammation, systemic inflammation, and gut microbiota interact in male 3 × Tg-AD and B6129SF1/J wild-type (WT) mice at 6 months-old (6-MO) and 12 months-old (12-MO). Employing a combination of behavioral assessments, diffusion kurtosis imaging (DKI), microbiota profiling, cytokine analysis, short-chain fatty acids (SCFAs), and immunohistochemistry, we explored the progression of AD-related pathology. Significant memory impairments in AD mice at both assessed ages were correlated with altered DKI parameters that suggest neuroinflammation and microstructural damage. We observed elevated levels of pro-inflammatory cytokines, such as IL-1β, IL-6, TNFα, and IFN-γ, in the serum, which were associated with increased activity of microglia and astrocytes in brain regions critical for memory. Although gut microbiota analysis did not reveal significant changes in alpha diversity, it did show notable differences in beta diversity and a diminished Firmicutes/Bacteroidetes (F/B) ratio in AD mice at 12-MO. Furthermore, a reduction in six kinds of SCFAs were identified at two time points of 6-MO and 12-MO, indicating widespread disruption in gut microbial metabolism. These findings underscore a complex bidirectional relationship between systemic inflammation and gut dysbiosis in AD, highlighting the gut-brain axis as a crucial factor in disease progression. This study emphasizes the potential of integrating DKI metrics, microbiota profiling, and SCFA analysis to enhance our understanding of AD pathology and to identify new therapeutic targets.

Engineered nanoparticles (ENPs) have widely revolutionized many fields, including medicine, technology, environmental science, and industry. However, with the wide use of ENPs in everyday life, concerns are increasingly being raised about their potential neurotoxic effects on the central nervous system (CNS), particularly in relation to neurodegeneration and neuroinflammation. The present systematic review focuses on reporting the current knowledge about the neurotoxic potential of ENPs, with particular attention to their mechanism of action in neuroinflammation and neurodegeneration. This PRISMA based systematic review encompassed studies from Pubmed, Embase, and Web of Science. Eligibility criteria included focusing on engineered NPs and their impacts on neuroinflammation, neurodegeneration, and neurotoxicity. Evidence shows that ENPs easily can cross the blood-brain barrier (BBB) inducing neuronal damage and neurotoxicity due to oxidative stress, inflammation, mitochondrial dysfunction, and cell death. Inflammation plays a crucial role in activating glial cells, such as microglia and astrocytes, leading to the release of pro-inflammatory cytokines, chemokines, and reactive oxygen species (ROS). This increases the vulnerability of the brain to systemic inflammation. In conclusion, as ENP exposure continues to increase, understanding their long-term effects on the brain is fundamental to developing effective strategies to mitigate their impact on neuronal human health.

Receptor-interacting protein kinase 1 (RIPK1) serves as a critical mediator of cell necroptosis and represents a promising therapeutic target for various human neurodegenerative diseases and inflammatory diseases. Nonetheless, the RIPK1 inhibitors currently reported are inadequate for clinical research due to suboptimal inhibitory activities or lack of selectivity. Consequently, there is a need for the discovery of novel RIPK1 kinase inhibitors. In this study, we integrated a deep learning model, specifically the fingerprint graph attention network (FP-GAT), with molecular docking-based virtual screening to identify potential RIPK1 inhibitors from a library comprising 13 million compounds. Out of 43 compounds procured, two compounds (designated as 24 and 41) demonstrated enzyme inhibition activity exceeding 50% at a concentration of 10 μM against RIPK1. The half-maximal inhibitory concentrations (IC₅₀) for compounds 24 and 41 were determined to be 2.01 and 2.95 μM, respectively. Furthermore, these compounds exhibited protective effects in an HT-29 cell model of TSZ-induced necroptosis, with half-maximal effective concentrations (EC₅₀) of 6.77 μM for compound 24 and 68.70 μM for compound 41. Finally, molecular dynamics simulations and binding free energy calculations were conducted to elucidate the molecular mechanism of compounds 24 and 41 binding to RIPK1. The results show that Met92, Met95, Ala155, and Asp156 are key residues for novel RIPK1 inhibitors. In summary, this work discovered two hit compounds targeting RIPK1, which can be further structurally modified to become promising lead compounds.

