Ursolic acid and its isomer oleanolic acid are responsible for the anti-dementia effects of Ocimum sanctum in olfactory bulbectomized mice

This study aims to clarify the bioactive constituents responsible for the anti-dementia effects of Ocimum sanctum Linn. ethanolic extract (OS) using olfactory bulbectomized (OBX) mice, an animal model of dementia. The effects of OS or its extract further fractionated with n-hexane (OS-H), ethyl acetate (OS-E), and n-butanol (OS-B) on the spatial cognitive deficits of OBX mice were elucidated by the modified Y-maze tests. The effects of the major constituents of the most active OS fraction were also elucidated using the reference drug donepezil. The administration of OS and OS-E ameliorated the spatial cognitive deficits caused by OBX, whereas OS-H or OS-B had no effect. Two major constituents, ursolic acid (URO) and oleanolic acid (OLE), and three minor constituents were isolated from OS-E. URO (6 and 12 mg/kg) and OLE (24 mg/kg) attenuated the OBX-induced cognitive deficits. URO (6 mg/kg) and donepezil reversed the OBX-induced down-regulation of vascular endothelial growth factor (VEGF) and choline acetyltransferase expression levels in the hippocampus. URO inhibited the ex vivo activity of acetylcholinesterase with similar efficacy to donepezil. URO inhibited the in vitro activity of acetylcholinesterase (IC50 =106.5 mu M), while the effects of OS, OS-E, and other isolated compounds were negligible. These findings suggest that URO and OLE are responsible for the anti-dementia action of OS extract, whereas URO possesses a more potent anti-dementia effect than its isomer OLE. The effects of URO are, at least in part, mediated by normalizing the function of central cholinergic systems and VEGF protein expression. [GRAPHICS] .