Table 3.

Characteristics of included animal studies related to GBE.

Author	Animal Model	Treatment	Method	Result	Mechanism of Action
Ward, C. P. et al. (2002) [12]	C57BL/6 mice, male, 20 months old	EGb 761 (100 mg/kg/day), orally for 82 consecutive days	1. Morris water maze test	↑the time of hidden platform ↓platform crossings (probe test)	Improved the learning and memory cognition
			2. Elevated plus-maze test	↓time on the open arms
			3. Protein levels of CREB	no significant differences	Antioxidant properties
Stackman, R. W. et al. (2003) [14]	Tg2576 mice, female, 8 months old	EGb 761 (70 mg/kg/day), orally for 6 months	1. Morris water maze test	↓average distance to the platform ↑search ratio	Alleviated the spatial learning impairment
			2. Fibrillar and soluble β-amyloid and protein oxidation products (ELISA)	↓soluble β-amyloid	N/A
			3. Histological assessment	↓β-amyloid
			4. Protein carbonyl	↑protein carbonyls	Antioxidant properties
Gong, Q. H. et al. (2005) [15]	Wistar rats, male, 8–12 weeks old, daily AlCl3 solution, (500 mg/kg, i.g, 0.5 mL/100 g), gavage for 1 month	EGb761 (50 mg/kg/day, 100 mg/kg/day, 200 mg/kg/day), orally for 2 months	1. Morris water maze test	↓searching distance ↓escape latency	Ameliorated the learning and memory abilities
			2. Level of caspase-3	↓caspase-3	Antiapoptosis
			3. Level of APP (immunohistochemistry)	↓APP	N/A
Wang, Y. et al. (2006) [16]	1. Wistar rats, male, 12–13 weeks old 2. Wistar rats, male, 74–78 weeks old (aged)	1. EGb761 (30 mg/kg/day) 2. EGb761 (60 mg/kg/day), orally for 30 consecutive days	1. Morris water maze test	↓escape latency ↑search time	Improved spatial learning in aged animals
			2. Changes in synaptic plasticity	↑hippocampal LTP	N/A
Gong, Q. H. et al. (2006) [17]	Wistar rats, male, 8–12 weeks old, daily 50 g/L AICI3, gavage for 2 months	EGb761 (50 mg/kg/day, 100 mg/kg/day, 200 mg/kg/day), orally for 2 months	1. Morris water maze test	↓escape latency ↓searching distance	Reduced learning and memory deficits
			2. Effect of AChE activity	↓AChE activity	Cholinergic improvement
Tchantchou, F. et al. (2007) [18]	1. TgAPP/PS1 founder mice, 6 months old 2. TgAPP/PS1 founder mice, 22 months old	EGb761 (100 mg/kg/day), orally for 1 month	1. Determine the neurogenic potential	↑cell proliferation in the hippocampus	Induced neurogenesis as compensation
			2. Levels of Aβ and CREB/pCREB	↓Aβ oligomers ↑pCREB levels in the hippocampus	N/A
Blecharz-Klin, K. et al. (2009) [19]	Wistar rats, male 18 months old	1. EGb761 (50 mg/kg b.w./day); 2. EGb761 (100 mg/kg b.w./day); 3. EGb761 (150 mg/kg b.w./day); orally for 3 months	1. Morris water maze test	↓crossings ↓escape latency ↓mean swimming speed	Improved spatial memory
			2. Hole-board test	↑motor activity
			3. HPLC detects the levels of DA, 5-HT, NA, and HVA	↑NA in prefrontal cortex and hippocampus ↓DA in prefrontal cortex and hippocampus ↑DOPAC in the prefrontal cortex ↓DOPAC in hippocampus ↑5-HT in the striatum	Neurotransmitter balance regulation
Hou, Y. et al. (2010) [20]	TgAPP/PS1 mice, male, 8 months old	1. Ginkgo biloba extract (50 mg/kg/day),gavage for 4 months; 2. flavonol (50 mg/kg/day), i.p. for 7 days	1. Morris water maze test	↓time needed to find the platform	Improved impaired spatial learning
			2. Levels of BDNF, pCREB, and Aβ	↑BDNF in neurons and hippocampus ↓both intracellular and medium Aβ levels	NMDA receptor Antagonist Anti-inflammatory activity
			3. Immunohistochemistry of Aβ deposition	↓Aβ deposition and plaque formation in hippocampus	N/A
Tian, X. et al. (2012) [21]	Sprague–Dawley rats, male, 3–4 months old, Aβ25-35 (1 µg/µL), i.c.v.	EGb761 (40 mg/tablets), gavage for 20 days	1. Morris water maze test	↓escape latencies ↑platform crossing times ↑percentage of swimming time in Quadrant 1	Improved the learning and memory cognition
			2. Histopathological changes in Aβ	↓density of the damaged neurons ↑neuronal number	Anti-inflammatory activity
