Neurochemical Research最新文献

Alzheimer's disease (AD) is the most frequent neurodegenerative disorder. It is characterized by the buildup of amyloid-β (Aβ) plaques, as well as of tangles made out of tau that increasingly damage and kill neurons while also impairing memory and thinking. Recent findings indicate that cellular senescence is implicated in the pathogenesis of AD. Senescence occurs when cells irreversibly stop dividing under stress. In the brain, it can be induced by chronic activation of astrocytes and microglia, Aβ toxicity, tau hyperphosphorylation and oxidative stress. Senescent cells secrete proinflammatory factors, i.e., the senescence-associated secretory phenotype (SASP). These molecules promote inflammation, destroy mitochondria and interfere with synapses in ways that speed up the progress of the disease. Blocking those senescent cells may offer a new approach to treatment. Approaches including VEGFR-1 and SIRT5 interference, senolytics or senomorphs drugs, NLRP3 antagonist, PAI-1 inhibitors and small vessels inhibitors (including aspirin, curcumin derivatives and sildenafil) have been suggested to promisingly mitigate brain injury. RNA based therapy (miRNAs- and lncRNAs-targeted) and exosomal derived biomarkers are also an optimistic approach. A clearer understanding of how senescence is implicated in AD would have implications regarding the design and application of novel treatments aimed at delaying disease onset, slowing down progression or preserving brain function.

Brain injury after cardiac arrest (CA) is a major cause of death and disability, with neuroinflammation increasingly recognized as a key driver. Although the sphingosine-1-phosphate receptor 3 (S1PR3)-a G protein-coupled receptor-has been linked to neurological disorders, its role in CA-induced brain injury remains unclear. We induced CA in mice via intravenous potassium chloride injection. S1PR3 expression and subcellular localization were assessed in cortex and hippocampus. Mice received intraperitoneal CAY10444 (a selective S1PR3 antagonist) alone or with Colivelin TFA (a Janus Kinase 2 (JAK2)/Signal Transducer and Activator of Transcription 3 (STAT3) agonist). Survival after return of spontaneous circulation (ROSC) was recorded. Neurological function was evaluated using neurological deficit score, rotarod, adhesive removal, and novel object recognition tests. Brain pathology was examined by H&E, Nissl, immunohistochemistry, and Golgi staining. Microglial and astrocyte activation were quantified by immunohistochemistry; IL-1β, TNF-α, and IL-6 mRNA levels were measured; and JAK2/STAT3 pathway activity was assessed by Western blot for p-JAK2 and p-STAT3. CA/CPR upregulated S1PR3 in the brain and increased its co-localization with neurons and glia. CAY10444 improved survival and all behavioral outcomes. It reduced neuronal loss, axonal damage, dendritic spine loss, and suppressed microglial and astrocytic activation in the hippocampus. CAY10444 also lowered IL-1β, TNF-α, and IL-6 expression and decreased CA-induced JAK2/STAT3 phosphorylation. Colivelin TFA partially reversed these benefits. CAY10444 confers neuroprotection after CA/CPR by inhibiting S1PR3 and downstream JAK2/STAT3 signaling, thereby dampening neuroinflammation and neuronal death. S1PR3 is therefore a promising therapeutic target for CA-induced brain injury.

Among heavy metals, cadmium (Cd²⁺) is the most widespread pollutant, exhibiting pronounced neurotoxicity and exacerbating neurodegenerative diseases. Even at nanomolar concentrations in plasma, Cd²⁺ increases the risk of multiple disorders. The mechanisms underlying the detrimental effects of nanomolar Cd²⁺ on the nervous system are far from fully understood. Using microelectrode recordings and fluorescence approaches, we investigated the effects of low Cd²⁺ concentrations on acetylcholine release and redox balance at the mouse neuromuscular junction. Similar to voltage-gated Ca²⁺ channel blockers, Cd²⁺ (≥ 100 nM) suppressed evoked neurotransmitter release, but at a concentration of 20 nM Cd²⁺ selectively desynchronized exocytotic events. The latter effect was completely prevented by general (N-acetyl-L-cysteine) and mitochondrial (mitoTEMPO) antioxidants, but not by a TRPV1 antagonist. Cd²⁺ (20 nM) markedly increased reactive oxygen species (ROS) production, which was accompanied by lipid peroxidation and was blocked by mitoTEMPO. An NADPH oxidase inhibitor, VAS 2870 had no effect on Cd²⁺-dependent elevation of ROS levels. Zn²⁺ at nanomolar concentration completely prevented both the Cd²⁺-induced desynchronization of neurotransmitter release and the associated increase in ROS production. At the same time, nanomolar Zn²⁺ itself did not affect either the timing of acetylcholine release or redox status. Thus, Cd²⁺ at a nanomolar concentration disturbs the synchrony of evoked exocytotic events at the mouse neuromuscular synapse by enhancing mitochondrial ROS production. Zn²⁺ might be considered as an effective modulator of the synaptotoxicity of low-level Cd²⁺ exposure.

