ABSTRACT
In the brains of patients with Alzheimer's disease (AD) and transgenic AD mouse models, astrocytes and microglia activated by amyloid-ß (Aß) contribute to the inflammatory process that develops around injury in the brain. Valproic acid (VPA) has been shown to have anti-inflammatory function. The present study intended to explore the therapeutic effect of VPA on the neuropathology and memory deficits in APPswe/PS1ΔE9 (APP/PS1) transgenic mice. Here, we report that VPA-treated APP/PS1 mice markedly improved memory deficits and decreased Aß deposition compared with the vehicle-treated APP/PS1 mice. Moreover, the extensive astrogliosis and microgliosis as well as the increased expression in interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in the hippocampus and cortex of APP/PS1 transgenic mice were significantly reduced following administration of VPA, which attenuated neuronal degeneration. Concomitantly, VPA alleviated the levels of p65 NF-κB phosphorylation and enhanced the levels of acetyl-H3, Bcl-2, and phospho-glycogen synthase kinase (GSK)-3ß that occurred in the hippocampus of APP/PS1 transgenic mice. These results demonstrate that VPA could significantly ameliorate spatial memory impairment and Aß deposition at least in part via the inhibition of inflammation, suggesting that administration of VPA could provide a therapeutic approach for AD.
Subject(s)
Alzheimer Disease/complications , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Memory Disorders/complications , Memory Disorders/drug therapy , Valproic Acid/therapeutic use , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Animals , Astrocytes/drug effects , Astrocytes/metabolism , Astrocytes/pathology , Brain/drug effects , Brain/metabolism , Brain/pathology , Cell Death/drug effects , Cytokines/genetics , Cytokines/metabolism , Histones/metabolism , Humans , Immunohistochemistry , Memory Disorders/genetics , Memory Disorders/pathology , Mice, Transgenic , Microglia/drug effects , Microglia/metabolism , Microglia/pathology , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Presenilin-1/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Spatial Learning/drug effects , Valproic Acid/pharmacologyABSTRACT
BACKGROUND: Snake venom contains a number of components with different pharmacological and biological activities, especially in cancer therapy, and has increasingly become a research focus. This study was designed to isolate and purify a novel anti-clotting protein component from the venom of Agkistrodon acutus, and to explore its physico-chemical properties and biological activity. METHODS: The venom of Agkistrodon was isolated and purified by ion-exchange chromatography on diethylaminoethyl (DEAE)-Sepharose Fast Flow, molecular sieve filtration through Sephadex G75, SP-Sepharose Fast Flow and molecular sieve filtration through Sephadex G50. We detected the activated partial thromboplastin time (APTT) of the eluant to select the anti-clotting protein component of interest. The molecular weight was determined by sodium dodecyl sulfate-polyacrylamid gel electrphoresis (SDS-PAGE) and liquid chromatography. Its protein content was detected by bicinchoninic acid (BCA). RESULTS: SDS-PAGE vertical gel electrophoresis showed that the anticoagulant factor is a tripolymer composed of three proteins whose molecular weights are 25 KDa, 30 KDa and 50 KDa. The factor contains about 65% percent protein. CONCLUSIONS: A novel anti-clotting protein component was purified by ion-exchange chromatography and molecular sieve filtration from the venom of Agkistrodon acutus and was found to be composed of three kinds of proteins.
