Neuroprotection of Catalpol for Experimental Acute Focal Ischemic Stroke: Preclinical Evidence and Possible Mechanisms of Antioxidation, Anti-Inflammation, and Antiapoptosis

Table 2

Basic characteristics of the included studies.

Study (years)	Species (sex, n = experimental/control group)	Weight	Random method	Model (method)	Anesthetic	Method of administration		Outcome index (time)	Intergroup differences
						Experimental group	Control group
Jia et al. [14]	Wistar rats (male, 6/6)	250–300 g	Not mention random	MCAO/1 h	1.0% isoflurane	Catalpol (98%, 100 μg, icv); 15 min before occlusion	Saline (same volume, icv); 15 min before occlusion	(1) NFS (ZL score, 2 d); (2) IV (TTC, 2 d)	(1); (2)
	Wistar rats (male, 7/7)	250–300 g	Not mention random	MCAO/1 h	1.0% isoflurane	Catalpol (98%, 100 μg, icv.) and saline (5 μL,icv); 15 min before occlusion	Saline (same volume, icv); 15 min before occlusion	(1) IV (TTC, 2 d)	(1)
Wan et al. [15]	SD rats (male, 10/10)	220–280 g	Not mention method	Permanent MCAO	NR	Catalpol (5 mg kg^−1, ip); 24 h after occlusion; once daily for 7 d	Normal saline (same volume, ip); 24 h after occlusion; once daily for 7 d	(1) NFS (Bederson score, 1, 4, 7, and 15 d); (2) NFS (muscular strength test, 1, 4, 7, and 15 d); (3) NFS (balance beam-walking test, 1, 4, 7, and 15 d); (4) NFS (skilled reaching task test, 1, 4, 7, and 15 d); (5) GAP43 express; (6) GAP43-positive cell count; (7) Synapse count	(1) P > 0.05; (2) P > 0.05; (3); (4) P > 0.05; (5); (6); (7)
Wan et al. 2013 [16]	Kunming mice (both, 10/10)	25–30 g	Not mention random	Permanent MCAO	NR	Catalpol (9 mg kg^−1, ip); 24 h after occlusion; once daily for 3 d	Normal saline (same volume, ip); 24 h after occlusion; once daily for 3 d	(1) NFS (ZL score, 1, 2, and 3 d); (2) IV (TTC, 3 d); (3) Cerebral blood flow ratio	(1); (2); (3)
Zhu et al. [17]	SD rats (male, 24/24)	220–280 g	Not mention method	Permanent MCAO	Chloral hydrate	Catalpol (5 mg kg^−1, ip); 24 h after occlusion; once daily for 7 d	Normal saline (same volume, ip); 24 h after occlusion; once daily for 7 d	(1) NFS (Bederson score, 1, 4, 7, and 15 d); (2) NFS (balance beam-walking test, 1, 4, 7, and 15 d); (3) VWF and PCNA colocalization point count; (4) EPO expression; (5) VEGF expression; (6) EPO-positive cell; (7) VEGF-positive cell; (8) Vascular pattern; (9) Brain capillary endothelial cell microstructure	(1); (2); (3); (4); (5); (6); (7); (8) NR; (9) NR
Wang [18]	Kunming mice (NR, 6/6)	23–28 g	Not mention method	Permanent MCAO	3.5% chloral hydrate (10 mL kg^−1)	Catalpol (1.42, 7, and 14.2 mg kg^−1, ip); after occlusion; once daily for 3 d	Normal saline (same volume, ip); after occlusion; once daily for 3 d	(1) NFS (neuromuscular function test, 3 d); (2) NFS (muscular strength test, 3 d); (3) IV (TTC, 3 d)	(1) P > 0.05; (2) P > 0.05; (3)
	Kunming mice (NR, 6/6)	23–28 g	Not mention method	Permanent MCAO	3.5% chloral hydrate (10 mL kg^−1)	Catalpol (14.2 mg kg^−1, ip); 0.5 h before, 1 h after or 24 h after occlusion; once daily for 3 d	Normal saline (same volume, ip); after occlusion; once daily for 3 d	(1) NFS (neuromuscular function test, 3 d); (2) NFS (muscular strength test, 3 d); (3) IV (TTC, 3 d)	(1) P > 0.05; (2) P > 0.05; (3) P > 0.05
