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. 2022 Jun 6;13:917375. doi: 10.3389/fphar.2022.917375

TABLE 2.

Basic characteristics of the 20 included studies.

Study (year) Species (sex, n = treatment/control group, age, weight) Modeling method and standard Berberine intervention (administration, drug dose, duration) Outcomes Intergroup difference
Bhutada et al. (2011) Wistar rats (male, 18/6, 200–220 g) Intraperitoneal injection of STZ (60 mg/kg), By intragastric 1. FBG 1. p < 0.01
BG > 250 mg/dl 25/50/100 mg/kg/d 2. MWM 2. p < 0.05
4 weeks 3. LPO 3. p < 0.01
4. GSH 4. p < 0.01
5. AChE 5. p < 0.01
Ma et al. (2012a) Sprague-Dawley rats (male, 18/6, 180–220 g) Intraperitoneal injection of STZ (40 mg/kg) + HSFD By intragastric 1. FBG 1. p < 0.01
BG > 11.1 mmol/L 50/100/200 mg/kg/d 2. MWM 2. p < 0.05
4 weeks 3. SOD, MDA 3. p < 0.05
4. AChE 4. p < 0.01
5. Bax, Bcl-2
6. IGF-1
Ma et al. (2012b) Sprague-Dawley rats (male, 18/6, 180–220 g) Intraperitoneal injection of STZ (40 mg/kg) + HSFD By intragastric 1. FBG 1. p < 0.05
BG ≥ 16.7 mmol/L 50/100/200 mg/kg/d 2. CAT 2. p < 0.01
4 weeks 3. LPO 3. p < 0.01
4. GSH 4. p < 0.01
5. BDNF
Kalalian-Moghaddam et al. (2013) Wistar rats (male, 12/6, 225–285 g) Intraperitoneal injection of STZ (55 mg/kg) By intragastric 1. FBG 1. p < 0.01
BG > 250 mg/dl 50/100 mg/kg/d 2. Y-maze 2. p < 0.05
11 weeks 3. Passive avoidance 3. p < 0.05
4. PS, EPSP 4. p < 0.01
5. Nissl/TUNEL neuron 5.p < 0.05
Moghaddam et al. (2013) Wistar rats (male, 20/10, 225–285 g) Intraperitoneal injection of STZ (55 mg/kg), By intragastric 1. FBG 1. p < 0.01
BG > 250 mg/dl 50/100 mg/kg/d 2. PS, EPSP 2. p < 0.01
12 weeks
Moghaddam et al. (2014) Wistar rats (male, 24/12, 225–285 g) Intraperitoneal injection of STZ (55 mg/kg), By intragastric 1. FBG 1. p < 0.05
BG > 250 mg/dl 50/100 mg/kg/d 2. MDA 2. p < 0.05
8 weeks 3. SOD 3. p < 0.05
4. NO 4. p < 0.05
5. GFAP 5. p < 0.05
Zhou et al. (2016) Wistar rats (male, 10/10, 180–220 g) Intraperitoneal injection of STZ (35 mg/kg) + HSFD By intragastric 1. FBG 1. p < 0.01
BG > 16.7 mmol/L 100 mg/kg/d 2. HbA1c 2. p < 0.01
23 weeks 3. MWM 3. p < 0.01
4. TG, TC 4. p < 0.01
5. p-p38/p38
6. p-JNK/JNK
7.p-ERK/ERK
5. p < 0.01
6. p < 0.01
7. p > 0.05
Chen et al. (2017) Wistar rats (male, 8/8, aged 4–5 weeks, about 200 g) Caudal vein injection of STZ (25 mg/kg) + HSFD By intragastric 1. Conditioned fear 1. p < 0.01
BG ≥ 11.2 mmol/L 187.75 mg/kg/d 2. PDG PET 2. p < 0.01
10 weeks 3. p-IRS-1 3. p < 0.01
4. p-PI3K/PI3K 4. p < 0.05
5. p-Akt/Akt 5. p < 0.05
6. p-GSK3β/GSK3β
7. p-IKKβ, p-NF-κB/NF-κB
8. p-JNK/JNK
6. p < 0.05
9. IL-1β, TNF-α 7. p < 0.05
10. GLUT3 8. p < 0.05
11. PKC 9. p > 0.05
12. APP 10. p < 0.01
13. BACE1 11. p < 0.05
12. p < 0.01
13. p < 0.05
Wang et al. (2018) Wistar rats (male, 15/12, aged 5–6 weeks, 180–200 g) Caudal vein injection of STZ (25 mg/kg) + HFD, By intragastric 1. FBG 1. p < 0.05
