Efficacy of Sailuotong (塞络通) on neurovascular unit in amyloid precursor protein/presenilin-1 transgenic mice with Alzheimer’s disease

doi:10.19852/j.cnki.jtcm.20240203.007

Abstract

Abstract:

OBJECTIVE: To discuss the influence of Sailuotong (塞络通, SLT) on the Neurovascular Unit (NVUs) of amyloid precursor protein (APP)/presenilin-1(PS1) mice and evaluate the role of gas supplementation in activating blood circulation during the progression of Alzheimer’s disease (AD).

METHODS: The mice were allocated into the following nine groups: (a) the C57 Black (C57BL) sham-operated group (control group), (b) ischaemic treatment in C57BL mice (the C57 ischaemic group), (c) the APP/PS1 sham surgery group (APP/PS1 model group), (d) ischaemic treatment in APP/PS1 mice (APP/PS1 ischaemic group), (e) C57BL mice treated with aspirin following ischaemic treatment (C57BL ischaemic + aspirin group), (f) C57BL mice treated with SLT following ischaemic treatment (C57BL ischaemic + SLT group), (g) APP/PS1 mice treated with SLT (APP/PS1 + SLT group), (h) APP/PS1 mice treated with donepezil hydrochloride following ischaemic treatment (APP/PS1 ischaemic + donepezil hydrochloride group) and (i) APP/PS1 mice treated with SLT following ischaemic treatment (APP/PS1 ischaemic + SLT group). The ischaemic model was established by operating on the bilateral common carotid arteries and creating a microembolism. The Morris water maze and step-down tests were used to detect the spatial behaviour and memory ability of mice. The hippocampus of each mouse was observed by haematoxylin and eosin (HE) and Congo red staining. The ultrastructure of NVUs in each group was observed by electron microscopy, and various biochemical indicators were detected by enzyme-linked immunosorbent assay (ELISA). The protein expression level was detected by Western blot. The mRNA expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR).

RESULTS: The results of the Morris water maze and step-down tests showed that ischemia reduced learning and memory in the mice, which were restored by SLT. The results of HE staining showed that SLT restored the pathological changes of the NVUs. The Congo red staining results revealed that SLT also improved the scattered orange-red sediments in the upper cortex and hippocampus of the APP/PS1 and APP/PS1 ischaemic mice. Furthermore, SLT significantly reduced the content of Aβ, improved the vascular endothelium and repaired the mitochondrial structures. The ELISA detection, western blot detection and qRT-PCR showed that SLT significantly increased the vascular endothelial growth factor (VEGF), angiopoietin and basic fibroblast growth factor, as well as the levels of gene and protein expression of low-density lipoprotein receptor-related protein-1 (LRP-1) and VEGF in brain tissue.

CONCLUSIONS: By increasing the expression of VEGF, SLT can promote vascular proliferation, up-regulate the expression of LRP-1, promote the clearance of Aβ and improve the cognitive impairment of APP/PS1 mice. These results confirm that SLT can improve AD by promoting vascular proliferation and Aβ clearance to protect the function of NVUs.

Key words: Alzheimer disease, amyloid beta-protein precursor, presenilin-1, mice, transgenic, replenishing Qi and activating blood, neurovascular unit, Sailuotong

SUN Linjuan, LI Chengfu, LIU Jiangang, LI Nannan, HAN Fuhua, QIAO Dandan, TAO Zhuang, ZHAN Min, CHEN Wenjie, ZHANG Xiaohui, TONG Chenguang, CHEN Dong, Qi Jiangxia, LIU Yang, LIANG Xiao, ZHENG Xiaoying, ZHANG Yunling. Efficacy of Sailuotong (塞络通) on neurovascular unit in amyloid precursor protein/presenilin-1 transgenic mice with Alzheimer’s disease[J]. Journal of Traditional Chinese Medicine, 2024, 44(2): 289-302.