	SD rats (NR, 8/8)	250–300 g	Not mention method	Permanent MCAO	3.5% chloral hydrate (10 mL kg^−1)	Catalpol (1, 5, and 10 mg kg^−1, ip); after occlusion; once daily for 7 d	Normal saline (same volume, ip); after occlusion; once daily for 7 d	(1) NFS (Bederson score, 1, 4, 7, 15, 21, and 28 d); (2) NFS (muscular strength test, 1, 4, 7, 15, 21, and 28 d); (3) NFS (balance beam-walking test, 1, 4, 7, 15, 21, 28 d); (4) IV (TTC, 3 d)	(1) P > 0.05; (2) P > 0.05; (3) P > 0.05; (4) P > 0.05
Xue [19]	Kunming mice (both, 10/10)	22–28 g	Not mention method	Permanent MCAO	Chloral hydrate	Catalpol (9 mg kg^−1, iv); 24 h after occlusion; once daily for 3 d	Normal saline (same volume, iv); 24 h after occlusion; once daily for 3 d	(1) NFS (ZL score, 1, 2, and 3 d); (2) IV (TTC, 3 d); (3) Cerebral blood flow ratio; (4) Hippocampal tissue morphology	(1); (2); (3); (4) NR
Zhang et al. [20]	Kunming mice (male, 10/10)	25–35 g	Not mention method	Permanent MCAO	Chloral hydrate (350 mg kg^−1)	Catalpol (9 mg kg^−1, iv); 3 h after occlusion; once daily for 7 d	MCAO without any intervention	(1) NFS (ZL score, 1, 4, and 7 d); (2) NFS (nerve comprehensive function test, 1, 4, and 7 d); (3) IV (TTC, 8 d)	(1); (2); (3)
Min et al. [21]	SD rats (NR, 8/8)	260–280 g	Random digit table	MCAO/2 h	Pentobarbital (60 mg kg^−1)	Catalpol (1 and 5 mg kg^−1, ip); 2 h after occlusion	Dimethyl sulfoxide (0.1 mol kg^−1, ip); 2 h after occlusion	(1) NFS (ZL score, 2 d); (2) IV (TTC, 2 d)	(1); (2)
Min [22]	SD rats (male, 6/6)	280–320 g	Not mention method	MCAO/2 h	Pentobarbital (60 mg kg^−1)	Catalpol (1 and 5 mg kg^−1, ip); 2 h after occlusion	MCAO without any intervention	(1) NFS (ZL score, 2 d); (2) IV (TTC, 2 d)	(1); (2)
	SD rats (male, 6/6)	280–320 g	Not mention method	MCAO/2 h	Pentobarbital (60 mg kg^−1)	Catalpol (1 and 5 mg kg^−1, ip); 2 h after occlusion	MCAO without any intervention	(1) NFS (ZL score, 2 d); (2) IV (TTC, 2 d)	(1); (2)
Liu 2011 [23]	SD rats (male, 11/10)	260–280 g	Not mention method	MCAO/2 h	NR	Catalpol (15, 30, and 60 mg kg^-1, ig); 2 d after occlusion; once daily for 12 d	Edible oil (same volume, ig); 2 d after occlusion; once daily for 12 d	(1) NFS (ZL score, 3, 7, 10, and 14 d); (2) NFS (balance beam-walking test, 3, 7, 10, and 14 d); (3) NFS (adhesive removal test, 3, 7, 10, and 14 d); (4) NFS (bar-grasping test, 3, 7, 10, and 14 d); (5) Lactic acid content; (6) Pyruvic acid content; (7) Lactic acid content/pyruvic acid content; (8) Na^+, K^+-ATPase activity; (9) Ca^2+, Mg^2+-ATPase activity	(1); (2); (3); (4); (5); (6); (7); (8); (9)
Wan et al. 2012 [24]	SD rats (both, 6/6)	220–250 g	Not mention method	Permanent MCAO	NR	Catalpol (1, 5, and 10 mg kg^−1, ip); 24 h after occlusion; once daily for 7 d	Normal saline (same volume, ip); 24 h after occlusion; once daily for 7 d	(1) NFS (corner test, 1, 4, 7, and 15 d); (2) IV (MRI, 1 and 15 d); (3) Dendritic branch; (4) Spine density; (5) P38 IOD	(1); (2) P > 0.05; (3); (4); (5)
