Neurochemistry international最新文献

To investigate the role of GDF11 in acute neural trauma, this study focused on the effects of GDF11 on pericytes and the blood-spinal cord barrier (BSCB) following spinal cord injury (SCI). We established a mouse SCI model and administered GDF11 infusion for three consecutive days. Spinal cord samples were collected early after injury, and the integrity of the BSCB was evaluated using pathomorphological analysis, Western blotting, immunofluorescence, and transmission electron microscopy. The results demonstrated that GDF11 infusion significantly reduced BSCB damage at 7 days post-SCI, as evidenced by improved intercellular junction integrity and enhanced pericyte coverage. Since neurovascular communication is a critical function of the BSCB, we further assessed neuronal survival and myelin sheath integrity across different groups. In addition, we isolated primary central nervous system microvascular pericytes and simulated SCI through oxygen-glucose deprivation (OGD) culture, with and without GDF11 treatment and its critical receptor TGF-β receptor (TGFR) antagonist, ACE-536. The viability and migration ability of pericytes in each group were evaluated by flow cytometry and migration assays. We found that the GDF11/TGFR/SMAD3 signaling pathway mediates the beneficial effects of GDF11 on SCI. As functional recovery is a key measure of clinical outcome following SCI, behavioral assessments were performed at later stages. Our results showed that early GDF11 infusion significantly improved functional recovery, as demonstrated by enhanced gait performance and increased swimming scores. In conclusion, early post-SCI GDF11 infusion targeting pericytes to regulate BSCB integrity may offer a promising therapeutic approach for SCI recovery.

Multiple factors contribute to the physiopathology of inflammatory bowel diseases (IBD) and the enteric nervous system is emerging as a key player in this context. In particular, enteric glial cells (EGCs) share very similar properties with central astrocytes, play a homeostatic function under basal conditions, but can be activated by inflammatory stimuli further contributing to mucosal damage. Calcineurin (CN) is an important mediator of astrocyte inflammation and has been described also in EGCs. The aim of this study was to establish an in vitro model of EGCs challenged with an inflammatory insult to better delineate the role of CN in their inflammatory reaction and interaction with immune cells. EGCs stimulated with LPS + ATP (5 μg/mL-2 mM) for 24 h showed typical inflammatory features with increased expression of the astrocyte marker GFAP, the inflammasome component NLRP3 and the alarmin HMGB1. Inhibition of CN by cyclosporin A (CsA, 1 μM) counteracted these effects and increased the expression of nuclear HMGB1. Nuclear translocation of NF-κB p65 induced by LPS + ATP was also blunted by CsA pre-treatment. The migration of RAW 264.7 macrophages co-cultured with LPS + ATP-stimulated EGCs was enhanced, an effect prevented by CsA. This was accompanied by activation of macrophages to a pro-inflammatory phenotype, as shown by increased COX-2, IL-1β and TNF-α gene expression. Inhibition of CN in EGCs reduced this response while increasing the phagocytic capacity of macrophages. Altogether the results here reported identify a central role for CN in the inflammatory response of EGCs and their crosstalk with cells of the immune system, supporting potential new sites of intervention for drugs targeting CN.

Background: Influenza A virus (IAV), although primarily a respiratory pathogen, is increasingly recognized to affect central nervous system (CNS) function. Astrocytes are key regulators of neurochemical homeostasis and neuroinflammation, but the molecular pathways underlying their response to IAV remain incompletely defined.

Methods: Primary rat astrocytes were infected with wild-type IAV (PR8, H1N1) or PB1-F2-deficient IAV (PB1-F2[-]). Regulation of the plasminogen activator inhibitor-1 (PAI-1)/tissue-type plasminogen activator (tPA) system was examined by qPCR, Western blotting, zymography, and ELISA. ERK pathway activation was assessed using phospho-specific antibodies, and pathway dependency was tested using the ERK inhibitor U0126. Functional consequences on neurons were evaluated by neurite outgrowth assays using astrocyte-conditioned medium (ACM).

Results: IAV infection induced a robust increase in astrocytic PAI-1 expression and a marked reduction in tPA activity, accompanied by selective activation of ERK signaling. Pharmacological ERK inhibition completely abolished PAI-1 upregulation, indicating that ERK is required for this neurochemical shift. PB1-F2 deletion did not alter PAI-1 induction but partially modified cytokine expression profiles, demonstrating PB1-F2-independent regulation of the PAI-1/tPA axis. Compared with lipopolysaccharide (LPS), IAV elicited substantially lower cytokine levels yet induced markedly higher PAI-1 expression, suggesting a sustained antifibrinolytic phenotype. Neurons exposed to ACM from IAV-infected astrocytes exhibited reduced neurite extension and branching, indicating impaired neuronal structural development through paracrine mechanisms.

Conclusions: IAV triggers an ERK-dependent induction of PAI-1 in astrocytes, leading to suppression of tPA activity and disruption of neuronal outgrowth. These findings identify a neurochemical mechanism linking astrocyte-specific MAPK signaling to neuroinflammatory and antifibrinolytic dysfunction during viral infection.