TABLE 1.
Overview of animal studies of diabetic drugs in treatment of AD.
| Diabetic drugs | Object of study | Brief cohort description | Outcome characteristics | References |
|---|---|---|---|---|
| Metformin | Male rats | HFD-fed rats were assigned into three subgroups with vehicle, nec-1, or metformin for 8 weeks. | Cognitive function, synaptic plasticity, dendritic spine density, microglial morphology, brain mitochondrial function, brain insulin sensitivity↑; hyperphosphorylated-tau and necroptosis↓ | Jinawong et al. |
| Metformin | Wistar rats | Metformin 200 mg/kg was given intravenously to the cardiac I/R group, either during ischemia (D-MET) or at the onset of reperfusion (R-MET). | glucose level, IR,GSK3β, and JNK↓, GLP-1, insulin-like growth factor-1, AMPK, and PI3K/Akt↑ | Benjanuwattra et al. |
| Metformin | APP/PS1xdb/db mice | AD-T2DM mice were received polypills in the diet from 4 to 26 weeks of age. | Learning and memory deficits, brain atrophy and neuronal loss; metabolic parameters↑; synaptic loss, Aβ, and p-tau↓ | Infante-Garcia et al. |
| Metformin | APP/PS1 mice | APP/PS1 mice were treated with tap water with Metformin freely for 12 weeks. | cognition, CMA-activated degradation of Aβ↑ | Xu et al. |
| Metformin | db/db mice, High glucose-cultured HT22 cells | Twelve-week old male db/db mice received consecutive intraperitoneal injection of 200 mg/kg/d metformin or (and) 10 mg/kg/d chloroquine for 8 weeks. | Cognition, autophagy activity in an AMPK dependent manner↑; hyperphosphorylated tau↓ | Chen et al. |
| Metformin | Human ApoE (huApoE)-TR homozygous mice of the C57BL/6J background | Thirteen-month-old female ApoE3-TR and ApoE4-TR mice were respectively randomized into metformin group and normal saline (NS) group | mTOR signaling and tau phosphorylation↑ | Zhang et al. |
| Metformin | C57BL/6 mice | ICV-STZ-injected mice were treated with intranasal or oral metformin for 4 weeks. | Learning and memory functions, phosphorylated insulin receptor and pAkt↑ | Kazkayasi et al. |
| Metformin | transgenic Caenorhabditis elegans strain | Treated with metformin | normalized lifespan ↑; Aβ-induced metabolic defects, and protein aggregation↓ | Teo et al. |
| Metformin | SH-SY5Y cells Tg6799 AD model mice | Fourteen week-old female Tg6799 were injected daily with 200 μL intraperitoneal metformin or isotonic sodium chloride for 9 days. | gamma-secretase activity, Aβ generation, autophagy and AMPK↑; mTOR↓ | Son et al. |
| Metformin | APP/PS1 mice | Treated with metformin | autophagic activity in microglia↑; Aβ load and NP tau aggregation↓ | Chen et al. |
| Metformin | C57BL/6 mice | Treated with metformin | APP and Aβ↑; mitochondrial function of brain neurons↓ | Picone et al. |
| Metformin | N2a695 cells | Pretreated with metformin for 24 h | Aβ, AMPK and BACE1 ↑ | Chen et al. |
| Metformin | Sprague Dawley albino male mature rats | Following stereotaxic surgery, STZ received rats were treated with either saline or exenatide 20 mu gr/kg/day through intraperitoneally for 2 weeks. | Cholinergic activity and cognition↑; the inflammation response↓ | Solmaz et al. |
| Exendin-4 | Human neuroprogenitor cells | Pre-incubation of neurons with exendin-4 | Exendin-4 protected the neurons from apoptosis induced by Ab oligomers and stimulated cyclic AMP response element binding protein phosphorylation | Velmurugan et al. |
| Exenatide | PS1-KI mice 3xTg-AD mice | Daily injection of exenatide (500 mg/kg BW) or saline for 5 days a week. | In PS1-KI mice: long-term memory performances, brain lactate dehydrogenase activity, and lactate levels ↑; no effects were observed on mitochondrial respiration. In 3xTg-AD mice: exenatide had no effects on brain metabolism | Bomba et al. |
| Exendin-4 | Goto-Kakizaki (GK) rats | Exendin-4 was continuously administered for 28 days, via s.c. Implanted micro-osmotic pumps (5 mu g/kg/day; infusion rate 2.5 mu L/h). | GLP-1, insulin-like growth factor-1 (IGF-1), AMPK, and PI3K/Akt↑; glucose level, IR,GSK3β, and JNK↓ | Candeias et al. |
| Exendin-4 | Sprague-Dawley rats | T2DM rats were injected with exendin-4 for 28 consecutive days. | PI3K/Akt↑, GSK3β, and tau hyperphosphorylation↓ | Xu et al. |