BG ≥ 11.2 mmol/L 100/200 mg/kg/d 2. Serum insulin 2. p < 0.05
10 weeks 3. MWM 3. p < 0.01
4. p-Tau Ser202/Tau-5 4. p < 0.01
5. p-Tau Ser404/Tau-5
6. p-PI3K/PI3K
5. p < 0.01
7. p-Akt/Ak 6. p < 0.01
8. p-GSK3β/GSK3β 7. p < 0.01
8. p < 0.01
Li et al. (2018) db/db mice (female, 8/8,7 weeks) Spontaneous diabetic model By intragastric 1. Serum insulin 1. p < 0.05
50 mg/kg/d 2. 2hBG of OGTT 2. p > 0.05
10 weeks 3. 2hBG of ITT 3. p < 0.05
4. MWM 4. p < 0.05
5. Y-maze, conditioned fear 5. p < 0.01
6. TG, TC, HDL-C 6. p < 0.05
7. LDL-C 7. p < 0.01
8. PSD95, SYN, NGF 8. p < 0.01
9. TNF-α, NF-κB 9. p < 0.05
10. SIRT1
11. p-PERK/PERK
10. p < 0.05
12. p-IRE1α/IRE1α 11. p < 0.05
13. p-eIF2α/eIF2α 12. p < 0.05
14. CHOP 13. p < 0.05
14. p < 0.05
Wang et al. (2019) Wistar rats (male, 8/8, aged 4–5 weeks, 180–200 g) Caudal vein injection of STZ (25 mg/kg) + HSFD, By intragastric 1. FBG 1. p < 0.01
BG > 11.2 mmol/L 187.75 mg/kg/d 2. Serum insulin 2. p < 0.01
10 weeks 3. MWM 3. p < 0.01
4. PDG PET 4. p < 0.01
5. IL-18, IL-1β 5. p < 0.05
6. TNF-α
7. p-IKK/IKK
8. p-NF-κB/NF-κB
6. p < 0.01
9. GFAP 7. p < 0.05
10. AChE 8. p < 0.05
11. Insulin receptor, p-IRS1 9. p < 0.01
12. PI3K, p-Akt/Akt 10. p < 0.05
13. APP, BACE1 11. p < 0.05
14. Aβ42 12. p < 0.01
13. p < 0.01
14. p < 0.05
Tong et al. (2019) Sprague-Dawley rats (male, 9/9, 170–200 g) Intraperitoneal injection of STZ (55 mg/kg), By intragastric 1. FBG 1. p > 0.05
BG > 16.7 mmol/L 60 mg/kg/d 2. MWM 2. p < 0.05
6 weeks 3. Bcl-2, Caspase-3 3. p < 0.05
4. Notch1 4. p < 0.05
5. TUNEL neuron 5. p < 0.01
6. Brain pathology
Xuan (2021) ICR mice (male, 15/15, aged 8 weeks) Intraperitoneal injection of STZ (50 mg/kg) + HSFD, By intragastric 1. FBG 1. p < 0.05
BG ≥ 13.9 mmol/L 50 mg/kg/d 2. MWM 2. p < 0.05
8 weeks 3. Nissl neuron 3. p < 0.01
4. MDA 4. p < 0.01
5. Bcl-2, Bax 5. p < 0.01
6. Caspase-3 6. p < 0.01
7. Nrf2, HO-1 7. p < 0.01
8. NQO1 8. p < 0.01
Liu (2021) ICR mice (male, 15/15, aged 8 weeks, 25–30 g) Intraperitoneal injection of STZ (50 mg/kg) + HSFD, By intragastric 1. FBG 1. p < 0.05
BG ≥ 13.9 mmol/L 50 mg/kg/d 2. MWM 2. p < 0.05
8 weeks 3. Nissl neuron 3. p < 0.05
4. MDA 4. p < 0.05
5. NF-κB 5. p < 0.01
6. TNF-α 6. p < 0.05
7. IL-1β 7. p < 0.01
8. Nrf2, HO-1 8. p < 0.01
9. NQO1 9. p < 0.05
Adefegha et al. (2021) Rats (16/8, 200–230 g) Intraperitoneal injection of STZ (50 mg/kg) By intragastric 1. FBG 1. p < 0.05
BG ≥ 250 mg/dl 50/100 mg/kg/d 2. AChE 2. p < 0.01
2 weeks 3. BChE 3. p < 0.05
4. MAO, MDA 4. p < 0.01
5. SOD, GSH-Px 5. p < 0.05
6. GSH 6. p > 0.05
Zhang et al. (2021) Sprague-Dawley rats (male, 8/8, 180–220 g) Intraperitoneal injection of STZ (30 mg/kg) + HFD By intragastric 1. 2hBG of OGTT 1. p < 0.01
BG > 16.7 mmol/L 150 mg/kg/d 2. MWM 2. p < 0.01
4 weeks 3. Aβ 3. p < 0.05
4. Tau 4. p < 0.01
5. p-Tau 5. p < 0.05
6. Insulin receptor 6. p < 0.01
7. Nissl/TUNEL neuron 7. p < 0.01
