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

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. Aβ25-35 and D-gal-induced AD rats and Aβ25-35-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 Aβ25-35-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.

Study on the Multitarget Synergistic Effects of Kai-Xin-San against Alzheimer’s Disease Based on Systems Biology

“…Six groups of AD rats were administered intragastrically with KXS (10.0 g/kg), GR (3.0 g/kg), PR (2.0 g/kg), PO (3.0 g/kg), AT (2.0 g/kg), and Hup A (0.027 mg/kg) once a day from the third week until the end of the experiment [25]. At the end of the fourth week, the stereotaxic injection of 4 μg Aβ [25][26][27][28][29][30][31][32][33][34][35] (1 μg/μL) was operated at the following coordinates: anteroposterior-3.5; mediolateral-+2.0; and dorsoventral-2.8 mm [26]. Two weeks later, the Morris water maze test was used for evaluation.…”

“…The rats were tested to swim freely to find the removed platform within 90 s. The distance and time in the target quadrant as well as the times of crossing the platform were recorded to evaluate spatial memory. The drug administration and Morris water maze test were scheduled according to the experimental timelines ( Figure 1) and followed the methods of Guo et al 2019 [28].…”

Integrated meta-analysis, network pharmacology, and molecular docking to investigate the efficacy and potential pharmacological mechanism of Kai-Xin-San on Alzheimer's disease

“…Ten studies (Huang et al 1999;Li and Zhao 2009;Gao et al 2010;Chu et al 2016aChu et al , 2016bLu et al 2017;Dai et al 2018;Guo et al 2019;Xu et al 2019;Zhang et al 2019) were included in statistical analysis after screening 80 studies (Figure 1). The escape latency outcome was measured in seven of these studies (Li and Zhao 2009;Gao et al 2010;Chu et al 2016aChu et al , 2016bDai et al 2018;Guo et al 2019;Xu et al 2019). KXS treatment was found to significantly reduce escape latency in AD animal models (SMD ¼ À16.84, 95% CI ¼ À21.85 to À11.84, p < 0.00001).…”

“…The heterogeneity among studies was moderate (I 2 ¼ 73%, p ¼ 0.001) (Figure 2(A)). Six studies (Li and Zhao 2009;Chu et al 2016aChu et al , 2016bDai et al 2018;Guo et al 2019;Xu et al 2019) evaluated the number of platform crossings for retention memory. In the same line, four studies (Li and Zhao 2009;Gao et al 2010;Guo et al 2019;Xu et al 2019) adopted time in target quadrant as an outcome.…”

“…Six studies (Li and Zhao 2009;Chu et al 2016aChu et al , 2016bDai et al 2018;Guo et al 2019;Xu et al 2019) evaluated the number of platform crossings for retention memory. In the same line, four studies (Li and Zhao 2009;Gao et al 2010;Guo et al 2019;Xu et al 2019) adopted time in target quadrant as an outcome. The analysis revealed that AD model animals treated with KXS had a significant increase in the number of platform crossing compared with animals in the control groups (SMD ¼ 2.56, 95% CI ¼ 2.01-3.12, p < 0.00001).…”