Timosaponin AIII, a saponin isolated from Anemarrhenaasphodeloides, ameliorates learning and memory deficits in mice

Anemarrhenaasphodeloides Bunge (AA, family Liliaceae), which primarily contains xantones, such as mangiferin, and steroidal saponins, such as timosaponin AIII and sarsasapogenin, has been used as an anti-pyretic, anti-inflammatory, anti-diabetic, anti-platelet aggregation, and anti-depressant agent in traditional Chinese medicine. In the present study, the memory-enhancing effects of these saponins were investigated in scopolamine-treated mice. Among saponins, timosaponin AIII (TA3) significantly reversed the scopolamine-induced deficits in a passive avoidance test and in the Morris water maze test. TA3 also increased hippocampal acetylcholine levels in scopolamine-treated mice and dose-dependently inhibited acetylcholinesterase (AChE) activity (IC50 value, 35.4 μM). When TA3 (50 mg/kg) was orally administered to mice and its blood concentration was measured by liquid chromatography and tandem mass spectrometry, the Cmax of TA3 occurred 4–6 h after TA3 treatment. The memory-enhancing effect of TA3 was greater when it was administered 5 h before the acquisition trial than 1 h before. Scopolamine treatment in mice increased brain levels of TNF-α and IL-1β expression. However, treatment with TA3 and scopolamine inhibited the increase of TNF-α and IL-1β expression. These results suggest that scopolamine may cause learning and memory deficits that are further complicated by inflammation. TA3 also inhibited the activation of NF-κB signaling in BV-2 microglia and in SK-N-SH neuroblastoma cells induced with TNF-α or scopolamine. Nevertheless, TA3 may ameliorate memory deficits, mainly by inhibiting AChE.