Journal of Neurochemistry最新文献

Secondary bile acids (BAs) are metabolites produced by the gut microbiota and shown to impact digestive functions, at least in part through the enteric nervous system (ENS). In the ENS, enteric neurons express the BA receptor Takeda G protein-coupled receptor 5 (TGR5), making them potential direct cellular targets of secondary BAs, although their effects on enteric neuronal functions remain poorly understood. Enteric neuronal activity and connectivity form the basis of the regulatory control exerted by the ENS on gut functions. Yet, the influence of microbiota-derived metabolites, such as secondary BAs, on enteric neuron connectivity and synaptic activity remains largely unexplored. To address this question, we studied the effects of secondary BAs on neuronal connectivity using a model of rat primary culture of enteric neurons. We found that exposure to deoxycholic acid (DCA) increased the expression of key presynaptic proteins, synapsin-1 and synaptophysin, and enhanced synaptic density in enteric neurons. Moreover, DCA enhanced synaptic activity by increasing synaptic vesicle exocytosis upon KCl depolarisation, potentially through amplified phosphorylation of synapsin-1 at the Ser62–67 sites. In addition, we found that DCA modulated the intracellular Ca²⁺ response induced by acetylcholine, a major excitatory neurotransmitter in enteric neurons, through a mechanism mediated by the TGR5 receptor. Overall, this study identifies DCA as a microbiota-derived compound capable of reshaping the enteric neuronal functional network. These findings highlight the potential of bacterial metabolites like DCA to link the microbiome with modulation of enteric neuronal activity and connectivity, supporting the relevance of secondary BAs in digestive physiology and their possible roles in gastrointestinal disorders.

Recent research has revealed that BRD4, a bromodomain and extra terminal domain (BET) epigenetic “reader” protein, plays an essential role in regulating behavioral and molecular responses to cocaine. To date, the roles of BRD4 and other BET proteins in substance use disorder (SUD) models have been mainly studied using small molecule inhibitors that block the bromodomain interactions with acetylated histones. In other disease models, non-bromodomain BRD4-protein interactions have also been shown to play an important role in BRD4's molecular functions, but these interactions have yet to be studied in SUD models. Here, using BRD4 co-immunoprecipitation coupled to tandem mass spectrometry, we identified several putative BRD4-interacting proteins in the nucleus accumbens (NAc) that are altered by acute or repeated cocaine exposure in male and female Sprague Dawley rats. In BRD4-immunoprecipitated samples, gene ontology molecular function analysis revealed an enrichment of pathways associated with polymerase activity, SH3 domain binding, and chromatin-protein-adaptor activity in the cocaine treated groups. Notably, casein kinase 1 epsilon (CK1ε), a protein previously implicated in SUDs, was identified as a putative BRD4-interacting protein, and this association was increased following repeated cocaine injections. However, no significant change in total CK1ε protein expression was observed in the NAc via western blot following acute or repeated cocaine treatment. In additional experiments, we sought to determine the effects of CK1ε inhibition on the expression of a cocaine-related memory. Pharmacological inhibition of CK1ε with PF-4800567 diminished the expression of cocaine conditioned place preference. In a separate cohort of rats, an acute injection of PF-4800567 did not alter locomotor activity and anxiety-like behavior in the open field test. Collectively, these findings suggest that several novel proteins, including CK1ε, may play a role in BRD4-mediated molecular adaptations to cocaine exposure, and that CK1ε represents a potential target for future investigation in animal models of cocaine-seeking behavior.