Wang [25]	SD rats (NR, 8/8)	250–350 g	Not mention random	MCAO/2 h	3.5% chloral hydrate (10 mL kg^−1)	Catalpol (1, 5, and 10 mg kg^−1, ip); 12 h before and 1 h after occlusion	Normal saline (same volume, ip); 12 h before and 1 h after occlusion	(1) NFS (Bederson score, 1 d); (2) NFS (neuromuscular function test, 1 d); (3) NFS (corner test, 1 d); (4) IV (TTC, 1 d); (5) LC3 express	(1) P > 0.05; (2); (3); (4); (5) NR
Wang et al. [26]	SD rats (male, 6/6)	220–280 g	Not mention method	MCAO/1.5 h	3.5% chloral hydrate (10 mL kg^−1)	Catalpol (5 mg kg^−1, ip); 1.5 h after occlusion; once daily for 7 d	MCAO without any intervention	(1) NFS (ZL score, 1, 4, and 7 d); (2) NFS (stair test, 1, 4, and 7 d); (3) NFS (cylinder test, 1, 4, and 7 d)	(1); (2); (3)
Liu et al. 2011 [27]	SD rats (male, 12/14)	260–290 g	Not mention method	Permanent MCAO	10% chloral hydrate (350 mg kg^−1)	Catalpol (15, 30, and 60 mg kg^−1, ig); 2 d after occlusion; once daily for 12 d	Distilled water (same volume, ig); 2 d after occlusion; once daily for 12 d	(1) NFS (ZL score, 3,6, 9, 12, and 14 d); (2) NFS (balance beam-walking test, 3, 9, and 14 d); (3) NFS (adhesive removal test, 3, 9, and 14 d); (4) Lactic acid content; (5) Pyruvic acid content; (6) Lactic acid/pyruvic acid; (7) Na^+, K^+-ATPase activity; (8) Ca^2+, Mg^2+-ATPase activity	(1); (2); (3); (4); (5); (6); (7); (8)
Liu et al. 2011 [28]	SD rats (male, 11/10)	260–290 g	Not mention method	Permanent MCAO	10% chloral hydrate (350 mg kg^−1)	Catalpol (15, 30, and 60 mg kg^−1, ig); 2 d after occlusion; once daily for 12 d	Edible oil (same volume, ig); 2 d after occlusion; once daily for 12 d	(1) NFS (ZL score, 7, 10, and 14 d); (2) NFS (balance beam-walking test, 7, 10, and 14 d); (3) NFS (bar-grasping test, 7, 10, and 14 d); (4) NGF IOD; (5) BDN IOD; (6) NGF mRNA express; (7) BDNF mRNA express	(1); (2); (3); (4) P > 0.05; (5); (6) P > 0.05; (7)
Zhang et al. 2013 [29]	SD rats (male, 13/13)	210–240 g	Not mention method	Permanent MCAO	10% chloral hydrate (350 mg kg^−1)	Catalpol (15, 30, and 60 mg kg^−1, ig); after occlusion	Normal saline (same volume, ig); after occlusion	(1) NFS (ZL score, 6 and 24 h); (2) IV (TTC, 24 h); (3) Brain water content; (4) Water content	(1); (2) P > 0.05; (3) P > 0.05; (4)
	SD rats (male, 10/10)	260–290 g	Not mention method	Permanent MCAO	10% chloral hydrate (350 mg kg^−1)	Catalpol (15, 30, and 60 mg kg^−1, ig); 2 d after occlusion; once daily for 12 d	Edible oil (same volume, ig) and normal saline (same volume, ip); 2 d after occlusion; once daily for 12 d	(1) NFS (ZL score, 3, 7, 10, and 14 d); (2) NFS (balance beam-walking test, 3, 7, 10, and 14 d); (3) NFS (adhesive removal test, 3,7,10, and 14 d); (4) NFS (bar-grasping test, 3, 7, 10, and 14 d); (5) Normal neuron count; (6) Nissl body iod; (7) IL-6 content; (8) IL-10 content; (9) NF-kBp65 content; (10) Cerebral cortex ultrastructure	(1); (2); (3); (4); (5); (6); (7); (8) P > 0.05; (9) P > 0.05; (10) NR