Wu et al. (2021) Wistar rats (male, aged 6–8 weeks, 180–200 g) Caudal vein injection of STZ (25 mg/kg) + HSFD By intragastric 1. MWM 1. p <0.05
BG > 11.2 mmol/L 200 mg/kg/d 2. p-IRS-1
13 weeks 3. PI3K, PKC
4. GLUT3
Cao et al. (2021) db/db mice (female, 8/8, aged 10 weeks) Spontaneous diabetic model By intragastric 1. FBG 1. p < 0.01
135 mg/kg/d 2. 2hBG of OGTT 2. p < 0.01
10 weeks 3. 2hBG of ITT 3. p < 0.01
4. HbA1c 4. p < 0.01
5. MWM 5. p < 0.05
6. TNF-α 6. p < 0.01
7. IL-1β, IL-6 7. p < 0.01
8. NLRP3 8. p < 0.01
Tian et al., 2021 Wistar rats (male, 8/8, aged 6–8 weeks, 180–200 g) caudal vein injection of STZ (25 mg/kg) + HSFD By intragastric 1. FBG 1. p < 0.01
BG > 11.2 mmol/L 50/200 mg/kg/d 2. MWM 2. p < 0.01
4 weeks 3. MMP 3. p < 0.01
4. ROS, GSH, MDA 4. p < 0.01
5. RhoC, ROCK 5. p < 0.01
Ma and Liu et al. (2021) Kunming mice (male, 27/10, 20–25 g) Intraperitoneal injection of STZ (40 mg/kg) By intragastric 1. MWM 1. p < 0.05
BG > 11.1 mmol/L 20/40/80 mg/kg/d 2. TNF-α 2. p < 0.05
4 weeks 3. IL-1β 3. p < 0.05
4. AGEs 4. p < 0.05
5. RAGE 5. p < 0.05
6. NF-κB 6. p < 0.01

AChE, acetylcholinesterase; AGEs, advanced glycation end products; Akt, protein kinase B; APP, amyloid precursor protein; Aβ, amyloid β; BACE1, beta-secretase 1; BChE, butyrylcholinesterase; Bcl-2, B-cell lymphoma-2; Bax, bcl2-associated x; BDNF, brain-derived neurotrophic factor; CAT, catalase; CHOP, C/EBP homologous protein; eIF2α, eukaryotic initiation factor 2α; EPSP, excitatory post-synaptic potential; EPK, extracellular-regulated protein kinases; BG, blood glucose; FBG, fasting blood glucose; FDG PET, fluorodeoxyglucose positron emission tomography; GFAP, glial fibrillary acidic protein; GLUT3, glucose transporter 3; GSH, glutathione; GSH-Px, glutathione peroxidase; GSK3β, glycogen synthase kinase 3β; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; HO-1, haeme oxygenase-1; HFD, high-fat diet; HSFD, high-sugar and high fat diet; IGF-1, insulin-like growth factor 1; IKK, inhibitor of kappa B kinase; IL-1β, interleukin-1β; IRE1α, inositol-requiring enzyme 1α; IRS, insulin receptor substrate; ITT, insulin tolerance test; JNK, c-Jun N-terminal kinases; LDL-C, low-density lipoprotein cholesterol; LPO, lipid peroxidation; MAO, monoamine oxidase; MDA, malondialdehyde; MWM, Morris water maze; MMP, matrix metalloproteinase; NF-κB, nuclear factor-κB; NGF, nerve growth factor; NO, nitric oxide; NQO1, NADPH quinone oxidoreductase 1; Nrf2, nuclear factor erythroid-2 related factor 2; OGTT, oral glucose tolerance test; PERK, protein kinase R-like ER kinase; PI3K, phosphatidylinositide 3-kinases; PKC, protein kinase C; PS, population spike; PSD95, postsynapticdensity 95; RAGE, receptors for advanced glycation end products; ROCK, Rho-associated kinase; ROS, reactive oxygen species; SIRT1, sirtuin1; SOD, superoxide dismutase; STZ, streptozotocin; SYN, synaptophysin; TC, total cholesterol; TG, triglyceride; TNF-α, tumor necrosis factor α.