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. 2010 May;20(3):598-612.
doi: 10.1111/j.1750-3639.2009.00339.x. Epub 2009 Sep 21.

Purple sweet potato color alleviates D-galactose-induced brain aging in old mice by promoting survival of neurons via PI3K pathway and inhibiting cytochrome C-mediated apoptosis

Jun Lu  1 , Dong-mei Wu, Yuan-lin Zheng, Bin Hu, Zi-feng Zhang
Affiliations

Purple sweet potato color alleviates D-galactose-induced brain aging in old mice by promoting survival of neurons via PI3K pathway and inhibiting cytochrome C-mediated apoptosis

Jun Lu et al. Brain Pathol. 2010 May.

Abstract

Purple sweet potato color (PSPC), a class of naturally occurring anthocyanins, protects brain function against oxidative stress induced by D-galactose (D-gal) (Sigma-Aldrich, St. Louis, MO, USA). Our data showed that PSPC enhanced open-field activity, decreased step-through latency, and improved spatial learning and memory ability in D-gal-treated old mice by decreasing advanced glycation end-products' (AGEs) formation and the AGE receptor (RAGE) expression, and by elevating Cu,Zn-superoxide dismutase (Cu,Zn-SOD) (Sigma-Aldrich) and catalase (CAT) expression and activity. Cleavage of caspase-3 and increased terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end-labeling (TUNEL)-positive cells in D-gal-treated old mice were inhibited by PSPC, which might be attributed to its antioxidant property. PSPC also suppressed the activation of c-Jun NH(2)-terminal kinase (JNK) and the release of cytochrome c from mitochondria that counteracted the onset of neuronal apoptosis in D-gal-treated old mice. Furthermore, it was demonstrated that phosphoinositide 3-kinase (PI3K) activation was required for PSPC to promote the neuronal survival accompanied with phosphorylation and activation of Akt and p44/42 mitogen-activated protein kinase (MAPK) by using PI3K inhibitor LY294002 (Cell Signaling Technology, Inc., Beverly, MA, USA), implicating a neuronal survival mechanism. The present results suggest that neuronal survival promoted by PSPC may be a potentially effective method to enhance resistance of neurons to age-related disease.

