Potential Effects And Mechianism Of Action On Natural Products And Their Derivatives For The Treatment Of Alzheimer’s Disease And Diabetes

Alzheimer’s disease(AD)is the third leading disease that threatens the lives of older people.In the clinical,there are only five kinds of drugs approved by the FDA for the treatment of AD,but all of them cannot cure this disease.Nerve growth factor(NGF)is a candidate drug for the treatment of AD,which can promote the growth and maintain the function of neurons.However,due to the big molecular weight and high polarity of NGF,the application of NGF in clinical is limited.Therefore,finding small molecular compounds with NGF-mimic activity is a new direction for the development of anti-AD drugs.In our previous study,by using PC 12 cell line bioassay system to screen traditional Chinese medicine,the other members in our lab discovered that the gentisides A-K from Gentiana rigescens Franch are novel compounds exhibiting NGF-mimic activity on PC 12 cells,but their effect in vivo is still unknown.Because the content of each of these 11 compounds is extremely low in the plant,it is difficult to obtain enough single compound to perform the animal experiments.Therefore,we used the active fraction which mainly contained these 11 compounds(n-GS)to investigate the pharmacodynamics of n-GS.Since there is no acceptable animal model for the evaluation of NGF-mimic effect in vivo,the scopolamine(SCO)-induced model mouse which can be used to evaluate the activity of acetylcholinesterase inhibitors was used to estimate the anti-AD efficacy of n-GS in this study.The results indicated that n-GS could alleviate the pathologic symptom in SCO-induced AD model mice.The effect of n-GS at the dose of 1 mg/kg is similar to that of 3 mg/kg donepezil.Meanwhile,we found that n-GS could ameliorate memory via inhibiting of AChE activity and oxidative stress and regulating of the IGF-1R/ERK/CREB signaling pathways.The effects of n-GS in animal experiments encourage us to design and synthesize gentiside derivatives to perform further study.More than 200 gentiside derivatives were synthesized by other members in our lab,and tetradecyl 2,3-dihydroxybenzoate(ABG-001)was found to be the leading compound with the best neurogenic activity against PC 12 cell.This substance could induce the neurite outgrowth of PC 12 cells and primary neuron cells.ABG-001 and n-GS could alleviate the pathologic symptom in SCO-induced AD model mice.Meanwhile,IGF-1R signaling pathway is also involved in the NGF-mimic activity of ABG-001 in the PC 12 cells.Given that n-GS and ABG-001 could regulate the IGF-1R signaling pathway,we hypothesized that gentiside derivatives might have the potential function to treat diabetes.In the present study,we used streptozotocin(STZ)-induced diabetic mice to evaluate the anti-diabetic effects of ABG-001.ABG-001 could alleviate hyperphagia,polydipsia,and hyperglycemia,lipid metabolism disorder and insulin resistance in STZ-induced diabetes mice.The anti-diabetic effect of ABG-001 at dose of 20 mg/kg was equivalent to that of metformin at 140 mg/kg.Meanwhile,ABG-001 could decrease the fasting glucose concentration of transgenic db/db mice.Based on the results,we speculated that ABG-001 has the potential function to treat both AD and diabetes.Thus,we used high-fat diet to construct a diabetic model mouse with cognitive deficit.After administration of ABG-001 to the model mice,the blood glucose concentration of model mice was significantly reduced and the memory deficit was improved.The mechanism study results demonstrated that ABG-001 exerts antidiabetic and anti-AD effects via improving homeostasis of gut microbiota,inhibiting inflammatory responses and improving insulin resistance in peripheral tissues.These results suggested that ABG-001 could be a promising drug candidate for treatment of AD and diabetes.In addition,cucurbitacin B(CuB)with NGF-mimic activity was isolated from Cucumis melo L.using the same bioassay system.CuB has both NGF-mimic and NGF-enhancer activities via regulation of GR/PLC/PKC,TrkA/Ras/Raf/ERK and cofilin signaling pathways.As CuB is already clinically used to treat hepatitis and hepatic carcinoma,it could be a novel therapeutic for Alzheimer’s disease.