Tangeretin ameliorates sepsis-induced neurocognitive impairment in adult male mice by suppressing Akt-driven glycolytic reprogramming and neuroinflammation.
TL;DR
Tangeretin mitigates sepsis-associated neuroinflammation and cognitive impairment by targeting microglial Akt signalling and restraining glycolytic reprogramming and these data support tangeretin as a mechanistically informed candidate for adjunctive therapy in sepsis-related neurocognitive dysfunction.
Abstract
Background
AND
Purpose
Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, frequently leads to long-term cognitive impairment. Tangeretin, a polymethoxylated citrus flavonoid, has neuroactive and anti-inflammatory properties. We investigated whether tangeretin protects against sepsis-associated neurocognitive deficits and delineated the underlying mechanisms, focusing on Akt signalling and microglial metabolism. EXPERIMENTAL APPROACH Sepsis was induced by caecal ligation and puncture in mice. Tangeretin (15 or 30 mg·kg-1·day-1, intraperitoneal) was initiated immediately after surgery and maintained throughout the study. Cognitive function was assessed by Morris water maze and novel object recognition. Hippocampal microglial activation and neuroinflammation were quantified. In vitro, BV2 cells and primary microglia were exposed to lipopolysaccharide (LPS, 1 μg·ml-1) with/without tangeretin (40 μM) to measure cytokine production, migration and Akt activity. Direct tangeretin-Akt interaction was tested by surface plasmon resonance and cellular thermal shift assay. Metabolic readouts focused on glycolysis. KEY
Results
Tangeretin improved sepsis-induced cognitive deficits, decreased hippocampal microglial activation, and lowered proinflammatory cytokine levels and microglial migration. It exerted anti-inflammatory effects via inhibition of the Akt pathway, and pharmacological Akt activation blocked these effects. Surface plasmon resonance and cellular thermal shift assay showed hat tangeretin binds Akt. Metabolically, tangeretin reduced LPS-induced glycolysis (decreased extracellular acidification rate and glycolytic capacity), consistent with diminished Akt phosphorylation and microglial activation.
Conclusion
AND IMPLICATIONS Tangeretin mitigates sepsis-associated neuroinflammation and cognitive impairment by targeting microglial Akt signalling and restraining glycolytic reprogramming. These data support tangeretin as a mechanistically informed candidate for adjunctive therapy in sepsis-related neurocognitive dysfunction.