Mismatch between changes in baicalein-induced memory-related biochemical parameters and behavioral consequences in mouse

Baicalein is one of the major flavonoids originally isolated from the roots of Scutellaria baicalensis Georgi (Labiatae). Reports on baicalein-induced changes in memory-related biochemical parameters including extracellular signal-regulated kinases (ERK), Akt, cAMP response element-binding protein (CREB), and brain-derived neurotrophic factor (BDNF) have been scarce, and the action of baicalein is controversial. Baicalein promotes phosphorylation of ERK under normal conditions; on the other hand, it inhibits phosphorylation of ERK extracellularly under oxidative conditions. In the present study, we observed that baicalein (20 mg/kg, p.o.) as compared to vehicle significantly increased the expression of phosphorylated ERK (pERK), phosphorylated CREB (pCREB), and BDNF but did not increase phosphorylated Akt expression in the hippocampus of naive mice. Baicalein also significantly increased the expression of pERK and BDNF in the cortex of naive mice. However, baicalein had no effect on memory acquisition in the step-through passive avoidance task. On the contrary, baicalein (20 mg/kg, p.o.) co-injected with flumazenil (10 mg/kg, i.p.) significantly increased the retention latency in the passive avoidance task in comparison to the flumazenil-treated group, baicalein-treated group, and vehicle-treated control group. In addition, the number of platform crossings in the Morris water maze test during the probe trial session was significantly increased by co-administration of baicalein with flumazenil. Furthermore, the expressions level of BDNF was significantly increased in the baicalein with flumazenil-treated group compared to the baicalein- or flumazenil-treated groups in the hippocampus after an acquisition trial. These results suggest that the reasons why baicalein does not exert cognitive enhancement although it enhances the expression levels of pERK, pCREB, and BDNF are, in part, derived from its GABAA receptor agonistic property which is antagonized by flumazenil.

Research Highlights
► Baicalein increases the expression levels of pERK, pCREB, and BDNF.
► Baicalein alone does not alter memory performance in mice in the passive avoidance task.
► Co-administration of baicalein with flumazenil enhances the memory performances through the enhancement of ERK–CREB–BDNF signaling.