Astragaloside IV for Experimental Focal Cerebral Ischemia: Preclinical Evidence and Possible Mechanisms

Table 2

Characteristics of the 13 included studies.

Study (years)	Species (sex, = experimental/control group)	Weight	Model (method)	Anesthetic	Treatment group (Astragaloside IV)	Control group	Outcome index (time)	Intergroup differences
Sun et al. 2014 [8]	Wistar rats (male, 5/5)	230~250 g	MACO IR/2 H	10% chloral hydrate (3 mL/kg)/(intraperitoneal injection)	1.5, 3, 6 mL/kg (1 mg/mL AST-IV), ip; At (1) 0.5 H before ischemia; (2) 0 H after reperfusion; (3) 24 H after reperfusion; (4) 48 H after reperfusion	Model group; 6 mL/kg, ip, 0.9% NS; At (1) 0.5 H before ischemia; (2) 0 H after reperfusion; (3) 24 H after reperfusion; (4) 48 H after reperfusion	(1) NFS (Longa) (72 h after reperfusion); (2) morphological structure of cortical neurons; (3) apoptosis; (4) BDNF; (5) VEGF; (6) VEGFR2	(1); (2) /; (3); (4); (5); (6)
Huang et al. 2013 [9]	SD rats (male, 6/6)	About 250 g	MACO IR	NE	20 mg/kg, ip; At 0 H after reperfusion, then each 4 H after reperfusion until 24 H	Model group; 5 mL/kg, ip, 0.9% NS; At 0 H after reperfusion, then each 4 H after reperfusion until 24 H	(1) NFS (7-point) (waking after reperfusion); (2) TNF-α; (3) the mRNA of iNOS	(1); (2); (3)
Xu and Chen 2011 [10]	SD rats (male, 6/6)	230~250 g	MACO IR/2 H	NE	10, 40, 100 mg/kg, ip; At 0.5 H before ischemia	Model group; The same volume of 0.9% NS compared with treatment group, ip; At (1) 0.5 H before ischemia	(1) NFS (Bederson) (24 h after reperfusion); (2) IV (TTC) (24 h after reperfusion); (3) GFAP	(1); (2); (3)
Li et al. 2012 [11]	SD rats (male, 6/6)	250–320 g	MACO IR/1.5 H	5% chloral hydrate (400 mg/kg)/(intraperitoneal injection)	10, 20 mg/kg, ip; At (1) 0 H after reperfusion; (2) 12 H after reperfusion	Model group; The same volume of 0.9% NS compared with treatment group, ip; At (1) 0 H after reperfusion; (2) 12 H after reperfusion	(1) NFS (Garcia 18-point) (24 h after reperfusion); (2) IV (TTC) (24 h after reperfusion); (3) MPO concentration; (4) the upregulation of IL-1β and TNF-α; (5) CD11b/CD18-positive; percentage of neutrophils; (6) the expression of ICAM-1; (7) the expression of NF-κB	(1); (2); (3); (4); (5); (6); (7)
Luo et al. 2004 [12]	C57/B6 mice (male, 15/15)	25–30 g	MACO; IR/1.5 H	chloral hydrate (300 mg/kg)/(intraperitoneal injection)	20, 40 mg/kg, ip; At (1) 0 H after ischemia; (2) 24 H after reperfusion; (3) 48 H after reperfusion	Model group; The same volume of saline compared with treatment group; At (1) 0 H after ischemia; (2) 24 H after reperfusion; (3) 48 H after reperfusion	(1) IV (TTC) (72 h after operation); (2) MDA; (3) SOD; (4) GSH-PX	(1); (2); (3); (4)
Li et al. 2013 [13]	SD rats (male, 6/6)	250–320 g	MACO IR/1.5 H	5% chloral hydrate (400 mg/kg)/(intraperitoneal injection)	10, 20 mg/kg, ip; At (1) 0 H after reperfusion; (2) 12 H after reperfusion	Model group; The same volume of 0.9% NS compared with treatment group, ip; At (1) 0 H after reperfusion; (2) 12 H after reperfusion	(1) NFS (Bederson) (24 h after reperfusion); (2) BBB (brain water content) (NR); (3) BBB (Evans blue) (24 h after reperfusion); (4) vascular permeability; (5) immunohistochemical analysis of MMP-9 and AQP4	(1); (2); (3); (4) /; (5)
Zhang et al. 2013 [14]	SD rats (male, 10/10)	g	MACO IR/1 H	NE	5 mg/kg, ip; At (1) 0 H after reperfusion; (2) 6 H after reperfusion; (3) 23 H after reperfusion	Model group; The same volume of 0.9% NS compared with treatment group; At (1) 0 H after reperfusion; (2) 6 H after reperfusion; (3) 23 H after reperfusion	(1) NFS (Bederson) (24 h after reperfusion); (2) IV (TTC) (24 h after reperfusion); (3) BBB (brain water content) (24 h after reperfusion); (4) Brain index; (5) Activity of SOD; (6) Content of MDA; (7) Bcl-2 protein; (8) Bax expression; (9) Reducing or disappearing of Nissl body	(1); (2); (3); (4); (5); (6); (7); (8); (9)
Zhou and Liu 2008 [15]	SD rats (male, 10/10)	280–320 g	MACO IR/2 H	40 mL/L isoflurane induction then 20 mL/L isoflurane inhaled maintenance anesthesia	10, 20 mg/kg, intragastric; At (1) 3 D before reperfusion; (2) 2 D before reperfusion; (3) 1 H before reperfusion	Model group; The same volume of 0.9% NS compared with treatment group; At (1) 3 D before reperfusion; (2) 2 D before reperfusion; (3) 1 H before reperfusion	(1) NFS (Longa) (24 h after reperfusion); (2) Infarct weight (TTC) (24 h after reperfusion); (3) SOD; (4) GSH-PX; (5) MDA; (6) Apoptosis index	(1); (2); (3); (4); (5); (6)
Cao et al. 2015 [16]	SD rats (6 males and 6 females, 12/12)	250–300 g	MACO IR/2 H	2% pentobarbital sodium (40 mg/kg)/(intraperitoneal injection)	10, 40, 100 mg/kg, ip; At 0.5 H before reperfusion	Model group; The same volume of 0.9% NS compared with treatment group; At 0.5 H before reperfusion	(1) NFS (Bederson) (24 h after reperfusion); (2) Mitochondrial [^3H]PK11195 binding	(1); (2)
Yang et al. 2012 [17]	SD rats (male, 10/10 (8/8))	280 ± 20 g	MACO IR/1 H	1% pentobarbital sodium (40 mg/kg)/(intraperitoneal injection)	20 mg/kg, ip; At 0 H, 12 H, 1 D, 2 D, 3 D, till 7 D after reperfusion	Model group; The same dose of sterile saline compared with treatment group; At 0 H, 12 H, 1 D, 2 D, 3 D, till 7 D after reperfusion	(1) NFS (Longa) (24 h after reperfusion); (2) IV (TTC) (24 h after reperfusion); (3) Brain glucose metabolism; (4) SOD; (5) MDA; (6) iNOS; (7) Caspase-3; (8) Bcl-2	(1); (2); (3); (4); (5); (6); (7); (8)
Cao et al. 2014 [18]	SD rats (male, 8/8)	280 ± 20 g	MACO IR/2 H	chloral hydrate (400 mg/kg)/(intraperitoneal injection)	3 mL/kg, ip; At 0 H after reperfusion	Model group; The same volume of normal saline compared with treatment group; At 0 H after reperfusion	(1) NFS (Masuo) (24 h after reperfusion); (2) IV (TTC) (24 h after reperfusion); (3) WBV, PV; (4) ROS; (5) SOD, GSH-PX, MDA; (6) Nrf2	(1); (2); (3) /; (4); (5) /; (6) /
Yin et al. 2010 [19]	Wistar rats (male, 8/8)	250–325 g	MACO IR/2 H	10% chloral hydrate (300 mg/kg)/(intraperitoneal injection)	40 mg/kg, intragastric; At reperfusion 0 H, 8 H, 24 H, then once a day until 14 D	Model group; The same time with treatment group	(1) NFS (Bederson) (3 D after reperfusion); (2) IV (TTC) (14 D after reperfusion); (3) BBB (brain water content)/(at 3 D after reperfusion); (4) MDA (7 D); (5) SOD (7 D); (6) NO, NOS (7 D); (7) LD (7 D); (8) LDH (7 D); (9) iNOS (7 D), NGF (7 D), TrkA mRNA (14 D)	(1); (2); (3); (4); (5); (6); (7); (8); (9)
Luo and Qin 2000 [20]	SD rats (male, 20/20)	260 ± 10 g	MACO IR/1 H	10% chloral hydrate (3 mL/kg)/(intraperitoneal injection)	10 mg/kg, ip; At 1 H before reperfusion	Model group; the same volume of normal saline compared with treatment group; At 1 H before reperfusion	BBB (Evans blue) (23 h after reperfusion)

