Inhibition Of Cholinesterase By Octahydroaminoacridine Succinate

Alzheimer's Disease (AD) is a progressive neurodegenerative disease which is common among the elderly. AD is the fourth leading cause of the death afer cancer, cardiopathy and cardiovascular disease. Acetylcholinesterase (AChE) hydrolyzes acetylcholine and decreases the level of acetylcholine in the brain. The rationale for the use of Cholinesterase inhibitors is to inhibit AChE activity and thereby increase the available pool of the neurotransmitter acetylcholine. Cholinesterase consists of two forms: Acetylcholinesterase and Butyrylcholinesterase (BuChE). Recent evidence has confirmed that BuChE is also able to hydrolyze acetylcholine, but the efficiency is much lower. The role for AChE and its inhibition in AD has long been accepted, but it's reported that BuChE also plays an important role in the process of AD. While AChE activity decreases progressively in the brain of AD patients, BuChE activity remains unchanged or shows some increase. Findings from preclinical experiments and clinical trials have placed BuChE as an important contributor to the occurrence, symptoms, progression and reponses to treatment in dementia. In a word, inhibition of BuChE may bring us the additional benefit. Recent evidence indicates that cholinesterases may be involved in the pathogenesis of plaques. Both AChE and BuChE promote the aggregation of Aβand increase the toxcity of Aβ. The inhibition of Cholinesterases can decrease the toxcity of Aβand interfere with the production of Aβ. Current therapy for AD is mainly symptomatic treatment with AChE inhibitors. This approach does provide some short-term cognitive improvement, but does not prevent or delay the onset of the disease.Octahydroaminoacridine Succinate (OS) is a novel synthesized cholinesterase inhibitor(ChEI). The purpose of our study is to determine the inhibitory ability and the inhibition mechanism of OS against cholinesterase. The measuring method for cholinesterase activity is set up. The Michaelis-Menten constant(Km) for the hydrolysis of acetylthiocholine iodide was found to be 0.133mM , which is consistent with the result reported. This proves that our method used is rational. Through this method we obtain the IC50 values for OS in inhibiting AChE and BuChE activity. The IC50 values for the other known ChEI such as Tacrine, Donepezil and Huperzine A are also obtained. Analyzing these results, we arrive at a conclusion that the inhibition ability of OS against cholinesterase is similar to that of Tacrine. OS has no selective inhibition of AChE activity, but selectively inhibits BuChE activity. Because more and more evidence demenstrates the important role of BuChE in AD, OS may represent the excellent theapy strategy for the treatment of AD.We also make a close study of the inhibition nature of OS against cholinesterase. Lineweaver-Burk plots and Dixon plots indicate the nature of the inhibition of OS against AChE is of mixed but predominantly competitive type. Cornish-Bowden plots and Hanes-Woolf plots also indicate the same nature, which provides the further evidence. The nature of the inhibition of OS against BuChE is of mixed but predominantly competive type too. The four different plots are used to determine the nature of the inhibition and the results of these plots reach the same conclusion: the nature of the inhibition of OS against cholinesterase is of mixed but predominantly competitive type.Results of the enzymatic kinetics serve as the fundation of he following work including cell experiment, animal experimnent and clinical trials. Tacrine is a reversible and nonselective AChE inhibitor. It is prone to penetrate blood-brain barrier. Tacrine is capable of improving the cognitive ability and daily living activity of patients suffered from AD. Because of its side effect on liver it is less used clinically. The chemical structure of OS is related to that of Tacrine, but it is improved a lot. This may make OS an efficent drug with the potent effect as Tacrine but without the toxity to liver. Preclinical animal trials have proved that OS doesn't have side effect on liver. OS has hope of becoming one of the next generation effective drugs in the treatment of AD.