Study of Neuroprotective Effect of Cryptotanshinone, an Acetylcholinesterase Inhibitor, in Cell and Animal Models.

摘要

Alzhemier’s disease (AD) is a common form of dementia which is characterized by the deposition of amyloids in affected neurons and a cholinergic neurotransmission deficit in the brain. Current therapeutic intervention for AD is primarily based on inhibition of brain acetylcholinesterase (AChE) to restore the brain acetylcholine level. Cryptotanshinone (CT) is a diterprene which is extracted from the root of Salvia miltiorrhiza, an herb that is commonly prescribed in Chinese medicine to treat cardiovascular disease. The present study is aimed at verifying CT’s property as an AChE inhibitor using different models. By AChE activity assay, CT was found to be a dual inhibitor which inhibits both human acetylcholinesterase (AChE) and butylcholinesterase (BuChE) with similar IC50. CT inhibited human AChE in a reversible manner, and the inhibition showed the characteristics of mixed-type. To human BuChE, CT is an uncompetitive inhibitor. CT can also inhibit AChE from rat cortical neurons. Apart from AChE inhibition, CT was demonstrated to have ameliorating effect on glutamate excitotoxicity, which is a cause of neuron death in AD. Further study showing that CT treatment can reduce cellular tau phosphorylation, which is the downstream effector of glutamate-induced excitotoxicity. In animal model, the effect of CT on learning impairment in scopolamine-treated rats was also evaluated by the acquisition protocol of Morris water maze. The task learning ability of scopolamine-treated rats was significantly reversed by CT, and the CT-fed rats were able to develop spatial searching strategy comparable to the control animals. Chronic administration of CT at effective doses did not cause significant hepatotoxicity. Cholinergic side effect of muscle weakness was not observed in CT treated rats. On the contrary CT was found to increase the locomotor activity of NIH mice in forced swimming test through reducing the lactic acid in the circulation. Data in this study gives further support on CT’s potential as a therapeutic drug for treating AD.