Figures/Tables 11

Table 1 Effect of the method of replenishing Qi and activating blood on the spatial learning and memory ability of APP/PS1 double transgenic ischemic mice ($\bar{x}±s$)

Group	Dose (mg·kg^-1·d^-1)	n	Number of crossings	Swimming time (s)	Swimming distance (cm)
C57 sham-operated	-	16	7.1±1.3	46.9±12.2	318.3±89.2
C57 ischemia	-	16	5.2±1.3^a	39.1±10.4^a	252.1±101.4^a
APP/PS1 model	-	16	4.2±2.1^a	37.2± 9.9^a	275.2±97.3^e
APP/PS1 ischemia	-	16	3.4±1.7^a	33.0±11.2^a	237.2±98.3^e
C57BL ischaemic + aspirin	32	16	6.1±1.7^b	45.4±12.4^b	198.3±124.8^b
C57BL ischaemic + SLT	32	16	6.4±1.7^b	43.3±13.4^b	298.2±69.9^f
APP/PS1 + SLT	32	16	5.7±2.1^c	46.3±9.3^d	305.3±89.5^d
APP/PS1 ischaemic + donepezil hydrochloride	20	16	5.3±2.2^c	45.5±11.3^c	333.6±76.7^c
APP/PS1 ischaemic + SLT	32	16	6.8±2.2^f	44.2±8.0^f	341.3±81.1^f

Table 2 Effect of the method of replenishing Qi and activating blood on step-down test of APP/PS1 double transgenic ischemic mice ($\bar{x}±s$)

Group	Dose (mg·kg^-1·d^-1)	n	Number of errors (times)	Incubation period (s)
C57 sham-operated	-	15	1.3±1.2	226.5±53.1
C57 ischemia	-	15	2.2±1.4^a	179.2±55.3^a
APP/PS1 model	-	14	2.6±1.3	167.7±61.2^a
APP/PS1 ischemia	-	15	3.1±1.7^a	156.8±54.9^a
C57BL ischaemic + aspirin	32	15	1.3±1.3	217.5±64.4
C57BL ischaemic + SLT	32	15	1.2±1.5^b	226.8±66.2^b
APP/PS1 + SLT	32	14	1.5±1.1^c	213.4±49.8^d
APP/PS1 ischaemic + donepezil hydrochloride	20	15	1.5±1.6^c	206.2±73.6^e
APP/PS1 ischaemic + SLT	32	16	1.6±1.5^c	239.5±62.5^e

Figure 1 Effect of replenishing Qi and activating blood on pathological morphology and amyloid in the brain of APP/PS1 double transgenic ischemic mice A: HE pathological staining × 400; B: Congo red staining × 40. A1/B1: C57 sham-operated group; A2/B2: C57 ischemia group; A3/B3: APP/PS1 model group; A4/B4: APP/PS1 ischemia group; A5/B5: C57BL ischaemic + aspirin group at dose of 20 mg·kg-1·d-1 A6/B6: C57BL ischaemic + SLT group at dose of 32 mg·kg-1·d-1; A7/B7: APP/PS1 + SLT group at dose of 32 mg·kg-1·d-1; A8/B8: APP/PS1 ischaemic + donepezil hydrochloride group at dose of 32 mg·kg-1·d-1; A9/B9: APP/PS1 ischaemic + SLT group at dose of 32 mg·kg-1·d-1. Ischaemic treatment: both right and left common carotid arteries were separated, and the arterial blood vessel was stimulated with a temperature-controlled current of 80 mu A using an in vivo thrombometer to cause thrombosis. Duration: two months. SLT: Sailuotong; APP: amyloid precursor protein; PS1: presenilin-1presenilin-1.

Figure 2 Effects of Invigorating Qi and Activating blood circulation on APP and Aβ1-42 brain tissue of APP/PS1 double transgenic ischemic mice A: APP positive expression × 400; B: Aβ1-42 positive expression × 400. A1/B1: C57 sham-operated group; A2/B2: C57 ischemia group; A3/B3: APP/PS1 model group; A4/B4: APP/PS1 ischemia group; A5/B5: C57BL ischaemic + aspirin group at dose of 20 mg·kg-1·d-1 A6/B6: C57BL ischaemic + SLT group at dose of 32 mg·kg-1·d-1; A7/B7: APP/PS1 + SLT group at dose of 32 mg·kg-1·d-1; A8/B8: APP/PS1 ischaemic + donepezil hydrochloride group at dose of 32 mg·kg-1·d-1; A9/B9: APP/PS1 ischaemic + SLT group at dose of 32 mg·kg-1·d-1. Ischaemic treatment: both right and left common carotid arteries were separated, and the arterial blood vessel was stimulated with a temperature-controlled current of 80 mu A using an in vivo thrombometer to cause thrombosis. Duration: two months. SLT: Sailuotong; APP: amyloid precursor protein; PS1: presenilin-1presenilin-1.