Parkinson's disease (PD) poses a global menace, as the available treatment methods solely aim to mitigate symptoms. An effective strategy to address the pathogenesis of PD involves eliminating the accumulation of aggregated alpha-synuclein, emphasizing the role of epigenetics. Aberrant epigenetic changes significantly influence gene expression, which is pivotal in PD progression, impacting neuronal growth and degeneration. Epigenetic-related genes are regulated by histone modification and DNA methylation processes. Nevertheless, their significance in PD has not been confirmed. This research was carried out using both in vitro and in vivo approaches. In the in vitro investigations, N2A neuronal cell lines were utilized, and the neuroprotective effect of decitabine (DB) was observed at concentrations of 0.1 μM and 0.5 μM. In the in vivo study, PD induction led to significant motor deficits, which were notably ameliorated at the highest treatment dose. This improvement was accompanied by a marked attenuation of inflammatory mediators, including TNF-α, IL-6, IL-1β, and CRP levels. Additionally, there was a significant enhancement in antioxidative defense, evidenced by increased GSH (glutathione) levels and reduced oxidative stress marker NO (nitric oxide). Neurochemical analysis revealed a substantial rise in dopamine levels, a critical PD marker, alongside an elevation in BDNF, indicating neuroprotective effects. Furthermore, gene expression analysis indicated a notable upregulation in the mRNA expression of epigenetic genes and proteins linked to PD pathology. Histological assessments, including IHC, H&E, and CV staining of the substantia nigra, showed enhanced structural integrity following treatment. Collectively, these insights reveal DB's promise as a therapeutic solution for mitigating PD symptoms and pathology exacerbated by 6-OHDA.

Amyloid β peptide (Aβ) aggregation in the brain represents an initial detrimental episode in the etiology of Alzheimer's disease (AD). Recently, it has been discovered that inhibiting Aβ neurotoxicity by modulating highly toxic Aβ oligomers (AβOs) is more rewarding than reducing the overall amyloid fibril production. In line with this, here, we discussed the efficiency of multifunctional quinazolinone and vanillin acrylamide hybrids (QVA_1-5) as modulators of aggregation behavior. The thioflavin T (ThT) assay inferred dose-dependent intensification of Aβ_1-42 aggregation by QVA_1-5, which may be due to the coassembly of hybrids with AβOs. Field emission-scanning electron microscopy (FE-SEM) disclosed enormously distinctive differences among the aggregate morphologies of Aβ_1-42 and Aβ_1-42+ QVA_1-5, which intensely reinforced the modulatory action of QVA_1-5 on the molecular assembly of the Aβ_1-42 peptide. Supportingly, the Alamar Blue assay proved QVA_1-5 as an effective neuroprotector in the SH-SY5Y cell line against Aβ_1-42-induced toxicity. Consistent with these findings, western blot data showed an increased number of Aβ_1-42 fibrils in SH-SY5Y cells treated with QVA_1-5. In our molecular docking approach, all ligands had identical binding positions at sites 4-6 of the Aβ fibril structure (PDB ID: 2M4J). In the interaction pattern, ligands spanned across five Aβ monomers that were stacked together and stabilized the fibril formation by hydrophobic interactions with the Aβ monomer residues as well as neighboring ligands. In the molecular dynamics simulations, the lower RMSD and similar rGyr values for the ligands further supported the stability of the ligands inside the binding pocket of the 2M4J Aβ fibril. Overall, the present study provided a mechanistic explanation at the atomic level for the impact of small molecules (QVA_1-5) on Aβ fibril stabilization for the first time. Hence, we strongly believe that these findings will be a resource for the development of imminent drug candidates against AD that can manipulate Aβ aggregate formation.

