Fig 1.
Vehicle, rats treated with distilled water (1.5 ml/kg/day, s.c); Met, rats treated with metformin (500 mg/kg/day, p.o); Saxa, rats treated with saxagliptin (1 mg/kg/day, p.o); D-gal, rats treated with D-galactose (150 mg/kg/day, s.c); D-gal/Met, rats treated with D-galactose and metformin; D-gal/Saxa, rats treated with D-galactose and saxagliptin. Each value represents the mean weight as a percent of the mean weight of the Vehicle group ± S.E. for each group; n = 8. a Significantly different from Vehicle group at p < 0.05. b Significantly different from D-gal group at p < 0.05.
Fig 2.
Spontaneous locomotor activity of rats.
Vehicle, rats treated with distilled water (1.5 ml/kg/day, s.c); Met, rats treated with metformin (500 mg/kg/day, p.o); Saxa, rats treated with saxagliptin (1 mg/kg/day, p.o); D-gal, rats treated with D-galactose (150 mg/kg/day, s.c); D-gal/Met, rats treated with D-galactose and metformin; D-gal/Saxa, rats treated with D-galactose and saxagliptin. Each value represents the mean counts per 10 min as an indication of the rats spontaneous locomotor activity ± S.E. for each group (n = 8).
Table 1.
The mean escape latency time in Morris water maze.
Fig 3.
The mean time spent in the target quadrant in Morris water maze.
MWM, Morris water maze; Vehicle, rats treated with distilled water (1.5 ml/kg/day, s.c); Met, rats treated with metformin (500 mg/kg/day, p.o); Saxa, rats treated with saxagliptin (1 mg/kg/day, p.o); D-gal, rats treated with D-galactose (150 mg/kg/day, s.c); D-gal/Met, rats treated with D-galactose and metformin; D-gal/Saxa, rats treated with D-galactose and saxagliptin. Each value represents mean ± S.E; n = 8. a Significantly different from Vehicle group at p < 0.05. b Significantly different from D-gal group at p < 0.05.
Fig 4.
Blood glycated hemoglobin level.
HbA1c, glycated hemoglobin; Vehicle, rats treated with distilled water (1.5 ml/kg/day, s.c); Met, rats treated with metformin (500 mg/kg/day, p.o); Saxa, rats treated with saxagliptin (1 mg/kg/day, p.o); D-gal, rats treated with D-galactose (150 mg/kg/day, s.c); D-gal/Met, rats treated with D-galactose and metformin; D-gal/Saxa, rats treated with D-galactose and saxagliptin. Each value represents mean ± S.E; n = 8. a Significantly different from Vehicle group at p < 0.05. b Significantly different from D-gal group at p < 0.05.
Fig 5.
Brain contents of MDA, GSH, NOx, and TNF-α.
MDA, malondialdehyde; GSH, reduced glutathione; NOx, nitrite and nitrate, stable metabolites of NO; TNF-α, tumor necrosis factor alpha; Vehicle, rats treated with distilled water (1.5 ml/kg/day, s.c); Met, rats treated with metformin (500 mg/kg/day, p.o); Saxa, rats treated with saxagliptin (1 mg/kg/day, p.o); D-gal, rats treated with D-galactose (150 mg/kg/day, s.c); D-gal/Met, rats treated with D-galactose and metformin; D-gal/Saxa, rats treated with D-galactose and saxagliptin. Each value represents mean ± S.E; n = 6. a Significantly different from Vehicle group at p < 0.05. b Significantly different from D-gal group at p < 0.05.
Fig 6.
Insulin resistance markers in the brain.
Vehicle, rats treated with distilled water (1.5 ml/kg/day, s.c); Met, rats treated with metformin (500 mg/kg/day, p.o); Saxa, rats treated with saxagliptin (1 mg/kg/day, p.o); D-gal, rats treated with D-galactose (150 mg/kg/day, s.c); D-gal/Met, rats treated with D-galactose and metformin; D-gal/Saxa, rats treated with D-galactose and saxagliptin. Each value represents mean ± S.E; n = 6. a Significantly different from Vehicle group at p < 0.05. b Significantly different from D-gal group at p < 0.05.
Fig 7.
Brain contents of neurotransmitters, acetylcholine and glutamate.