Table 3 Effect of replenishing Qi and activating blood on APP and Aβ1-42 expression in hippocampal CA1 region of APP/PS1 double transgenic ischemic mice ($\bar{x}±s$)

Group	Dose (mg/kg·d)	Visual field number (n)	APP	Aβ_1-42
C57 sham-operated	-	12	1.15±0.5	3.75±1.2
C57 ischemia	-	12	1.46±0.5	8.12±1.0^d
APP/PS1 model	-	12	5.53±0.8^a	19.12±5.2^d
APP/PS1 ischemia	-	12	9.77±0.6^a	31.43±9.2^a
C57BL ischaemic + aspirin	32	12	1.28±0.4	7.18±3.2
C57BL ischaemic + SLT	32	12	1.14±0.5	5.12±4.4^e
APP/PS1 + SLT	32	12	3.38±0.5^b	14.38±5.4^b
APP/PS1 ischaemic + donepezil hydrochloride	20	12	6.23±0.6^c	16.24±6.4^c
APP/PS1 ischaemic + SLT	32	12	7.18±0.4^c	19.38±6.0^c

Table 4 Effect of replenishing Qi and activating blood on Aβ protein content in the cerebrospinal fluid in APP/PS1 double transgenic ischemic mice of each group (ng/mL, $\bar{x}±s$)

Group	Dose (mg·kg^-1·d^-1)	n	Aβ
C57 sham-operated	-	10	0.79±0.25
C57 ischemia	-	10	1.06±0.16
APP/PS1 model	-	10	1.22±0.27^a
APP/PS1 ischemia	-	10	1.52±0.13^b
C57BL ischaemic + aspirin	32	10	0.75±0.29
C57BL ischaemic + SLT	32	10	0.79±0.29
APP/PS1 + SLT	32	10	0.75±0.29
APP/PS1 ischaemic + donepezil hydrochloride	20	10	0.82±0.30^c
APP/PS1 ischaemic + SLT	32	10	0.79±0.26^c

Figure 3 Effect of the method of replenishing Qi and activating blood on the ultrastructure of hippocampus and cortical blood vessels in APP/PS1 double transgenic ischemic mice A: ultrastructure of brain tissue hippocampus; B: ultrastructure of cortical blood vessels. Scale bars = 500 nm. A1/B1: C57 sham-operated group; A2/B2: C57 ischemia group; A3/B3: APP/PS1 model group; A4/B4: APP/PS1 ischemia group; A5/B5: C57BL ischaemic + aspirin group at dose of 20 mg·kg-1·d-1 A6/B6: C57BL ischaemic + SLT group at dose of 32 mg·kg-1·d-1; A7/B7: APP/PS1 + SLT group at dose of 32 mg·kg-1·d-1; A8/B8: APP/PS1 ischaemic + donepezil hydrochloride group at dose of 32 mg·kg-1·d-1; A9/B9: APP/PS1 ischaemic + SLT group at dose of 32 mg·kg-1·d-1. Ischaemic treatment: both right and left common carotid arteries were separated, and the arterial blood vessel was stimulated with a temperature-controlled current of 80 mu A using an in vivo thrombometer to cause thrombosis. Duration: two months. SLT: Sailuotong; APP: amyloid precursor protein; PS1: presenilin-1.

Table 5 Effects of supplementing Qi and Activating blood circulation on VEGF, Ang, bFGF content in APP/PS1 double transgenic ischemic mice (ng/mg, $\bar{x}±s$)

Group	n	VEGF	Ang	bFGF
C57 sham-operated	10	9.6±1.2	1.6±0.5	6.4±2.1
C57 ischemia	10	12.4±2.4^a	1.5±0.2	6.6±0.5
APP/PS1 model	10	6.8±1.7^a	1.2±0.8	5.8±2.4
APP/PS1 ischemia	10	10.5±3.0	1.4±0.5	5.6±1.6
C57BL ischaemic + aspirin	10	10.4±2.3	1.9±0.6	8.7±2.5
C57BL ischaemic + SLT	10	14.3±1.5^b	2.9±0.7^b	9.6±2.5^b
APP/PS1 + SLT	10	13.6±4.1^c	1.9±0.7	9.8±1.6
APP/PS1 ischaemic + donepezil hydrochloride	10	10.4±2.0^c	2.0±0.3^c	5.8±1.4
APP/PS1 ischaemic + SLT	10	13.7±1.3^c	2.0±0.4^c	7.0±1.9^c

