timosaponin-b-ii and Alzheimer-Disease

Alzheimer's disease (AD) is a common and severe brain disease with a high mortality among the elders, but no highly efficient medications are currently available. For example, timosaponin BII, an efficient anti-AD agent, has low oral bioavailability. Here, timosaponin BII was formulated in a temperature/ion-sensitive in situ hydrogel (ISG) that was well transformed into gels in the nasal environment. Timosaponin BII protected the PC12 cells injured by lipopolysaccharides (LPS) by decreasing TNF-α and IL-1β and stabilizing F-actin. Timosaponin BII ISGs were intranasally administered to the mice every day for 38 days. On Day 36, LPS was injected to the mice to establish an AD model. Morris water maze experiments showed that the number of the animals that were able to cross the platform returned to normal and the total distance over which the animals moved in the open field also increased, which demonstrated that the spatial memory and spontaneous behavior were improved after treatment compared to the model. Moreover, an AD improver, inducible nitric oxide synthase (iNOS) in the brain, was reduced after treatment. High brain targeting effect of timosaponin BII ISGs was confirmed by in vivo fluorescence imaging. The nasal timosaponin BII dually sensitive ISGs can serve as a promising medication for local prevention of AD.

Topics: Administration, Intranasal; Alzheimer Disease; Animals; Anura; Cell Line, Tumor; Female; Hydrogels; Interleukin-1beta; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type II; Nose; PC12 Cells; Rabbits; Rats; Saponins; Sheep; Steroids; Tumor Necrosis Factor-alpha

Our previous studies indicated that oxidative stress up-regulated the expression of β-amyloid precursor protein cleavage enzyme-1 (BACE1) in rat retina. Pharmacological reports have shown Timosaponin-BII, a purified extract originating from Chinese medical herb Rhizoma Anemarrhenae, is characterized as an antioxidant. Our present study aimed to determine whether Timosaponin-BII affected the expression of BACE1, β-amyloid precursor protein cleavage production of Aβ1-40 and β-C-terminal fragment (β-CTF) in rat retina, which were pre-treated with the oxidizing agent (solution of FeCl₃).. Few distinctions of BACE1 distribution were observed among all groups (normal control group, model group, Timosaponin-BII treated and vehicle control groups). Rat retinas in model group and vehicle control group manifested an apparent up-regulation of BACE1 expression. Meanwhile, the level of malonaldehyde (MDA), Aβ1-40 and β-CTF were increased. However, when comparing with the vehicle control group, the retinas in Timosaponin-BII treated group showed significantly less BACE1 (p<0.05) and accumulated less Aβ1-40 or β-CTF (p<0.05). It also showed significantly decreased level of MDA (p<0.05) and prolonged partial thromboplastin time (p<0.05).. Our data suggested that Timosaponin-BII remarkably inhibited the up-regulation of BACE1 and reduced the over-production of β-CTF and Aβ in rat retina, which was induced by FeCl₃. The mechanism of Timosaponin-BII on BACE1 expression may be related to its antioxidant property.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Anemarrhena; Animals; Antioxidants; Chlorides; Disease Models, Animal; Drugs, Chinese Herbal; Ferric Compounds; Male; Malondialdehyde; Oxidative Stress; Partial Thromboplastin Time; Phytotherapy; Rats; Rats, Sprague-Dawley; Retina; Rhizome; Saponins; Steroids; Up-Regulation