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Figures

Figure 1
Figure 1
Effect of purple sweet potato color (PSPC) on the behavior of D‐galactose (D‐gal)‐treated old mice in the open field (n = 8). All values are expressed as means ± standard deviation. A. Comparison of crossing numbers (within 5 minutes). B. Comparison of rearing/leaning numbers (within 5 minutes). C. Comparison of grooming numbers (within 5 minutes). **P < 0.01, ***P < 0.01 vs. control group; ##P < 0.01, ###P < 0.001 vs. D‐gal group; +P < 0.05, ++P < 0.01 D‐gal/PSPC group vs. D‐gal/PSPC/LY294002 group.
Figure 2
Figure 2
Effect of purple sweet potato color (PSPC) on the step‐through latency in D‐galactose (D‐gal)‐treated old mice (n = 8). All values are expressed as means ± standard deviation. *P < 0.05 vs. control group; #P < 0.05 vs. D‐gal group; +P < 0.05 D‐gal/PSPC group vs. D‐gal/PSPC/LY294002 group.
Figure 3
Figure 3
Effect of purple sweet potato color (PSPC) on the behavior of D‐galactose (D‐gal)‐treated old mice in Morris water maze (n = 8). All values are expressed as means ± standard deviation. A. Comparison of latency to platform during 5 training days. B. Comparison of numbers of crossing over platform site on day 6. ***P < 0.001 vs. control group; #P < 0.05, ###P < 0.001 vs. D‐gal group; +P < 0.05 D‐gal/PSPC group vs. D‐gal/PSPC/LY294002 group. C. Comparison of the time spent in target quadrant with other quadrants on day 6. *P < 0.05, **P < 0.01, ***P < 0.01 compared with any other quadrant.
Figure 4
Figure 4
Effect of purple sweet potato color (PSPC) on the expression of advanced glycation end‐products (AGEs), Carboxymethyl‐lysine (CML), carboxyethyl‐lysine (CEL) and AGE receptor (RAGE) in the brain of D‐galactose (D‐gal)‐treated old mice (n = 3). A. Immunoreactivity of AGEs, CML, CEL, RAGE and β‐actin in all treated groups. B. Relative density analysis of the AGEs, CML, CEL and RAGE protein bands. β‐Actin was probed as an internal control. The relative density is expressed as the ratio (AGEs/β‐actin, CML/β‐actin, CEL/β‐actin, RAGE/β‐actin), and the vehicle control is set as 1.0. Values are averages from three independent experiments. Each value is the mean ± standard deviation. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control group; #P < 0.05, ##P < 0.01, ###P < 0.001 vs. D‐gal group; ++P < 0.01, +++P < 0.001 D‐gal/PSPC group vs. D‐gal/PSPC/LY294002 groups.
Figure 5
Figure 5
Effect of purple sweet potato color (PSPC) on the expression of Cu,Zn‐superoxide dismutase (Cu,Zn‐SOD) and catalase (CAT) in the brain of D‐galactose (D‐gal)‐treated old mice (n = 3). A. Immunoreactivity of Cu,Zn‐SOD, CAT and β‐actin in all treated groups. B. Relative density analysis of the Cu,Zn‐SOD protein bands. C. Relative density analysis of the CAT protein bands. β‐Actin was probed as an internal control. The relative density is expressed as the ratio (Cu,Zn‐SOD/β‐actin, CAT/β‐actin), and the vehicle control is set as 1.0. Values are averages from three independent experiments. Each value is the mean±standard deviation. *P < 0.05, ***P < 0.001 vs. control group; ###P < 0.001 vs. D‐gal group; +++P < 0.001 D‐gal/PSPC group vs. D‐gal/PSPC/LY294002 group.
Figure 6
Figure 6
Effect of purple sweet potato color (PSPC) on the activity of Cu,Zn‐superoxide dismutase (Cu,Zn‐SOD) and catalase (CAT) in the brain of D‐galactose (D‐gal)‐treated old mice (n = 5). Values are averages from five independent experiments. Each value is the mean ± standard deviation. A. Cu,Zn‐SOD. B. CAT. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control group; #P < 0.05, ###P < 0.001 vs. D‐gal group; +P < 0.05 D‐gal/PSPC group vs. D‐gal/PSPC/LY294002 group.
Figure 7
Figure 7
A. In situ detection of fragmented DNA [deoxyribonucleotidyl transferase‐mediated dUTP‐FITC nick‐end labeling (TUNEL) assay] in the hippocampus of old mice. The brain tissues were processed for TUNEL and photographed using a fluorescence microscope with either a propidium iodide (PI) filter alone (left) or an FITC filter alone (middle). The merged images show that apoptotic cells appear yellow and non‐apoptotic cells appear red (right). Scale bars = 100 µm. B. The histogram showed the relative proportion of TUNEL‐positive cells in the hippocampus of old mice. Data are means ± standard deviation (n = 7). ***P < 0.001 vs. control group; ###P < 0.001 vs. D‐galactose (D‐gal) group; +++P < 0.001 D‐gal/purple sweet potato color (PSPC) group vs. D‐gal/PSPC/LY294002 group.
Figure 8
Figure 8