Zhang et al. 2013 [30]	SD rats (male, 18/18)	260–290 g	Not mention method	Permanent MCAO	10% chloral hydrate (3.5 mL kg^−1)	Catalpol (15, 30, and 60 mg kg^−1, ig); 6 h after occlusion; once daily for 14 d	Normal saline (same volume, ig); 6 h after occlusion; once daily for 14 d	(1) NFS (real-time gait behavior test, duty cycle, 15 d); (2) NFS (real-time gait behavior test, four feet swinging time, 15 d); (3) NFS (real-time gait behavior test, four feet supporting time, 15 d); (4) NFS (real-time gait behavior test, walking speed, 15 d); (5) NFS (real-time gait behavior test, the average of body angle, 15 d); (6) NFS (real-time gait behavior test, the absolute value of body angle, 15 d); (7) NFS (real-time gait behavior test, coordination index, 15 d); (8) NFS (real-time gait behavior test, several feet supporting time, 15 d)	(1) (A, B, LFL RF); P > 0.05(LB); (2) P > 0.05(LF, RB); (RF); (LB); (3) P > 0.05(LF, LB); (RF); (RB); (4) P > 0.05; (5) P > 0.05; (6); (7) (RF-LB, F-RB, RF-LF); (8) P > 0.05(LF&RB, LB&RF, LF&LB&RF)
Wan et al. 2012 [31]	SD rats (male, 9/9)	220–250 g	Not mention method	Permanent MCAO	3.5% chloral hydrate (10 mL kg^−1)	Catalpol (1, 5, and 10 mg kg^−1, ip); 6 h after occlusion; once daily for 7 d; catalpol (5 mg kg^−1, ip); 24 h after occlusion; once daily for 7 d	Normal saline (same volume, ip); 6 h after occlusion; once daily for 7 d	(1) NFS (Bederson score, 1, 4, 7, 15, and 21 d); (2) NFS (muscle strength test, 1, 4, 7, 15, and 21 d); (3) NFS (balance beam-walking test, 1, 4, 7, 15, and 21 d); (4) NFS (skilled reaching task test, 1, 4, 7, 15, and 21 d); (5) IV (TTC, 3 d); (6) GAP-43-positive cell count; (7) GAP-43 expression	(1); (2) P > 0.05; (3); (4); (5); (6); (7)
Zhou [32]	SD rats (both, 7/7)	250–300 g	Not mention method	Permanent MCAO	3.5% chloral hydrate (10 mL kg^−1)	Catalpol (1, 3, and 5 mg kg^−1, ip); 24 h after occlusion; once daily for 7 d	Normal saline (same volume, ip); 24 h after occlusion; once daily for 7 d	(1) NFS (Bederson score, 2, 4, 7, 15, and 21 d); (2) NFS (tray task box task test, 2, 4, 7, 15, and 21 d); (3) NFS (grasping test box test, 2, 4, 7, 15, and 21 d); (4) NFS (balance beam-walking test, 2, 4, 7, 15, and 21 d)	(1); (2); (3); (4)
Wan et al. 2013 [33]	SD rats (both, 6/6)	220–250 g	Random digit table	Permanent MCAO	Chloral hydrate	Catalpol (5 mg kg^−1, ip); 24 h after occlusion; once daily for 7 d	Normal saline (same volume, ip); 24 h after occlusion; once daily for 7 d	(1) NFS (adhesive removal test, 1, 4, 7, 14, 21, and 28 d); (2) NFS (foot-fault test, 1, 4, 7, 14, 21, and 28 d); (3) IV (MRI, 1 and 28 d); (4) Midline-crossing CST fiber; (5) CST axonal sprouting	(1); (2); (3) P > 0.05; (4); (5)
Tan et al. [34]	SD rats (NR, 6/6)	200–220 g	Not mention method	Permanent MCAO	3.5% chloral hydrate	Catalpol (5 mg kg^−1, ip); 6 h after occlusion; once daily for 7 d	Normal saline (same volume, ip); 6 h after occlusion; once daily for 7 d	(1) NFS (balance beam-walking test, 1, 4, 7, and 14 d); (2) NFS (cylinder test, 1, 4, 7, and 14 d); (3) Vessel length; (4) Neuron count; (5) Glial cell count; (6) Cell morphology	(1); (2); (3); (4); (5); (6) NR