| Exendin-4 | PC12 cells Wistar rats | Administered exendin-4 (10 μg/kg body weight;) by a twice-daily subcutaneous injection for 14 days. | GSK3β and tau hyperphosphorylation↓ | Chen et al. |
| Exendin-4 | APP/PS1 mice | Intraperitoneal injections of exendin (25 nmol/kg, dissolved in saline) for 3 weeks. | IRS-1 and JNK↑ | Bomfim et al. |
| Exenatide | Adult wild-type mice | 2-month treatment with exenatide | Long-term memory performances, and the BDNF-TrkB neurotrophic axis↑; apoptosis↓ | Bomba et al. |
| Exenatide | 3xTg-AD mice | administered exenatide (500 μg/kg body weight) via intraperitoneal injection 5 days per week. | BDNF signaling↑; inflammation↓ | Bomba et al. |
| Liraglutide | SH-SY5Y cells | Cells were pre-treated with 10, 100, and 200 nM Liraglutide | Cell viability and Akt↑; cytotoxicity and apoptosis↓ | Sharma et al. |
| Liraglutide | Sprague–Dawley rats | Dissolved peptide (0.05–5 nmol liraglutide and/or 4 nmol Aβ25–35) solution (4 μL) was injected into the bilateral hippocampus.Control rats received only saline. | The Aβ(25–35)-induced impairment of spatial memory, deficit of L-LTP↓ | Han et al. |
| Liraglutide | APP/PS1 mice | Injected liraglutide at 25 nmol/kg body weight intraperitonially for 8 weeks. | Young neurons in the dentate gyrus and LTP↑; memory impairments, synapse loss deterioration of synaptic plasticity, Aβ, inflammation↓ | McClean et al. |
| Liraglutide | C57BL/6 mice | Treated with liraglutide (200 μg/kg) or vehicle for 8 weeks. | Autophagy and AMPK/mTOR↑; cognitive impairment, neuronal injuries, and ultrastructural damage to synapses↓ | Kong et al. |
| Liraglutide | APPswe/PS1dE9 mice with a C57BL/6 background | Liraglutide treatment for 8 weeks at 25 nmol/kg body weight i.p. Once daily | IRS-1↑; IR aberrations, Aβ, astrocytosis, and microglial↓ | Long-Smith et al. |
| Liraglutide | Kunming mice | Injected with liraglutide (300 μg/kg) for 30 days. The control and AD model groups were injected with sterile 0.9% saline. | Learning and memory ability, tau bound to microtubules↑; hyperphosphorylation levels of tau and neurofilament proteins↓ | Xiong et al. |
| Liraglutide | C57BL/6 mice | Treated with either 0.9% NaCl or 25 nmol/kg liraglutide intraperitonially for 30 days. | The activated microglia load, the activated astrocyte load, the pro-inflammatory cytokine levels of IL-6, IL-12p70, IL-1 β, and total nitrite concentration↓ | Parthsarathy and Hoelscher |
| Liraglutide | 10-month-old 3xTg-AD female mice | Treated for 28 days with liraglutide (0.2 mg/kg) | Cortical Aβ(1–42), brain estradiol and GLP-1, oxidative/nitrosative stress and inflammation↓ | Duarte et al. |
| Lixisenatide | APP/PS1/tau female mice | Injected lixisenatide for 60 days at 10 nmol/kg i.p. | PKA-CREB signaling pathway↑; Aβ, NFTs, neuroinflammation and p38-MAPK↓ | Cai et al. |
| (Val(8))GLP-1 | Wistar rats | Treated with STZ (i.c.v.), or treated with STZ+(Val8)GLP-1 i.c.v. | Learning and memory↑; tau, hyperphosphorylated tau, damaged cell nuclei and nucleolus↓ | Li et al. |
| Semaglutide | SH-SY5Y cell line | Treated by semaglutide. | Autophagy↑; apoptosis↓ | Chang et al. |
| DA5-CH | APP/PS1 mice | Injected DA5-CH intraperitoneally at a dose of 10 nmol/kg for 28 days. | Working-memory and long-term spatial memory, L-LTP, and activation of the PI3K/AKT↑; Aβ and p-tau↓, | Cao et al. |
| TA | APP/PS1 transgenic mice | Mice were injected with TA (10 nmol/kg body weight) i.p. Or saline for 2 months. | The anti-apoptotic signaling molecule Bcl-2, BDNF, synaptophysin, and neurogenesis in the dentate gyrus↑; memory deficit, the mitochondrial pro-apoptotic signaling molecule BAX, Aβ, neuroinflammation, and oxidative stress↓ | Kim et al. |
| Saxagliptin | Wistar rats | Orally administered with Saxagliptin (0.25, 0.5 and 1 mg/kg) for 60 days. | GLP-1↑; Aβ, tau phosphorylation and inflammatory markers↓ | Kosaraju et al. |
| Vildagliptin | Wistar rats | Orally administered with vildagliptin (2.5, 5 and 10 mg/kg) for 30 days. | Memory retention↑, GLP-1 levels↑; Aβ↓, tau phosphorylation↓, inflammatory markers↓ | Kosaraju et al. |