Bispecific antibodies (bAbs) that engage cerebrovascular targets, induce transport across the blood-brain barrier (BBB), and redistribute to secondary targets within the brain parenchyma have the potential to transform the diagnosis and treatment of a wide range of central nervous system disorders. Full understanding of the pharmacokinetics (PK) of these agents, including their potential for delivering cargo into brain parenchymal cells, is a key priority for the development of numerous potential therapeutic applications. To date, the brain PK of bAbs that target transferrin receptor (TfR-1) and CD98 heavy chain (CD98hc) has been characterized using techniques incapable of distinguishing between CNS clearance of intact protein from uptake and catabolism by brain parenchymal cells. Herein, we address this knowledge gap via a comparative radiotracing strategy using two radioisotopes with distinct residualizing properties, iodine-125 (I-125) and zirconium-89 (Zr-89). We first identify reaction conditions for tetravalent chelator modification and Zr-89 radiolabeling that do not adversely affect in vitro or in vivo function. We then use comparative radiotracing to define the PK of TfR-1 and CD98hc targeted bAbs without a parenchymal target, generating quantitative evidence of TfR-1-mediated cellular uptake and catabolism that implicates these processes in previously reported differences in the brain retention of IgGs shuttled across the BBB via these two pathways. Finally, we perform comparative radiotracing on a TfR-1 bAb with an internalizing neuronal target (TrkB), demonstrating rapid divergence of Zr-89 and I-125 PK curves, with a > 30-fold difference in brain content of the two radioisotopes. Together, these results establish comparative radiotracing as a valuable technique for identifying internalizing cellular targets within the brain parenchyma and quantifying the extent and timing of bAb uptake and catabolism following target engagement.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the leading cause of dementia, affecting nearly 55 million people across the world. One of the central pathological factors associated with AD is the aggregation of Aβ₄₂, a peptide product cleaved through pathological processes in AD. Under pathological conditions, Aβ₄₂ aggregates into insoluble plaques in the brain and impairs the function of neurons, which contributes to the cognitive decline associated with AD. Therefore, the modulation of Aβ₄₂ aggregation is considered a potential therapeutic intervention for AD. Using an Oligoquinoline-based foldamer library, we have identified a potent foldamer antagonist (SK-131) of Aβ₄₂ aggregation. SK-131 inhibits the aggregation by inducing a α-helical structure in monomeric Aβ₄₂. Here, we demonstrated that SK-131 rescues Aβ₄₂ aggregation-associated phenotypes in AD cellular and multiple Caenorhabditis elegans AD models, including intracellular inhibition of Aβ₄₂ aggregation, rescue of behavioral deficits, and attenuation of reactive oxygen species. It efficiently crosses the blood-brain barrier and demonstrates favorable pharmaceutical properties. It also potently inhibits Zn²⁺-mediated Aβ₄₂ aggregation by potentially displacing Zn²⁺ from Aβ₄₂. In summary, we have identified a potent brain-penetrating foldamer that efficiently rescues AD phenotypes in in vivo models. Unlike most of the therapeutic approaches that target Aβ aggregates, we have identified and validated a novel therapeutic pathway by inducing structural change in Aβ and rescuing AD phenotypes in in vivo models. This study will further aid in the quest to identify lead therapeutics to slow or stop the progression of AD.

Computational drug design is a rapidly evolving field, especially the latest breakthroughs in generative artificial intelligence (GenAI) to create new compounds. However, the potential of GenAI to address the challenges in designing central nervous system (CNS) drugs that can effectively cross the blood-brain barrier (BBB) and engage their targets remains largely unexplored. The integration of GenAI techniques with experimental data sets and advanced evaluation metrics provides a unique opportunity to enhance CNS drug discovery. In this viewpoint, we will introduce the definition of CNS drug-like properties and data resources in CNS drug discovery, highlighting the need to train specialized GenAI models aimed at designing novel CNS drug candidates by efficiently exploring the CNS drug-like space.