Dehydroevodiamine attenuates tau hyperphosphorylation and spatial memory deficit induced by activation of glycogen synthase kinase-3 in rats.

Tau hyperphosphorylation and memory deficit are characteristic alterations of Alzheimer's disease (AD), and glycogen synthase kinase-3 (GSK-3) plays a crucial role in these AD-like changes. We have reported that activation of GSK-3 through ventricular injection of wortmannin and GF-109203X (WT/GFX, 100 microM each) induces tau hyperphosphorylation and memory impairment of rats [Liu, S.J. et al., 2003. Overactivation of glycogen synthase kinase-3 by inhibition of phosphoinositol-3 kinase and protein kinase C leads to hyperphosphorylation of tau and impairment of spatial memory. J. Neurochem. 87, 1333-1344]. By using this model, we explored in the present study the effects of dehydroevodiamine (DHED), a quinazoline alkaloid isolated from Evodia rutaecarpa Bentham, on the memory retention, tau phosphorylation and the activity of GSK-3. We found that pre-administration of DHED through vena caudalis for 1 week efficiently improved the WT/GFX-induced spatial memory retention impairment of the rats; it also antagonized tau hyperphosphorylation at multiple AD sites and arrested the overactivation of GSK-3 induced by WT/GFX. Our study gave the first in vivo evidence that DHED could suppress the overactivation of GSK-3 and improve tau hyperphosphorylation and spatial memory deficit of the rats, suggesting that this chemical may be served as a candidate for arresting AD-like pathological and behavioral alterations.