BACKGROUND Neuroinflammation is a major contributor to cognitive dysfunction, yet the mechanisms linking inflammatory signaling to synaptic dysfunction remain incompletely understood. Kynurenic acid (KYNA), an endogenous metabolite derived from tryptophan catabolism, modulates neuronal and synaptic activity, yet its involvement in neuroinflammation-associated cognitive dysfunction remains largely unexplored. METHODS A lipopolysaccharide (LPS)-induced neuroinflammation mouse model was established to evaluate recognition memory, synaptic plasticity, and molecular changes in the hippocampus. KYNA levels and KAT2 expression were assessed, along with HMGB1/TLR4 signaling activity. Pharmacological interventions using a KAT2 inhibitor (PF04859989) and an HMGB1 antagonist (glycyrrhizic acid) were applied to dissect the mechanistic pathway. RESULTS LPS administration induced robust neuroinflammation, increased KYNA production, and impaired novel object recognition. These changes were accompanied by reduced expression of NMDAR subunits (NR2A and NR2B), decreased levels of synaptic proteins (PSD95 and vGluT1), impaired long-term potentiation, and reduced sEPSC frequency. Inhibition of KAT2 lowered KYNA levels and restored synaptic function and recognition-memory performance without affecting HMGB1/TLR4 signaling. In contrast, HMGB1 blockade suppressed neuroinflammation, decreased KAT2 expression and KYNA production, and improved synaptic plasticity. CONCLUSIONS These findings identify an HMGB1/TLR4-KAT2/KYNA-synapse axis linking neuroinflammation to recognition-memory impairment. KYNA, which is primarily synthesized in astrocytes, acts as a key downstream effector mediating synaptic dysfunction, highlighting KYNA metabolism as a potential therapeutic target for neuroinflammation-associated recognition-memory impairment.
Stroke remains the leading cause of brain injury worldwide, yet current therapeutic strategies primarily focus on restoring cerebral blood flow and do not directly target the brain parenchyma. Ischemic stroke, which accounts for approximately 87% of all cases, induces neuronal damage through depletion of oxygen and metabolic substrates, resulting in acidosis, inflammation, excitotoxicity, and oxidative stress. Carbon monoxide (CO) is an endogenous gasotransmitter generated by heme oxygenase-mediated degradation of heme. Increasing evidence indicates that CO exerts cytoprotective effects by attenuating inflammation and preventing cell death in multiple tissues, including the brain. Previous studies in the mouse middle cerebral artery occlusion (MCAo) model have shown that CO administration prior to ischemia produces histological neuroprotection. The present pilot study introduces two main novelties. First, CO was administered after stroke onset, providing a more clinically relevant therapeutic framework. Second, a multimodal imaging approach was employed to characterize the effects of CO at metabolic, vascular, and anatomical levels. Neuroprotection following MCAo was evaluated using three intraperitoneal injections of the CO-releasing molecule CORM-A1 (3 mg/kg), administered 6, 24, and 48 h after reperfusion. Magnetic resonance imaging was performed at 1 and 7 days post-reperfusion, including T2-weighted and diffusion-weighted sequences, proton spectroscopy (1H-MRS), and dynamic contrast-enhanced perfusion imaging. Motor activity was evaluated by Open Field and Vertical Pole assays. Metabolite profiles obtained by 1H-MRS enabled comparison of metabolic signatures between early and later stages following MCAo. CORM-A1 treatment reduced BBB disruption and decreased the mortality rate at early phase. Thus, metabolite profiles revealed a dissociation between robust BBB protection and lack of metabolic preservation, suggesting that metabolic dysfunction occurs independently of BBB disruption. Overall, this pilot study suggests that CO may promote recovery after ischemic stroke, primarily by preserving BBB integrity and supporting brain metabolic function, but further studies are needed to confirm this effect.