Note. SD rats: Sprague-Dawley rats. NR: no report. MACO: middle carotid artery occlusion. IR: ischemic reperfusion. Ip: intraperitoneal injection. H: hour. D: day. AST-IV: Astragaloside IV. NS: normal saline. NFS: neurological function score. IV: infarct volume. TTC: triphenyltetrazolium chloride. BBB: blood-brain barrier. BDNF: brain derived neurotrophic factor. VEGF: vascular endothelial growth factor. VEGFR2: receptor of vascular endothelial growth factor. GFAP: glial fibrillary acidic protein. MPO: myeloperoxidase. TNF-α: tumor necrosis factor-α. iNOS: inducible nitric oxide synthase. NOS: nitric oxide synthase. IL-1β: interleukin-1β. ICAM-1: intercellular adhesion molecule-1. NF-κB: nuclear factor κB. MDA: malondialdehyde. SOD: superoxide dismutase. GSH-PX: glutathione peroxidase. MMP-9: matrix metalloproteinase-9. AQP4: aquaporin 4. Bcl-2: B-cell lymphoma/leukemia-2. Bax: B-cell lymphoma/leukemia-2 associated X protein. WBV: whole blood viscosity. PV: plasma viscosity. ROS: reactive oxygen species. Nrf2: nuclear factor erythroid 2-related factor 2. LD: lactate. LDH: lactate dehydrogenase. NGF: nerve growth factor. TrkA: tropomyosin receptor kinase A. NO: nitric oxide.