Figure 4 Effect of replenishing Qi and activating blood on the expression of related proteins in APP/PS1 ischemia model mice ($\bar{x}±s$, n = 10) 1: C57 sham-operated group; 2: C57 ischemia group; 3: APP/PS1 model group; 4: APP/PS1 ischemia group; 5: C57BL ischaemic + aspirin group at dose of 20 mg·kg-1·d-1; 6: C57BL ischaemic + SLT group at dose of 32 mg·kg-1·d-1; 7: APP/PS1 + SLT group at dose of 32 mg·kg-1·d-1; 8: APP/PS1 ischaemic + donepezil hydrochloride group at dose of 32 mg·kg-1·d-1; 9: APP/PS1 ischaemic + SLT group at dose of 32 mg·kg-1·d-1. Ischaemic treatment: both right and left common carotid arteries were separated, and the arterial blood vessel was stimulated with a temperature-controlled current of 80 mu A using an in vivo thrombometer to cause thrombosis. Duration: two months. SLT: Sailuotong; APP: amyloid precursor protein; PS1: presenilin-1.

Table 6 Effect of replenishing Qi and activating blood on VEGF, Aβ1-42, α7-nAChRs, RAGE and LRP-1 protein content in the brain tissues in APP/PS1 double transgenic ischemic mice of each group ($\bar{x}±s$)

Group	n	VEGF	Aβ_1-42	α7-nAChRs	RAGE	LRP-1
C57 sham-operated	10	1.000±0.172	1.000±0.073	1.000±0.131	1.000±0.074	1.000±0.203
C57 ischemia	10	1.710±0.088^a	0.930±0.122	1.410±0.153^a	1.052±0.091	0.970±0.072
APP/PS1 model	10	0.620±0.045^a	1.550±0.124^d	1.560±0.065^a	1.150±0.116	0.800±0.103
APP/PS1 ischemia	10	0.500±0.046^a	2.730±0.270^a	2.250±0.083^a	1.518±0.077^a	0.600±0.054^d
C57BL ischaemic + aspirin	10	1.330±0.022^b	1.040±0.111	1.380±0.142	1.050±0.062	1.160±0.104 ^f
C57BL ischaemic + SLT	10	1.880±0.042	0.960±0.115	1.110±0.144	1.010±0.052	1.050±0.200
APP/PS1 + SLT	10	1.040±0.081^c	1.200±0.132^c	1.160±0.120^c	1.020±0.079^c	1.260±0.064^c
APP/PS1 ischaemic + donepezil hydrochloride group	10	0.580±0.084	1.560±0.127^c	1.250±0.256^c	1.230±0.075^e	1.180±0.085^c
APP/PS1 ischaemic + SLT	10	0.839±0.095^c	1.460±0.273^c	1.480±0.135^ac	1.240±0.151^ac	1.220±0.032^c

Table 7 Effect of replenishing Qi and activating blood on mRNA expressions of VEGF, APP, α7-nAChRs, RAGE and LRP-1 in APP/PS1 double transgenic ischemic mice of each group ($\bar{x}±s$)

Group	n	VEGF	APP	α7-nAChRs	RAGE	LRP-1
C57 sham-operated	10	0.800±0.150	0.720±0.392	1.200±0.291	1.090±0.392	1.160±0.713
C57 ischemia	10	1.450±0.730^a	0.680±5.254	1.120±3.022	0.730±2.991	1.570±0.959^a
APP/PS1 model	10	0.180±0.080^a	1.070±0.045^a	0.190±0.040^a	2.090±0.031^a	0.380±0.191^a
APP/PS1 ischemia	10	0.540±0.481^a	2.730±1.132^a	0.320±0.903^a	2.670±0.675^a	0.850±1.052^a
C57BL ischaemic + aspirin	10	0.860±0.421^b	0.680±5.250	0.400±0.212^d	0.480±0.214^b	1.380±2.053^b
C57BL ischaemic + SLT	10	1.490±0.111	0.150±0.190^d	0.320±0.192^d	0.110±0.091^d	1.250±0.312^c
APP/PS1 + SLT	10	0.630±0.450^c	0.580±0.626	0.700±0.580	0.501±0.455	1.680±0.523^e
APP/PS1 ischaemic + donepezil hydrochloride	10	0.160±0.121	0.420±0.480	0.630±0.002	1.240±0.244	1.490±0.422^e
APP/PS1 ischaemic + SLT	10	0.930±0.345^c	0.690±0.242	1.180±1.591	2.090±0.915	1.420±0.560^e

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