| Objective:With the increasing trend of the aging of the world population,the incidence of Alzheimer’s disease(AD)is rising year by year,and has become a major global public health problem.At present,the pathogenesis of AD is not completely clear,and there is a lack of effective therapeutic drugs.Therefore,it is particularly urgent to develop effective drugs for AD and clarify its material basis and mechanism of action in the treatment of AD.According to traditional Chinese medicine,AD belongs to the category of "senile dementia" and "collaterals disease",and the theory of "toxin damaging brain collaterals" is the key to its pathogenesis.There are many theories about the pathogenesis of AD in western medicine.Through literature research,it was found that there is a direct or indirect relationship between abnormal metabolism of aluminum ions(Al3+)in the brain and a variety of pathogenesis of AD.It is known that both emodin and chrysophanol have the effects of anti-aging and antioxidation,and can pass through the blood-brain barrier(BBB)and chelate with Al3+.Therefore,this study proposed that Al3+is the key factors leading to the production of "endogenous toxins"in AD pathogenesis of "toxin damaging brain collaterals".Emodin and chrysophanol can be used as ligands to improve the memory and behavior of AD mice induced by Al3+ by chelating excessive Al3+,so as to treat ADMethods:1.The quantum chemical computation method is used to study the coordination interaction of emodin and chrysophanol with Al3+,and to predict the coordination chemical parameters during the formation of ligands to guide the follow-up experiments2.AD mice were established by intragastric administration of AICl3(200 mg/kg),and then low-,medium-and high-dose(0.1 mg/kg,1 mg/kg,10 mg/kg)of emodin were injected intraperitoneally:(1)the growth and development of mice were observed and recorded every day,(2)the memory and behavior changes of mice before and after administration were detected by Morris water maze,(3)the changes of biological indexes of acetylcholinesterase(AChE),superoxide dismutase(SOD)and malondialdehyde(MDA)in mice brain before and after administration were determined by kit method,and(4)the contents of aluminum(Al)in mice brain and serum were determined by inductively coupled plasma mass spectrometry(ICP-MS).3.AD mice were established by intragastric administration of AlCl3(200 mg/kg),and then low-,medium-and high-dose(0.1 mg/kg,1 mg/kg,10 mg/kg)chrysophanol were injected intraperitoneally:(1)the growth and development of mice were observed and recorded every day,(2)the memory and behavior changes of mice before and after administration were detected by Morris water maze,(3)the changes of biological indexes of AChE,SOD and MDA in mice brain before and after administration were determined by kit method,and(4)the contents of Al in mice brain and serum were determined by ICP-MS.Results:1.The results of quantum chemical computation showed that emodin and chrysophanol can coordinate with Al3+ to form 1:1,2:1,and 3:1 complex,and the complex coordinated at 3:1 may have higher stability.2.(1)During the modeling period,compared with the blank group,the growth and development of mice in the aluminum-exposed group were worse,such as slow movement,disheveled hair and no luster,and from the third week,the body weight of mice in the aluminum-exposed group showed a significant downward trend(P<0.05).After the administration of emodin in the fifth week,the action of aluminum-exposed mice became agile and the glossiness of the hair gradually recovered.(2)The results of Morris water maze showed that compared with the blank group,the escape latency of mice exposed to aluminum was significantly longer(P<0.05)and the frequency of crossing the platform was significantly lower(P<0.05).Compared with the aluminum-exposed group,the escape latency of mice treated with different doses of emodin was decreased,while the frequency of crossing the platform was increased.(3)The results of kit test showed that compared with the blank group,the activity of SOD in the brain of aluminum-exposed group was significantly decreased(P<0.001),while the activity of AChE(P<0.05)and the content of MDA(P<0.01)were increased significantly.Compared with aluminum-exposed group,emodin high-dose group(10 mg/kg)could increase the activity of SOD(P<0.01)in mice brain,decrease the activity of AChE(P<0.001)and the content of MDA(P<0.001).Emodin medium-dose group(1 mg/kg)could increase the activity of SOD(P<0.05)in mice brain,decrease the activity of AChE(P<0.05)and the content of MDA(P<0.001).Emodin low-dose group(0.1 mg/kg)could increase the activity of SOD in mice brain,decrease the activity of AChE and the content of MDA(P<0.001).