Jujuboside A ameliorates cognitive deficiency in delirium through promoting hippocampal E4BP4 in mice

JuA protects against delirium-associated cognitive impairment through promoting hippocampal E4BP4 in mice. Our findings are of great significance to the drug development of JuA against delirium and related disorders.

Delirium models of mice were established by injecting lipopolysaccharide (LPS) plus midazolam and implementing a jet lag protocol. Novel object recognition test and Y maze test were used to evaluate the effects of JuA on delirium-associated cognitive impairment. The mRNA and protein levels of relevant clock factors and inflammatory factors were measured by qPCR and Western blotting. Hippocampal Iba1+ intensity was determined by immunofluorescence staining. Key findings: JuA ameliorated delirium (particularly delirium-associated cognitive impairment) in mice, which was proved by the behavioural tests, including a preference for new objects, an increase of spontaneous alternation and improvement of locomotor activity. Furthermore, JuA inhibited the expression of ERK1/2, p-p65, TNFα and IL-1β in hippocampus, and repressed microglial activation in delirious mice. This was attributed to the increased expression of E4BP4 (a negative regulator of ERK1/2 cascade and microglial activation). Moreover, loss of E4bp4 in mice abrogated the effects of JuA on delirium as well as on ERK1/2 cascade and microglial activation in the hippocampus of delirious mice. Additionally, JuA treatment increased the expression of E4BP4 and decreased the expression of p-p65, TNFα and IL-1β in LPS-stimulated BV2 cells, supporting a protective effect of JuA on delirium. Conclusions: JuA protects against delirium-associated cognitive impairment through promoting hippocampal E4BP4 in mice. Our findings are of great significance to the drug development of JuA against delirium and related disorders.

Delirium (acute brain syndrome) is a common and serious neuropsychiatric disorder characterized by an acute decline in cognitive function. However, there is no effective treatment clinically. Here we investigated the potential effect of jujuboside A (JuA, a natural triterpenoid saponin) on cognitive impairment in delirium.