Xanthoceraside attenuates tau hyperphosphorylation and cognitive deficits in intracerebroventricular-streptozotocin injected rats

Rationale Xanthoceraside, a novel triterpenoid saponin extracted from the fruit husks of Xanthoceras sorbifolia Bunge, reverses cognitive deficits in intracerebroventricular injection of A beta 25-35 or A beta 1-42 mice. However, whether xanthoceraside has a positive effect on hyperphosphorylated tau protein remains unclear. We investigated the effects of xanthoceraside on behavioural impairments induced by intracerebroventricular injection of streptozotocin (STZ) in rats and its potential mechanisms. The rats were administered with xanthoceraside (0.06, 0.12 or 0.24 mg/kg) or vehicle once daily after STZ intracerebroventricular injections. The Y-maze test and novel object recognition test were performed 21 and 22 days after the second STZ injection, respectively. The levels of hyperphosphorylated tau, phosphatidylinositol-3-kinase (PI3K)/serine/threonine protein kinase B (Akt), glycogen synthase kinase-3 beta (GSK-3 beta), protein phosphatase 1 (PP-1) and protein phosphatase 2A (PP-2A) were also tested by Western blot. Xanthoceraside treatment significantly attenuated learning and memory impairments and reduced the level of STZ-induced hyperphosphorylated tau protein. Xanthoceraside also enhanced PP-2A and PP-1 expressions, increased PI3K (p85) and Akt (Ser473) phosphorylation and decreased GSK-3 beta (tyr216) phosphorylation. Xanthoceraside has protective effect against learning and memory impairments and inhibits tau hyperphosphorylation in the hippocampus, possibly through the inhibition of the PI3K/Akt-dependent GSK-3 beta signalling pathway and an enhancement of phosphatases activity.