People with HIV (PWH) have a higher risk of central nervous system (CNS) diseases and a timely differential diagnosis may be essential for patient management. Cerebrospinal fluid (CSF) biomarkers have proven effective in diagnosing neuronal and astrocyte involvement in neurological disorders, but the invasiveness of this method makes it difficult to obtain results; thus, easy-to-obtain matrices (e.g., plasma) have to be analysed. Consequently, the aim of this study was to quantify biomarkers in both serum and CSF with different kits, correlating levels obtained in the two matrices and understanding their impact on blood brain barrier (BBB) permeability. CSF and serum from PWH were analysed through Single Molecule Array (Simoa SR-X, Quanterix). We measured markers of neuronal damage (NfL, tau, ptau), β-amyloid peptides (Aβ_1–40 and Aβ_1–42), signalling and neuronal plasticity (BDNF), astrocyte activation (GFAP), ubiquitin-proteasome involvement (UCH-L1), and programmed death ligand-1 (PD-L1). BBB permeability was assessed through CSF-to-serum albumin ratio (CSAR). We included 286 samples: median age was 42.1 years (30.6–51), 69.2% were male. Median CSAR was 5.4 (3.9–7.3). We observed statistically significant correlations for all serum/CSF pairs, but rho values > 0.5 for tau, p-tau, GFAP, Aβ_1–40 and Aβ_1–42 only, when using different kits. NfL CSF-to-plasma ratios were higher in participants with higher CSAR (p = 0.0000016), with a higher ratio in participants with age-adjusted abnormal BBB (n = 34 for intact BBB and n = 66 for altered BBB, p = 0.001). We observed an average-to-high correlation between serum and CSF biomarkers in PWH, suggesting the possible use of serum levels for assessing CNS involvement: it is the first time that BBB permeability was found to influence such correlations.

Glutathione (GSH), the brain's primary endogenous antioxidant, is integral to the cerebral antioxidant defense system and essential for maintaining redox homeostasis and neuronal health. Brain GSH levels naturally decrease with age, potentially contributing to cognitive vulnerability through diminished antioxidant capacity. Currently, the relationship between brain GSH and cognitive function in humans remains poorly understood. Using multiple quantum chemical shift imaging, we measured brain GSH levels in 206 cognitively unimpaired older adults (mean age 69.8 ± 3.9 years) and assessed cognitive performance across five core domains: working memory, episodic memory, visuospatial processing, executive function/attentional control, and processing speed. We hypothesized that higher GSH would be associated with better cognitive performance across all five domains, reflecting the putative role of antioxidant capacity in cognitive function. Using multiple regression with age, sex, years of education, and study site as covariates in the model, we found that higher regional brain GSH levels, including frontal and parietal regions, were associated with better working memory (p = 0.008), episodic memory (p = 0.040), and visuospatial processing (p = 0.001), but not with executive function/attentional control or processing speed. These findings highlight the critical neuroprotective role of GSH within the cerebral antioxidant defense system in supporting cognitive health in late adulthood.

This study describes the rational design, synthesis, and evaluation of forty 2′-R-6′H-spiro(cycloalkyl/heterocyclyl)[1,2,4]triazolo[1,5-c]quinazolines as potential neuroprotective agents targeting multiple receptor systems implicated in cognitive dysfunction. The molecular design integrated structural features from established nootropic and anxiolytic pharmacophores to create compounds with putative multi-target activity. In silico ADMET analyses assessed drug-likeness parameters, while molecular docking studies evaluated binding interactions with nine neuroreceptor targets: glutamate GluA3, GABA(A)R, dopamine D2, serotonin 5-HT1A and 5-HT7, cannabinoid CB2, muscarinic M2 acetylcholine, corticotropin-releasing factor receptor 1 (CRF1R), and metabotropic glutamate receptor 5 (mGluR5). Based on computational predictions, selected compounds underwent preliminary in vivo screening using a ketamine-induced cognitive impairment model in rats. Behavioral assessments examined anxiety-related responses and cognitive performance relative to piracetam and fabomotizole controls. Biochemical analyses measured inflammatory markers (IL-1β, caspase-1), cell survival indicators (Bcl-2), and hypoxic adaptation responses (HIF-1 mRNA). Docking studies indicated favorable binding profiles across tested receptor targets compared to reference ligands, with calculated affinities suggesting potential modulatory interactions. The experiments showed that compounds 25, 26, and 32 attenuated ketamine-induced behavioral alterations, demonstrating effects in anxiety reduction and cognitive performance that appeared numerically greater than piracetam and fabomotizole, though the magnitude and statistical robustness of these differences require further characterization. Compound 31 reduced IL-1β expression by 72% and caspase-1 by 80% relative to ketamine-treated controls. Compound 26 increased Bcl-2 expression by 96% and HIF-1 mRNA levels by 3.5-fold compared to control conditions. These findings suggest that spirotriazoloquinazolines may function as positive modulators at cognitive-enhancing receptors, potentially exerting neuroprotective effects through anti-inflammatory and anti-apoptotic mechanisms. Further investigation is necessary to validate the observed effects, establish dose–response relationships, and elucidate the molecular mechanisms underlying the apparent neuroprotective properties of these compounds.