. 2023 Nov 29;9(12):e22957. doi: 10.1016/j.heliyon.2023.e22957

Table 3.

Neuroprotection of butylphthalide in different animal experimental models of brain impairment.

Animal	Model	Dosage	Administration	Effects	Mechanisms	Reference
Male CD-1 mice	Cerebral infarction by permanent MCAO	120 mg/kg	–	Neurologic function deficits, Infarction volume, Edema, BBB permeability, MMP- 9↓	Nrf-2/HO-1	[109]
Male CD-1 mice	Cerebral infarction by permanent MCAO	120 mg/kg	–	Claudin-5, VEGF, GFAP, Ultrastructure in capillary endothelial cells, Nrf-2, HO-1↑	Nrf-2/HO-1	[109]
Female SD rats	Cerebral infarction by MCAO	15 mg/kg	i.p.	Neurological score, White region, Apoptosis rate, p38 and MAPK ↓	p38/MAPK	[37]
Male C57BL/6 mice	Cerebral ischemia by transient MCAO or photothrombosis	60 mg/kg	i.g. daily for 3 days	Intercellular adhesion molecule 1, Protease-activated receptor 1, Brain infiltration of myeloid cells↓	Neurovascular inflammation	[110]
Male C57BL/6 mice	Cerebral ischemia by transient MCAO or photothrombosis	60 mg/kg	i.g. daily for 3 days	CBF↑	Neurovascular inflammation	[110]
Male Wistar rats	Cerebral ischemia	70 mg/kg	p.o. daily for 14 days	Number and length of crossing corticospinal tract fibers, Synapse-associated proteins including PSD95 and VGlut-1, Behavioral performance↑	Axonal growth and neurogenesis	[111]
Male C57BL/6J mice	CCH by BCAS	80 mg/kg	p.o. daily for 60 days	Spatial memory dysfunction, BBB leakage, Endothelial cells damage, Endothelial tight junctions disruption↓	–	[16]
Male C57BL/6J mice	CCH by BCAS	80 mg/kg	p.o. daily for 60 days	Cerebral perfusion, White matter integrity↑	–	[16]
Male APP/PS1 transgenic mice	AD	15 mg/kg	p.o. daily for 90 days	Number of synapses, Apical dendritic thorns, Thickness of PSD, Synapse-associated proteins including PSD95, synaptophysin (SYN), b-catenin, and GSK-3β, Synaptic and Spine function↑	Wnt/β-catenin	[112]
Male APP/PS1 transgenic mice	AD	15 mg/kg	p.o. daily for 90 days	Aβ plaques and Neuroinflammatory responses↓	Wnt/β-catenin	[112]
Male APP/PS1 transgenic mice	AD	20 and 60 mg/kg	p.o. daily for 150 days	Oxidative stress, Learning and memory deficits, Soluble amyloid beta, Amyloid beta oligomer, ↓	CREB/CBP/Nrf-2	[113]
Male APP/PS1 transgenic mice	AD	20 and 60 mg/kg	p.o. daily for 150 days	Synaptic plasticity, CBP, CREB phosphorylation, Recruitment of CBP to the promoters of best-characterized genes downstream of Nrf-2, NADPH quinone oxidoreductase 1, and g-glutamyl cysteine synthetase modifier subunit↑	CREB/CBP/Nrf-2	[113]
Male C57BL/6 mice	PD by MPTP	100 mg/kg	i.p. daily for 9 days	Dopaminergic neurodegeneration, Motor deficits, Microglial activation, Pro-inflammatory mediators↓	MAPK, NF-kB and PI3K/Akt	[15]
Male C57BL/6 mice	PD by LPS	120 mg/kg	i.g. daily for 30 days	Behavioral deficits, Dopaminergic neurodegeneration, Phosphorylation of JNK and p38↓	JNK	[114]
Transgenic (SOD1-G93A) mice	ALS	30 and 60 mg/kg	p.o.	Motor performance, Survival interval, Nrf2, HO-1↑	Nrf2/HO-1/NF-kB	[115]
Transgenic (SOD1-G93A) mice	ALS	30 and 60 mg/kg	p.o.	Motor neuron loss, Motor unit reduction, Immunoreactivity of CD11b and GFAP, NF-kB p65, TNF-a protein↓	Nrf2/HO-1/NF-kB	[115]