| Linagliptin | 3xTg-AD mice | Administered linagliptin orally (5, 10, and 20 mg/kg) for 8 weeks. | Cognitive deficits present↑, brain incretin levels↑; Aβ↓, tau phosphorylation↓, neuroinflammation↓ | Kosaraju et al. |
| Sitagliptin | APP/PS1 mice | The APP/PS1 mice received daily gastric gavage administration of sitagliptin (20 mg/kg) for 8 weeks. | Cognition function, LTP, GLP-1, BDNF-TrkB signalings↑ | Dong et al. |
| Linagliptin | SK-N-MC human neuronal cells | Exposed to 10–100 μM of linagliptin for 24 h | Aβ-induced cytotoxicity↓, GSK3β and tau hyper-phosphorylation↓, Aβ-induced mitochondrial dysfunction and intracellular ROS generation↓ | Kornelius et al. |
| Sitagliptin | OLETF T2DM rats | Given standard rat food or rat food supplemented with 100 mg/kg/day sitagliptin for 12 weeks. | Pathological tau phosphorylation GSK3β and ser-616 phosphorylation of IRS-1↑ | Kim et al. |
| Empagliflozin | db/db mice | Treated the standard diet containing 0.03% empagliflozin for 7 days, 10 weeks, and 16 days respectively | Cardiovascular injury, vascular dysfunction, and cognitive decline↓ | Lin et al. |
| Dapagliflozin | Wistar rats | Rotenone (1.5 mg/kg) was subcutaneously administered every other day for 3 weeks. Dapagliflozin (1(mg/kg)/day, by gavage for 3 weeks) | PI3K/AKT/GSK-3βpathway and glial cell line-derived neurotrophic factor↑; ROS-dependent neuronal apoptosis, neuroinflammation, NF-κB pathway, and TNF-α↓ | Arab et al. |
| Insulin | Adult male Sprague-Dawely rats | Insulin treatment (0.5 or 6 mU) for 6 days. | Aβ-induced memory deterioration, hippocampal caspase-3, ERK and P38 activation↓ | Ghasemi et al. |
| Insulin | 3xTg-AD mice | An intravenous injection of insulin (3.8 units/kg of human insulin) or saline. | Memory ability↑; soluble Aβ levels↓ | Vandal et al. |
| Insulin | APPswe/PS1dE9 mice | 6 weeks of Intranasal insulin treatment in APPswe/PS1dE9 mice. | Cognitive deficits, Aβ production and plaque formation↓ | Mao et al. |
| Insulin | Wild-type mice The immortalized human cerebral microvascular endothelial cell line | Saline (100 µLl) or insulin (1IU) was administered via internal carotid artery. Cells were pre-treatmented with 100 mIU/mL insulin on the luminal side for 20 min. | Upon peripheral insulin administration in wild-type mice: The plasma clearance of Aβ40↑, the plasma-to-brain influx of Aβ40↑, the clearance of intracerebrally injected Aβ42↑; the plasma clearance of Aβ42↓, the plasma-to-brain influx of Aβ42 ↓, the clearance of intracerebrally injected Aβ40↓ In hCMEC/D3 monolayers exposed to insulin: the luminal uptake and luminal-to-abluminal permeability of Aβ40↑, the abluminal-to-luminal permeability of Aβ42 permeability↑; the abluminal-to-luminal permeability of Aβ40↓, the luminal uptake and luminal-to-abluminal permeability of Aβ42↓ Aβ cellular trafficking machinery was altered. | Swaminathan et al. |
| Liraglutide exendin (9–39)amide | Wistar rats | 5 µL of peptides solution were injected icv. | LTP↑; exendin (9–39)amide: LTP↓ | McClean et al. |
| Lixisenatide, Liraglutide | APP/PS1 mice | Ten weeks of daily i.p. Injections with liraglutide (2.5 or 25 nmol/kg) or lixisenatide (1 or 10 nmol/kg) or saline | Performance in an object recognition task↑; LTP, Aβ, chronic inflammation response↓ | McClean and Hoelscher |
| Liraglutide, Insulin | db/db mice | Daily injected subcutaneously with liraglutide, insulin, or saline. | Liraglutide injection: CSF insulin↑; hyperphosphorylation of tau protein↓ insulin injection had no effects on CSF insulin or phosphorylation of tau protein. | Ma et al. |
| Metformin, Insulin | LAN5 neuroblastoma cells | Treated with 12.5, 25, 50, 100 and 200 mM of metformin (SIGMA) in serum free medium for 24 and 48 h, and with 0.1, 1 and 2.5 mM of metformin for 5 or 10 days. | Metformin: APP, presenilin, Aβ, oxidative stress, and mitochondrial damage ↑ Insulin: Aβ, oxidative stress, mitochondrial dysfunction, and cell death↓ | Picone et al. |
Symbol explanation: “↑” means upregulating, increasing, improving and so on. “↓” means downregulating, decreasing, impairing and so on.