A. In situ detection of fragmented DNA [deoxyribonucleotidyl transferase‐mediated dUTP‐(FITC) nick‐end labeling (TUNEL) assay] in the cerebral cortex of old mice. The brain tissues were processed for TUNEL and photographed using a fluorescence microscope with either a propidium iodide (PI) filter alone (left) or an FITC filter alone (middle). The merged images show that apoptotic cells appear yellow and non‐apoptotic cells appear red (right). Scale bars = 100 µm. B. The histogram showed the relative proportion of TUNEL‐positive cells in the cerebral cortex of old mice. Data are means ± standard deviation (n = 7). ***P < 0.001 vs. control group; ###P < 0.001 vs. D‐galactose (D‐gal) group; +++P < 0.001 D‐gal/purple sweet potato color (PSPC) group vs. D‐gal/PSPC/LY294002 group.
Figure 9
Figure 9
Effect of purple sweet potato color (PSPC) on the cleavage of caspase‐3 in the brain of D‐galactose (D‐gal)‐treated old mice (n = 3). A. Immunoreactivity of cleaved caspase‐3 and β‐actin in all treated groups. B. Relative density analysis of the cleaved caspase‐3 protein bands. β‐Actin was probed as an internal control. The relative density is expressed as the ratio of cleaved caspase‐3 to β‐actin, and the vehicle control is set as 1.0. Values are averages from three independent experiments. Each value is the mean ± standard deviation. *P < 0.05, ***P < 0.001 vs. control group; #P < 0.05, ###P < 0.001 vs. D‐gal group; +P < 0.05, +++P < 0.001 D‐gal/PSPC group vs. D‐gal/PSPC/LY294002 group.
Figure 10
Figure 10
Effect of purple sweet potato color (PSPC) on the phosphorylation of stress‐activated protein kinase (SAPK)/c‐Jun NH2‐terminal kinase (JNK) in the brain of D‐galactose (D‐gal)‐treated old mice. A. Immunoreactivity of phospho‐JNK (p‐JNK) and β‐actin in all treated groups. B. Relative density analysis of the p‐JNK protein bands. β‐Actin was probed as an internal control. The relative density is expressed as the ratio of p‐JNK to β‐actin, and the vehicle control is set as 1.0. Values are averages from three independent experiments. Each value is the mean ± standard deviation. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control group; #P < 0.05, ##P < 0.01, ###P < 0.001 vs. D‐gal group; +P < 0.05, ++P < 0.01 D‐gal/PSPC group vs. D‐gal/PSPC/LY294002 group.
Figure 11
Figure 11
Effect of purple sweet potato color (PSPC) on the release of cytochrome c (Cyt.c) from cytochondria in the brain of D‐galactose (D‐gal)‐treated old mice. A. Immunoreactivity of cytosolic and mitochondrial Cyt.c and COX IV in all treated groups. B. Relative density analysis of the mitochondrial and cytosolic Cyt.c protein bands. COX IV was probed as an internal control. The relative density is expressed as the ratio of mitochondrial and cytosolic Cyt.c to β‐actin, and the vehicle control is set as 1.0. Values are averages from three independent experiments. Each value is the mean ± standard deviation. ***P < 0.001 vs. control group; ###P < 0.001 vs. D‐gal group; +++P < 0.05 D‐gal/PSPC group vs. D‐gal/PSPC/LY294002 group.
Figure 12
Figure 12
Effect of purple sweet potato color (PSPC) on the phosphorylation of Akt, p44/42 MAPK and Bad in the brain of D‐gal‐treated old mice. A. Immunoreactivity of p‐Akt(Thr308/Ser473), p‐p44/42 mitogen‐activated protein kinase (MAPK)(Thr202/Tyr204), p‐Bcl‐2‐associated death protein (Bad)(Ser112/Ser136), total‐Akt (t‐Akt), t‐p44/42 MAPK and t‐Bad in all treated groups. B. Relative density analysis of the p‐Akt, p‐p44/42 MAPK and p‐Bad protein bands. t‐Akt, t‐p44/42 MAPK and t‐Bad were probed as internal controls, respectively. The relative density is expressed as the ratio (p‐Akt/t‐Akt; p‐p44/42/t‐p44/42; p‐Bad/t‐Bad), and the vehicle control is set as 1.0. Values are averages from three independent experiments. Each value is the mean ± standard deviation. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control group; ##P < 0.01, ###P < 0.001 vs. D‐gal group; ++P < 0.01, +++P < 0.001 D‐gal/PSPC group vs. D‐gal/PSPC/LY294002 group.
Figure 13
Figure 13
Schematic diagram for the protective effects of purple sweet potato color (PSPC) against D‐galactose (D‐gal)‐induced neurotoxicity. Abbreviations: AGEs = advanced glycation end‐products; RAGE = AGE receptor; CAT = catalase; Bad = Bcl‐2‐associated death protein; Cu,Zn‐SOD = Cu,Zn‐superoxide dismutase; PI3K =  phosphoinositide 3‐kinase; ROS = reactive oxygen species; JNK = c‐Jun NH2‐terminal kinase; MAPK = mitogen‐activated protein kinase.
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