ACS Chemical Neuroscience最新文献

Neuroinflammation is a key factor in age-related cognitive decline and memory impairment. UAS03, a potent synthetic analogue of Urolithin-A, has demonstrated anti-inflammatory and antioxidant properties. This investigation examined the neuroprotective effect of UAS03 on lipopolysaccharide (LPS) induced neuroinflammation, and its associated cognitive impairments, memory deficits, and depression-like behaviors. Intracerebroventricular administration of LPS (12 μg/kg) was performed to induce neuroinflammation in mice, followed by a 7 day treatment with UAS03 at 10 and 30 mg/kg doses. Mice were evaluated for depressive and anxiety-like behavior, spatial memory, and learning functions using a series of neurobehavioral test paradigms. Histopathological and molecular analyses were conducted using hematoxylin–eosin and cresyl violet staining, immunohistochemistry, ELISA, and Western blotting techniques. We have found that, UAS03 significantly enhanced cognitive and memory functions impaired by LPS while concurrently reducing depressive symptoms. Furthermore, the compound attenuated neuronal damage and decreased the expression of IBA-1 and GFAP in hippocampal region. Through the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, UAS03 effectively mitigated markers of oxidative stress and reduced levels of pro-inflammatory factors, including IL-1β, TNF-α, and COX-2. Cumulatively, this study provides compelling evidence that UAS03 exerts neuroprotective effects by regulating essential pathways involved in anti-inflammatory and neuroprotective mechanisms, suggesting its potential as a preventative measure against age-related cognitive decline and memory impairments associated with neuroinflammation.

The aggregation of the microtubule-associated protein tau is a distinctive characteristic of several neurodegenerative disorders like Alzheimer’s disease and frontotemporal dementia. Small-molecule inhibitors have been investigated as a potential therapy for tau aggregation-related diseases. Here, we identified 4-Amino-3′,4′-dihydroxychalcone (4-ADHC), a substituted aminochalcone, as an inhibitor of different stages of tau aggregation, namely, liquid–liquid phase separation, oligomerization, and filamentation. Size exclusion chromatography, absorbance, and fluorescence spectroscopic experiments suggested that 4-ADHC bound to purified tau. The dissociation constant for the binding of 4-ADHC to tau was determined to be 5.1 ± 0.8 μM using surface plasmon resonance. The compound potently inhibited heparin and arachidonic acid-induced tau aggregation in vitro. However, 4-ADHC neither inhibited tubulin polymerization nor the enzymatic activity of alcohol dehydrogenase and alkaline phosphatase. Fluorescence recovery after photobleaching experiments showed that 4-ADHC increased tau dynamics in phase-separated droplets, suggesting that the compound impeded the maturation of the droplets by increasing their liquid-like behavior. Further, atomic force microscopy, dot blot assay, and dynamic light scattering experiments demonstrated that the compound suppressed tau oligomerization. In addition, 4-ADHC inhibited tau filamentation and disaggregated preformed filaments. Thus, 4-ADHC is a candidate for developing potent tau aggregation inhibitors.

Simultaneous fiber photometry and optogenetics is a powerful emerging technique for precisely studying the interactions of neuronal brain networks. However, spectral overlap between photometry and optogenetic components has severely limited the application of an all-optical approach. Due to spectral overlap, light from optogenetic stimulation saturates the photosensor and occludes photometry fluorescence, which is especially problematic in physically smaller model organism brains like mice. Here, we demonstrate the multi-frequency interpolation X-talk removal algorithm (MuFIX or μFIX) for recovering crosstalk-contaminated photometry responses recorded with lock-in amplification. μFIX exploits multifrequency lock-in amplification by modeling the remaining uncontaminated data to interpolate across crosstalk-affected segments (R² ≈ 1.0); we found that this approach accurately recovers the original photometry response after demodulation (Pearson’s r ≈ 1.0). When applied to crosstalk-contaminated data, μFIX recovered a photometry response closely resembling the dynamics of noncrosstalk photometry recorded simultaneously. Upon further verification using simulated and empirical data, we demonstrated that μFIX reproduces any signal that underwent simulated crosstalk contamination (r ≈ 1.0). We believe adopting μFIX will enable experimental designs using simultaneous fiber photometry and optogenetics that were previously not feasible due to crosstalk.

Traditional drug development, which predominantly focuses on single target/phenotype evaluation, often fails to achieve optimal therapeutic outcomes in multifactorial and multitarget conditions like ischemia-reperfusion injury. In this viewpoint, we highlight a novel dual-phenotypic drug screening strategy targeting neuronal protective and anti-inflammatory effects for treatment of ischemia-reperfusion injury. This strategy involves the utilization of primary neuron treated with oxygen-glucose deprivation/reoxygenation (OGD/R), lipopolysaccharide (LPS)-activated microglial models and coculture systems or brain organoids as in vitro models, as well as mouse middle cerebral artery occlusion/reperfusion (MCAO/R) models for in vivo evaluation. The dual-phenotypic drug screening strategies marks a paradigm shift from single-factorial approach to a system biology-based integrated methodology, offering significant advantages for developing therapies for the complex multifactorial disease ischemia-reperfusion injury.

Depression is a complex mental disorder. Studies have shown that purine metabolism disorders in depression and regulation of purine metabolites and related purinergic receptors may be an effective way to alleviate depression. Chaigui granules (CG) are a Chinese medicine prescription with antidepressant effects. Its antidepressant effect has been shown to be related to the improvement of purine metabolism disorders in depression. In this study, exogenous purine metabolite adenosine supplementation and adenosine A1 receptor antagonist (DPCPX) were employed to investigate the potential of Chaigui granules to exert an antidepressant effect by examining the behavioral indices of CUMS rats. The aim of this study was to determine whether the antidepressant effect of Chaigui granules is mediated by A1R receptors using DPCPX, an A1R receptor antagonist. Nontargeted metabolomic analysis was employed to compare and analyze the alterations in the metabolic profile of plasma and peripheral blood mononuclear cells (PBMCs) in each experimental group. Subsequently, combining the results from the metabolomics profile, targeted metabolomics was employed to identify key metabolites for purine metabolism. The objective was to investigate the effects of Chaigui granules, exogenous adenosine supplementation, and DPCPX on purine metabolism in depressed rats. Finally, the relevant signal pathways were validated by molecular biological means. The results of the depression-like behavior indicate that the antidepressant efficacy of Chaigui granules was associated with the modulation of adenosine and adenosine A1 receptor. Metabolomic analysis demonstrated that the Chaigui granule and adenosine exerted a pronounced regulatory effect on purine metabolism, and the regulatory effect on peripheral blood mononuclear cells (PBMCs) was markedly superior to that observed in plasma. In addition, targeted quantitative analysis showed that all eight purine metabolites were reversed after the administration of Chaigui granules and adenosine. Concurrently, the administration of an adenosine A1 receptor antagonist may serve to mitigate the regulatory impact of Chaigui granules on purine metabolites. Finally, the molecular biological results indicate that the antidepressant effect of Chaigui granules may be mediated by the A1R receptor, and it can play an antidepressant role by regulating the CAMP-PKA-CREB-BDNF pathway.

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.

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 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.

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.