Tangeretin prevents cognitive deficit in delirium through activating RORα/γ-E4BP4 axis in mice
Min Chen1, Yifei Xiao2, Fugui Zhang2
1College of Pharmacy, Jinan University, Guangzhou, China; Institute of Molecular Rhythm and Metabolism, Guangzhou University of Chinese Medicine, Guangzhou, China.
Abstract:
Delirium is a common and serious neuropsychiatric syndrome characterized with acute cognitive and attentional deficits, however, the effective therapies are lacking. Here, using mouse models of delirium, we investigated the effects of tangeretin (TAN, a natural flavonoid) on cognitive impairment by assessing object preference with novel object recognition (NOR) test and spontaneous alternation with Y maze test. We found that TAN, as a RORα/γ agonist, prevented cognitive decline in delirious mice as evidenced by a normal novel object preference and increased spontaneous alternation. This was accompanied by decreased expression of ERK1/2, TNFα and IL-1β as well as diminished microglial activation in delirious mice. The protective effect of TAN on delirium was mainly attributed to increased hippocampal E4BP4 expression (a known target of RORs and a regulator of cognition in delirium through modulating the ERK1/2 cascade and microglial activation) via activation of RORα/γ. In addition, TAN treatment modulated the expression of RORα/γ target genes (such as E4bp4 and Bmal1) and inhibited the expression of TNFα and IL-1β in lipopolysaccharide (LPS)-stimulated cells, supporting a beneficial effect of TAN on delirium. In conclusion, TAN is identified as a RORα/γ agonist which promotes E4BP4 expression to prevent cognitive decline in delirious mice. Our findings may have implications for drug development of TAN for prevention and treatment of various diseases associated with cognitive deficiency.
Insights
Tangeretin (TAN), a natural flavonoid, prevents cognitive decline in delirium by activating RORα/γ. This natural compound reduces neuroinflammation and increases E4BP4 expression, offering potential therapeutic benefits for cognitive deficits.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Delirium is a prevalent neuropsychiatric syndrome marked by acute cognitive and attentional deficits.
- Effective therapeutic interventions for delirium remain limited, highlighting the need for novel treatment strategies.
Purpose of the Study:
- To investigate the potential of tangeretin (TAN), a natural flavonoid, in ameliorating cognitive impairment associated with delirium.
- To elucidate the molecular mechanisms underlying TAN's effects, focusing on its role as a RORα/γ agonist.
Main Methods:
- Utilized mouse models of delirium to assess cognitive function using the novel object recognition (NOR) test and Y maze test.
- Analyzed the expression of key proteins (ERK1/2, TNFα, IL-1β, E4BP4, Bmal1) and assessed microglial activation.
- Investigated TAN's effects on lipopolysaccharide (LPS)-stimulated cells to further understand its anti-inflammatory properties.
Main Results:
- Tangeretin (TAN) treatment prevented cognitive decline in delirious mice, normalizing novel object preference and increasing spontaneous alternation.
- TAN administration led to decreased expression of ERK1/2, TNFα, and IL-1β, along with reduced microglial activation.
- The protective effects were attributed to TAN's ability to increase hippocampal E4BP4 expression via RORα/γ activation, modulating the ERK1/2 cascade and neuroinflammation.
Conclusions:
- Tangeretin (TAN) acts as a RORα/γ agonist, enhancing E4BP4 expression to protect against cognitive deficits in delirium.
- TAN demonstrates anti-inflammatory effects by inhibiting TNFα and IL-1β expression.
- These findings suggest tangeretin holds promise for the development of novel therapeutics for delirium and other cognitive disorders.