(4)The results of ICP-MS showed that the A1 contents of mice brain and serum in aluminum-exposed group were significantly higher than those in blank group(P<0.001).Compared with the aluminum-exposed group.the A1 contents of mice brain and serum in each dose of emodin groups were decreased.High-and medium-dose emodin could significantly reduce the Al contents of mice brain(P<0.001).High-dose emodin could significantly reduce the Al contents of mice serum(P<0.01).3.(1)During the modeling period,compared with the blank group,the growth and development of mice in the aluminum-exposed group were worse,such as slow movement,disheveled hair and no luster,and from the third week,the body weight of mice in the aluminum-exposed group showed a significant downward trend(P<0.01).After the administration of chrysophanol in the fifth week,the action of aluminum-exposed mice became agile and the glossiness of the hair gradually recovered.(2)The results of Morris water maze showed that compared with the blank group,the escape latency of mice exposed to aluminum was significantly longer(P<0.05)and the frequency of crossing the platform was significantly lower(P<0.01).Compared with the aluminum-exposed group,the escape latency of mice treated with different doses of chrysophanol was decreased,while the frequency of crossing the platform was increased.The results of kit test showed that compared with the blank group,the activity of SOD in the brain of aluminum-exposed mice was significantly decreased(P<0.01),while the activity of AChE(P<0.01)and the content of MDA(P<0.01)were increased significantly.Compared with aluminum-exposed group,chrysophanol high-dose group(10 mg/kg)could increase the activity of SOD(P<0.001)in mice brain,decrease the activity of AChE and the content of MDA(P<0.001).Chrysophanol medium-dose group(1 mg/kg)could increase the activity of SOD(P<0.05)in mice brain,decrease the activity of AChE and the content of MDA(P<0.001).Chrysophanol low-dose group(0.1 mg/kg)could increase the activity of SOD in mice brain,decrease the activity of AChE and the content of MDA(P<0.001).(4)The results of ICP-MS showed that the Al contents of mice brain and serum in aluminum-exposed group were significantly higher than those in blank group(P<0.001).Compared with the aluminum-exposed group,the Al contents of mice brain and serum in each dose of chrysophanol groups were decreased.High-and medium-dose chrysophanol could significantly reduce the Al contents of mice brain(P<0.001).High-dose chrysophanol could significantly reduce the Al contents of mice serum(P<0.05).Conclusions:1.Both emodin and chrysophanol could coordinate with Al3+to form 1:1,2:1,and 3:1 complex,and the complex coordinated at 3:1 may have higher stability.2.Both emodin and chrysophanol could improve the growth retardation of AD mice induced by Al and promote the growth and development of AD mice to a certain extent.3.Both emodin and chrysophanol could reduce the escape latency of mice exposed to Al in Morris water maze test and increase the frequency of mice crossing the platform.4.Both emodin and chrysophanol could protect the cholinergic system and antioxidant system of AD mice by reducing the activity of AChE,increasing the activity of SOD and reducing the content of MDA in the brain of mice exposed to Al.5.Both emodin and chrysophanol could eliminate Al to a certain extent.To sum up,both emodin and chrysophanol can improve the learning and memory of AD mice induced by AlCl3.Its mechanism may be to reduce the production of"endogenous toxins" in the brain of AD mice by chelating and excreting excessive"exogenous toxin" Al3+in mice,so as to treat AD.The successful implementation of this study can not only explain the mechanism of emodin and chrysophanol in the treatment of AD,prove the correctness of AD pathogenesis of "toxin damaging brain collaterals" theory,but also provide reference for the development of other ligands of traditional Chinese medicine. |
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