			3. Activity of SOD, MDA, and NO	↓SOD ↓MDA ↓NO	Antioxidant properties
Tian, X. et al. (2013) [22]	Sprague–Dawley rats, male, 4–5 months old, Aβ25–35 (1 µg/µL), i.c.v.	EGB761 (20 mg/kg/day), gavage for 20 days	1. Morris water maze test	↓escape latency ↑platform crossings	Improved the learning and memory cognition
			2. Levels of SOD, GSH, and MDA	↓SOD ↑GSH ↓MDA	Antioxidant properties
			3. Levels of caspase-9 and caspase-3	↓caspase-9 ↓caspase-3	Inhibited cell apoptosis
			4. TUNEL staining	↓neuronal apoptosis
			5. RT-PCR of Bcl-2	and Bax ↑Bcl-2 ↓Bax	Inhibited cell apoptosis
Jahanshahi, M. et al. (2013) [23]	Wistar rats, male, Scopolamine (3 mg/kg), intraperitoneal injection	Ginkgo biloba extract (40 and 80 mg/kg, IP), everyday injection for a week	1. TUNEL staining	↓apoptotic cells in the hippocampus	Antioxidant and hydroxyl radical scavenging activity
Zhang, L.-D. et al. (2015) [24]	Sprague–Dawley rats, male, 5–6 months old, Aβ25–35 (10 μL; 1 g/L), i.c.v.	EGB761 (20 mg/kg/day), gavage for 20 days	1. Morris water maze test	↑times of crossing the former platform ↑percentage of time spent in the quadrant	Improved cognitive and memory capacities
			2. TUNEL staining	↓brown precipitate (apoptosis identification)	Inhibited cell apoptosis
			3. Levels of p-IKKα/β, p-IκBα, and p-NFκB	↑p-IKKα/β ↑p-IκBα ↑p-NFκB	Anti-inflammatory activity
Liu, X. et al. (2015) [25]	TgCRND8 APP-transgenic mice, female, 2 months old	EGb761 (600 mg/kg/day) (0.6%), orally for 5 months	1. Barnes maze test	↓time and ↓distance to reach the escape chamber	Improved cognitive function
			2. Level of Aβ (ELISA) (%)	↓Aβ	N/A
			3. Immunofluorescent staining of Aβ
			4. Histological analysis of Iba1	↓Iba1 positive cell number	Neuroinflammatory inhibition
			5. Levels of tnf-α, il-1β, ccl-2, and IL-10	↓TNF-α, IL-1β, ccl-2, iNOS, and IL-10
Wan, W. et al. (2016) [26]	APP/PS1 transgenic mice, male, 2 months old	EGb761 (50 mg/kg/day), orally for 6 months	1. Morris water maze test	↓escape latency ↓time of passing the platform ↑crossing times	Improved cognitive function
			2. Level of Aβ (ELISA)	↓Aβ	N/A
			3. Ratio of fluorescence intensity	↑microglia around the plaque	Attenuated inflammatory reactions
Zeng, K. et al. (2018) [27]	Sprague–Dawley rats, male, 8 weeks old, Hhcy (400 μg/kg/day), for 14 days i.p.	EGb761 (400 mg/kg/day), gavage for 7 days	1. Morris water maze test	↓escape latency	Ameliorated memory deficits
			2. Levels of SOD and MDA	↓SOD↓MDA	Antioxidant properties
			3. Levels of tau phosphorylation, PSD95, and synapsin-1	↓tau phosphorylation ↑PSD95 ↑synapsin-1	Attenuated oxidative damage
Verma, S. et al. (2019) [28]	Sprague–Dawley rats, female, 12 months old, Al(lac)3 (10 mg/kg b.wt), daily for 6 weeks	Ginkgo biloba extract, EGb761 (100 mg/kg/day), orally for 6 weeks	1. Morris water maze test	↓time to find the platform ↓escape latency	Improved spatial memory
			2. Histopathological changes in Aβ	↓ThT positive cells in hippocampusand cortex ↓Congo red	Antioxidative stress
			3. Levels of 5-HT, GSH, GST, and SOD	↑5-HT↓SOD↑GSH↓GST
			4. AChE activity	↓AChE activity in the hippocampus and cortex
Verma, S. et al. (2020) [29]	Sprague–Dawley rats, female, 12 months old, Al(lac)3 (10 mg/kg b.wt), daily for 6 weeks	Ginkgo biloba extract, EGb761 (100 mg/kg/day), orally for 6 weeks	1. Morris water maze test	↓escape latency	Prevented behavioral impairments
			2. Level of ROS	↓ROS	Antioxidative stress
			3. Protein level of APP, Aβ, and p-Tau (ELISA)	↓APP ↓Aβ ↓p-Tau	N/A
			4. Histopathological changes	↓silver positive deposits in CA1, CA3 ↓congo red positive deposits in CA1, CA3 ↓ThT positive deposits	Antioxidative stress
			5. AchE activity	↓AChE enzyme activity	Cholinergic improvement Neurotransmitter balance regulation
			6. Level of MAO-B	↓MAO-B enzyme activity
			7. Immunohistochemistry of Aβ (17–23)	↓Aβ (17–23)	N/A