Classic Prescription, Kai-Xin-San, Ameliorates Alzheimer's Disease as an Effective Multitarget Treatment: From Neurotransmitter to Protein Signaling Pathway.

Sirui Guo,Jiahong Wang,Ziyue Yuan,Kaishun Bi,Fucheng Xie,Weiwei Rong,Cheng Gao,Huarong Xu,Zhou Zhang,Qing Li

doi:10.1155/2019/9096409

Sirui Guo, Jiahong Wang + Show 8 more

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https://doi.org/10.1155/2019/9096409

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Abstract

Alzheimer's disease (AD) is a widespread neurodegenerative disease caused by complicated disease-causing factors. Unsatisfactorily, curative effects of approved anti-AD drugs were not good enough due to their actions on single-target, which led to desperate requirements for more effective drug therapies involved in multiple pathomechanisms of AD. The anti-AD effect with multiple action targets of Kai-Xin-San (KXS), a classic prescription initially recorded in Bei Ji Qian Jin Yao Fang and applied in the treatment of dementia for thousands of years, was deciphered with modern biological methods in our study. Aβ 25-35 and D-gal-induced AD rats and Aβ 25-35-induced PC12 cells were applied to establish AD models. KXS could significantly improve cognition impairment by decreasing neurotransmitter loss and enhancing the expression of PI3K/Akt. For the first time, KXS was confirmed to improve the expression of PI3K/Akt by neurotransmitter 5-HT. Thereinto, PI3K/Akt could further inhibit Tau hyperphosphorylation as well as the apoptosis induced by oxidative stress and neuroinflammation. Moreover, all above-mentioned effects were verified and blocked by PI3K inhibitor, LY294002, in Aβ 25-35-induced PC12 cells, suggesting the precise regulative role of KXS in the PI3K/Akt pathway. The utilization and mechanism elaboration of KXS have been proposed and dissected in the combination of animal, molecular, and protein strategies. Our results demonstrated that KXS could ameliorate AD by regulating neurotransmitter and PI3K/Akt signal pathway as an effective multitarget treatment so that the potential value of this classic prescription could be explored from a novel perspective.

Highlights

Alzheimer’s disease (AD) is the widespread neurodegenerative disease that accounted for 60-70% cases of dementia characterized by amnesia, cognition impairment, and mental behavioral changes [1]
The AD animal model induced by D-gal and Aβ25-35 was applied in order to simulate human pathological processes
huperzine A (Hup A) (AChEIs), an alkaloid isolated from the Chinese herbal medicine Huperzia serrata, was licensed as a nutraceutical in the United States and widely used for AD treatment in China [16]

Summary

Introduction

Alzheimer’s disease (AD) is the widespread neurodegenerative disease that accounted for 60-70% cases of dementia characterized by amnesia, cognition impairment, and mental behavioral changes [1]. All FDAapproved drugs were developed for specific single-target, such as cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and N-methyl-D-aspartate receptor agonist (memantine) [3], and the symptoms of AD could be alleviated to some extent. Their therapeutic effects were far from the expectation by reason of their actions on singletarget, which could not match multiple pathogenetic factors mainly including abnormal β-amyloid and Tau [4, 5], providing imperious demands for more effective multitarget drug therapies. Based on literatures to date, researches of KXS were mainly focused

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