Male SD rats	ICH	25 mg/kg	p.o. daily for 15 days	Longa's motor scores, Neurological defects↓	Angiogenesis	[116]
Male SD rats	ICH	25 mg/kg	p.o. daily for 15 days	Numeric density of blood vessels, VEGF, Ang-2 proteins↑	Angiogenesis	[116]
Male SD rats	ICH	25 mg/kg	i.p. twice daily for 2 days	Neurological function↑	Inflammation	[117]
Male SD rats	ICH	25 mg/kg	i.p. twice daily for 2 days	Hematoma volume, Brain edema, BBB permeability, TNF-α, MMP-9 ↓	Inflammation	[117]
Male Wistar rats	Concussive head injury	40 and 60 mg/kg	i.p.	BBB breakdown, Brain pathology↓	Glial activation	[118]
Male SD rats	Diffuse brain injury	80 and 160 mg/kg	i.p. daily for 3 days	Cerebral ultrastructure damage, BBB age, Cerebral edema↓	Microcirculation disorder	[119]
Male SD rats	Diffuse brain injury	80 and 160 mg/kg	i.p. daily for 3 days	Vascular density, CBF, Motor and sensory functions↑	Microcirculation disorder	[119]
Male ICR mice	Traumatic Brain Injury	100 mg/kg	i.p.	Neurological deficits, Brain water content, Cortical neuronal apoptosis↓	Nrf2-ARE	[120]
Male ICR mice	Traumatic Brain Injury	100 mg/kg	i.p.	MDA, SOD activity, GPx, Translocation of Nrf2 protein from the cytoplasm to the nucleus, HO-1, NQO1↑	Nrf2-ARE	[120]
Male C57BL/6 mice	Traumatic brain injury	100 mg/kg	p.o. daily for 7 days	BBB disorder, Mitochondrial apoptosis, Autophagy-related proteins, including ATG7, Beclin1 and LC3II↓	Autophagy	[121]
Male C57BL/6 mice	Traumatic brain injury	100 mg/kg	p.o. daily for 7 days	Neuronal survival, Tight junction proteins, Locomotor functional recovery↑	Autophagy	[121]
Female SD rats	SCI	80 mg/kg	p.o. daily for 7 days	Locomotor recovery↑	TLR4/NF-κB	[122]
Female SD rats	SCI	80 mg/kg	p.o. daily for 7 days	Lesion cavity area of the spinal cord, Apoptotic activity in neurons, Number of TUNEL-positive cell, Activation of microglia, Release of inflammatory mediators, Microglial TLR4/NF-κB↓	TLR4/NF-κB	[122]
Female SD rats	SCI	80 mg/kg	p.o. daily for 7 days	BSCB permeability, Breakdown of AJ and TJ proteins, ER stress, ER stress-associated proteins↓	ER stress	[123]
Female SD rats	SCI	80 mg/kg	p.o. daily for 7 days	Locomotion recovery↑	ER stress	[123]
Male SD rats	VD by CCH	60 and 120 mg/kg	p.o. daily for 28 days	Spatial learning and memory impairment, Loss of neurons in the CA1 region of the hippocampus, Endoplasmic reticulum stress-related markers↓	Shh/Ptch1	[124]
Male SD rats	VD by CCH	60 and 120 mg/kg	p.o. daily for 28 days	Plasticity‐related synaptic markers, Shh/Ptch1 pathway↑	ER stress	[124]
Male SD rats	VD by CCH	5 mg/kg	i.v. daily for 21 days	Cognitive function, GDNF/GFRa1/Ret signaling, Phosphorylation AKT (p-AKT) and ERK1/2 (p-ERK1/2) signaling, Bcl-2↑	GDNF/GFRa1/Ret	[125]
Male SD rats	VD by CCH	5 mg/kg	i.v. daily for 21 days	Hippocampal neuron apoptosis, Bax, Cleaved caspase-3↓	AKT/ERK1/2	[125]
Male SAMR1 and SAMP8 mice	Age-related dementia	40 and 80 mg/kg	p.o. daily for 90 days	Cognitive impairment↓	Brain-derived neurotrophic factor/TRK-B signaling	[126]
Male SAMR1 and SAMP8 mice	Age-related dementia	40 and 80 mg/kg	p.o. daily for 90 days	Synaptophysin, Postsynaptic density protein 95, Hippocampal structural synaptic plasticity↑	Brain-derived neurotrophic factor/TRK-B signaling	[126]