Vehicle, rats treated with distilled water (1.5 ml/kg/day, s.c); Met, rats treated with metformin (500 mg/kg/day, p.o); Saxa, rats treated with saxagliptin (1 mg/kg/day, p.o); D-gal, rats treated with D-galactose (150 mg/kg/day, s.c); D-gal/Met, rats treated with D-galactose and metformin; D-gal/Saxa, rats treated with D-galactose and saxagliptin. Each value represents mean ± S.E; n = 6. a Significantly different from Vehicle group at p < 0.05. b Significantly different from D-gal group at p < 0.05.
Fig 8.
Phosphorelated tau concentration in the brain homogenate.
Vehicle, rats treated with distilled water (1.5 ml/kg/day, s.c); Met, rats treated with metformin (500 mg/kg/day, p.o); Saxa, rats treated with saxagliptin (1 mg/kg/day, p.o); D-gal, rats treated with D-galactose (150 mg/kg/day, s.c); D-gal/Met, rats treated with D-galactose and metformin; D-gal/Saxa, rats treated with D-galactose and saxagliptin. Each value represents mean ± S.E; n = 6. a Significantly different from Vehicle group at p < 0.05. b Significantly different from D-gal group at p < 0.05.
Fig 9.
Histopathological changes in the cerebral cortex of rats.
The micrographs represent the following groups: (a) Vehicle, (b) Met, (c) Saxa, (d, e, f) D-gal, (g) D-gal/Met, and (h) D-gal/Saxa. (H&E, X40). Vehicle, rats treated with distilled water (1.5 ml/kg/day, s.c); Met, rats treated with metformin (500 mg/kg/day, p.o); Saxa, rats treated with saxagliptin (1 mg/kg/day, p.o); D-gal, rats treated with D-galactose (150 mg/kg/day, s.c); D-gal/Met, rats treated with D-galactose and metformin; D-gal/Saxa, rats treated with D-galactose and saxagliptin. (a,b,c) showing normal histological structure; (d,e,f) showing neuronal degeneration associated with neuronophagia in which the degenerated neurons appeared shrunken and surrounded by microglia cells (arrow) (d), amyloid plaque surrounded by astrocytes and microglia cells (e) and flame shape neurofibrillary tangles (arrow) (f); (g) showing decreased number of degenerated neurons; (h) showing neuronal degeneration.
Fig 10.
Congo red-stained brain sections of rats for visualization of amyloid plaques.
The micrographs represent the following groups: (a) D-gal-treated group showing red amyloid plaques (arrow) associated with cerebral amyloid angiopathy (arrow head), (b) D-gal/Met group showing sparse deposition of amyloid plaque (arrow), and (c) D-gal/Saxa group showing multiple amyloid plaques (arrows). (Congo red stain, X20). D-gal, rats treated with D-galactose (150 mg/kg/day, s.c); D-gal/Met, rats treated with D-galactose and metformin; D-gal/Saxa, rats treated with D-galactose and saxagliptin.
Table 2.
The number of degenerated and or necrotic neurons and amyloid plaques recorded in the brain of the rats.
Fig 11.
Histopathological changes in the hippocampi of rats.
The micrographs represent the following groups: (a,b,c) Vehicle, Met, and Saxa, respectively, showing normal histological structure, (d) D-gal showing marked degeneration of neuronal cells associated with neuronophagia (arrow), (e) D-gal/Met group showing decreased number of degenerated neurons, and (f) D-gal/Saxa group showing degeneration of pyramidal neuronal cells associated with amyloid plaques deposition (arrow). (H&E, X40). Vehicle, rats treated with distilled water (1.5 ml/kg/day, s.c); Met, rats treated with metformin (500 mg/kg/day, p.o); Saxa, rats treated with saxagliptin (1 mg/kg/day, p.o); D-gal, rats treated with D-galactose (150 mg/kg/day, s.c); D-gal/Met, rats treated with D-galactose and metformin; D-gal/Saxa, rats treated with D-galactose and saxagliptin.
Fig 12.
Glial fibrillary acidic protein (GFAP)-immune stained astrocytes in brain sections of rats.
The micrographs represent the following groups: (a) Vehicle, (b) Met, (c) Saxa, (d) D-gal, (e) D-gal/Met, and (f) D-gal/Saxa. (GFAP immunohistochemical stain, X40). Vehicle, rats treated with distilled water (1.5 ml/kg/day, s.c); Met, rats treated with metformin (500 mg/kg/day, p.o); Saxa, rats treated with saxagliptin (1 mg/kg/day, p.o); D-gal, rats treated with D-galactose (150 mg/kg/day, s.c); D-gal/Met, rats treated with D-galactose and metformin; D-gal/Saxa, rats treated with D-galactose and saxagliptin.