Leucine is an essential amino acid which is imported into the brain parenchyma with high capacity. Animal studies have demonstrated that leucine plays a significant role in several cellular and physiological processes in brain parenchyma. In addition to its role in protein synthesis, leucine possesses signaling and regulatory functions. Furthermore, leucine catabolism may provide brain cells with amino nitrogen for the synthesis of glutamate and glutamine with an impact on sustaining glutamatergic and GABA-ergic neurotransmission. The entry of leucine's carbon skeleton into the intermediary metabolism of astrocytes yields the production of ketone bodies and acetyl-CoA. In order to investigate the metabolic capabilities of human astrocytes regarding leucine, we enriched their culture media with ¹³C₆,¹⁵N-leucine and conducted a metabolomic study using liquid chromatography-mass spectrometry (LC-MS) to identify and quantify isotopically labelled metabolites. Furthermore, we employed an antiserum against 3-methylcrotonyl-CoA carboxylase (MCC), the unique enzyme in the irreversible phase of leucine catabolism, to identify MCC-expressing cells both in culture and in situ. Our results indicate that cultured human astrocytes efficiently removed leucine from the medium, which was then enriched with several compounds containing nitrogen and/or carbon atoms derived from leucine. Among the released metabolites, glutamine and citrate were the most abundant. Leucine uptake was independent of glucose concentration; however, hyperglycemic conditions stimulated the capacity for the irreversible catabolism of the leucine-derived carbon skeleton. Immunoprobing with the MCC antiserum confirmed the mitochondrial expression of MCC in astrocytes in culture as well as in situ. In addition to astrocytes, immunofluorescent double-labelling revealed the colocalization of MCC with a neuronal marker in human brain sections. This study confirms that human astrocytes are capable of catabolizing leucine and incorporating leucine-derived atoms into the intermediary metabolism. The presence of MCC in cultured astrocytes underscores their ability to convert leucine into acetyl-CoA and ketone bodies. Additionally, MCC expression in astrocytes and neurons present in brain parenchyma suggests that these cells are enzymatically equipped to catabolize leucine into compounds entering their cellular metabolism.

Glioblastoma (GBM), a highly aggressive primary brain tumor, presents substantial treatment challenges due to its resistance to genotoxic therapies and frequent recurrence. Oncogenic alterations significantly impact lipid metabolism in GBM cells. G Protein-Coupled Receptor 40 (GPR40), a receptor for polyunsaturated fatty acids (PUFAs), plays a key role in neural development and neurogenesis. Additionally, ferroptosis induction in GBM relies on PUFA peroxidation within cell membranes. Considering the persistent oxidative stress in the central nervous system, aberrant GPR40 activation in glioma lipid metabolism might suppress ferroptosis, thus contributing to chemotherapy resistance. Transcriptomic analysis of TCGA data revealed upregulated GPR40 expression in malignant gliomas, alongside alterations in ferroptosis-related and drug resistance pathways. To model GBM temozolomide (TMZ) resistance, a TMZ-resistant GL261 cell line was established. Additionally, key ferroptosis markers, including iron metabolism, lipid peroxidation, and glutathione levels, as well as TMZ treatment sensitivity, were assessed. Our findings confirm that GPR40 reduces glioma sensitivity to TMZ chemotherapy by inhibiting ferroptosis. These results highlight the GPR40-ferroptosis regulatory axis as a potential therapeutic target to enhance ferroptosis-induced treatment and overcome TMZ chemotherapy resistance in GBM.

The research on the pathoetiology of vascular dementia (VaD) highlights a notable deficiency in effective therapies within present medical practices. Morin exhibits promising therapeutic benefits due to its strong antioxidant and anti-inflammatory properties. However, its specific functions and mechanisms in VaD require further elucidation. In this study, VaD animals were established by permanent bilateral common carotid artery occlusion (2VO). Cognitive functions and behavioral analysis were performed in rats. Moreover, the state of oxidative stress, inflammation, and apoptosis was evaluated. Western blotting and ELISA were performed to investigate synaptic plasticity-related proteins, such as SYP, PSD-95, and NMDA receptor proteins (NR1, NR2A, NR2B). The results revealed that morin reduced oxidative stress in the hippocampus by lowering MDA and recombinant reactive oxygen species modulator 1 (Romo-1) levels, while simultaneously enhancing the activities of SOD and GPx. In addition, morin increased the levels of anti-inflammatory cytokines (IL-10 and IL-4), while reducing the levels of pro-inflammatory cytokines (IL-1β and IL-6), and suppressed apoptosis through downregulation of caspase 3 and upregulation of BCL-2. Additionally, morin promoted the expression of PSD95, SYP, and NMDAR proteins in animals with VaD. The obtained data suggest that morin is associated with improved cognitive impairments in VaD rats, which may be mediated by the reduction of apoptosis, oxidative stress, and inflammation in the hippocampus, as well as by restoring the signaling of NMDARs.