Zhang et al. [35]	SD rats (male, 10/10)	200–250 g	Not mention random	Permanent MCAO	Chloral hydrate (300 mg kg^−1)	Catalpol (15, 30, 60 mg kg^−1, ig); 3 d after occlusion; once daily for 12 d	Edible oil (same volume, ig) and normal saline (same volume, ip); 3 d after occlusion; once daily for 12 d	(1) NFS (Zea Longa score, 3, 7, 10, and 14 d); (2) LFB IOD; (3) MBP IOD; (4) Brain pathohistology	(1); (2); (3); (4) NR
Qin [36]	SD rats (male, 6/6)	220–280 g	Not mention method	Permanent MCAO	3.5% chloral hydrate	Catalpol (5 and 10 mg kg^−1, ip); 6 h after occlusion; once daily for 21 d	Normal saline (100 g/1 mL, ip); 6 h after occlusion; once daily for 21 d	(1) NFS (Bederson score, 1, 3, 7, 14, and 21 d); (2) NFS (corner test, 1, 3, 7, 14, and 21 d); (3) NFS (ladder rung walking test, 1, 3, 7, 14, and 21 d)	(1) P > 0.05; (2) P > 0.05; (3); (4) P > 0.05
Zhang [37]	SD rats (male, 10/10)	180–220 g	Not mention method	Permanent MCAO	Chloral hydrate	Catalpol (NR, iv); 3 h after occlusion; once daily for 7 d	1, 2-Propylene glycol (NR, iv); 3 h after; occlusion; once daily for7 d	(1) NFS (Zea Longa score, 7 d); (2) NFS (balance beam-walking test score, 7 d); (3) IV (TTC, 7 d)	(1); (2); (3)
Wan et al. [38]	SD rats (male, 9/9)	220–250 g	Not mention method	Permanent MCAO	Chloral hydrate	Catalpol (5 mg kg^−1, ip); 1 d after occlusion; once daily for 7 d	MCAO without any intervention	(1) NFS (cylinder test, 1, 4, 7, and 15 d); (2) NFS (foot-fault test, 1, 4, 7, and 15 d); (3) Cerebral blood flow ratio; (4) VWF-PCNA colocalization number; (5) VWF-PCNA colocalization area IOD; (6) pSTAT3 translocation number; (7) pSTAT3-positive cell IOD; (8) EPO/NADPH IOD; (9) EPOR/GAPDH IOD; (10) pJAK2/NADPH IOD; (11) pSTAT3/GAPDH IOD; (12) pSTAT3-VEGF DNA-binding activity; (13) VEGF mRNA; (14) VEGF/NADPH IOD; (15) VEGF-positive cell IOD	(1); (2); (3); (4); (5); (6); (7); (8); (9); (10); (11); (12); (13); (14); (15)

A: average; BDNF: brain-derived neurotrophic factor; CST: corticospinal tract; d: day; EPO: erythroprotein; EPOR: erythroprotein receptor; g: gram; GAP-43: growth-associated protein 43; h: hour; icv: central venous injection; ig: intragastrical injection; IL: interleukin; IOD: integral optical density; ip: intraperitoneal injection; IV: infarct volume; iv: intravenous injection; kg: kilogram; LB: left behind; LF: left front; LFB: Luxol fast blue; MBP: myelin basic protein; MCAO: middle carotid artery occlusion; mg: milligram; NF-kBp65: nuclear transcription factors in rats Bp65; NFS: neurological function score; NGF: nerve growth factor; NR: not report; PCNA: proliferating cell nuclear antigen; pJAK2: phosphorylated janus kinase 2; pSTAT3: phosphorylated signal transducer and activator of transcription-3; RB: right behind; RF: right front; SD: Sprague Dawley; TTC: 2,3,5-triphenyltetrazolium chloride: VEGF: vascular endothelial growth factor; VWF: Von Willebrand factor; ZL: Zea Longa.