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Curcumin Improves Amyloid β-Peptide (1-42) Induced Spatial Memory Deficits through BDNF-ERK Signaling Pathway.

Zhang L, Fang Y, Xu Y, Lian Y, Xie N, Wu T, Zhang H, Sun L, Zhang R, Wang Z - PLoS ONE (2015)

Bottom Line: Curcumin, the most active component of turmeric, has various beneficial properties, such as antioxidant, anti-inflammatory, and antitumor effects.In addition, the beneficial effect of curcumin is accompanied by increased BDNF levels and elevated levels of phosphorylated ERK in the hippocampus.Furthermore, the cognition enhancement effect of curcumin could be mimicked by the overexpression of BDNF in the hippocampus and blocked by either bilateral hippocampal injections with lentiviruses that express BDNF shRNA or a microinjection of ERK inhibitor.

View Article: PubMed Central - PubMed

Affiliation: Key-Disciplines Laboratory Clinical-Medicine of Henan, Zhengzhou, Henan, PR China; Department of Neurology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China.

ABSTRACT
Curcumin, the most active component of turmeric, has various beneficial properties, such as antioxidant, anti-inflammatory, and antitumor effects. Previous studies have suggested that curcumin reduces the levels of amyloid and oxidized proteins and prevents memory deficits and thus is beneficial to patients with Alzheimer's disease (AD). However, the molecular mechanisms underlying curcumin's effect on cognitive functions are not well-understood. In the present study, we examined the working memory and spatial reference memory in rats that received a ventricular injection of amyloid-β1-42 (Aβ1-42), representing a rodent model of Alzheimer's disease (AD). The rats treated with Aβ1-42 exhibited obvious cognitive deficits in behavioral tasks. Chronic (seven consecutive days, once per day) but not acute (once a day) curcumin treatments (50, 100, and 200 mg/kg) improved the cognitive functions in a dose-dependent manner. In addition, the beneficial effect of curcumin is accompanied by increased BDNF levels and elevated levels of phosphorylated ERK in the hippocampus. Furthermore, the cognition enhancement effect of curcumin could be mimicked by the overexpression of BDNF in the hippocampus and blocked by either bilateral hippocampal injections with lentiviruses that express BDNF shRNA or a microinjection of ERK inhibitor. These findings suggest that chronic curcumin ameliorates AD-related cognitive deficits and that upregulated BDNF-ERK signaling in the hippocampus may underlie the cognitive improvement produced by curcumin.

No MeSH data available.


Related in: MedlinePlus

Effect of intra-hippocampal injections of ERK inhibitor or GSK3 activator on spatial learning function in the rat model of Alzheimer's disease.The ERK inhibitor PD98059 (20 μM) or GSK3 activator wortmannin (100 μM) (combined with chronic curcumin i.p. injection) was injected bilaterally into the hippocampus 30 min before the water-maze training trial. (A) Swim speed in each training trial. (B) The escape latency during the water maze training trials. (C) The time spent in the target quadrant and (D) the number of times crossing the platform in the probe task. n = 8/group. For panel B, *P < 0.05, **P < 0.01, Aβ1–42 + saline vs. sham control group; # P < 0.05, Aβ1–42 + Cur vs. Aβ1–42 + saline group; ^ P < 0.05, Aβ1–42 + Cur + wortmannin vs. Aβ1–42 + saline group. For other panels, * P < 0.05, ** P < 0.01, *** P < 0.0001 compared with Aβ1–42 + saline.
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pone.0131525.g006: Effect of intra-hippocampal injections of ERK inhibitor or GSK3 activator on spatial learning function in the rat model of Alzheimer's disease.The ERK inhibitor PD98059 (20 μM) or GSK3 activator wortmannin (100 μM) (combined with chronic curcumin i.p. injection) was injected bilaterally into the hippocampus 30 min before the water-maze training trial. (A) Swim speed in each training trial. (B) The escape latency during the water maze training trials. (C) The time spent in the target quadrant and (D) the number of times crossing the platform in the probe task. n = 8/group. For panel B, *P < 0.05, **P < 0.01, Aβ1–42 + saline vs. sham control group; # P < 0.05, Aβ1–42 + Cur vs. Aβ1–42 + saline group; ^ P < 0.05, Aβ1–42 + Cur + wortmannin vs. Aβ1–42 + saline group. For other panels, * P < 0.05, ** P < 0.01, *** P < 0.0001 compared with Aβ1–42 + saline.

Mentions: Because chronic curcumin affected both hippocampal ERK and GSK3β phosphorylation, we next investigated which of these factors plays a larger role in curcumin-induced hippocampus-dependent spatial memory enhancement. The ERK inhibitor PD98059 (20 μM) or GSK3 activator wortmannin (100 μM) (combined with chronic curcumin i.p. injection) was injected bilaterally into the hippocampus 30 min before the water-maze training trial. Thirty-six animals total were included in the final analyses (sham group, n = 8; Aβ1–42+saline group, n = 6; Aβ1–42+Cur group, n = 8; Aβ1–42+Cur+PD98059 group, n = 6; Aβ1–42+Cur+wortmannin group, n = 8). Four rats were discarded due to misplaced injection sites. No changes in swimming speed were observed in these rats during the entire water maze training period [Ftreatment (4, 159) = 0.02157, P = 0.9991; Ftime (4, 159) = 0.1366, P = 0.9686] (Fig 6A). A two-way ANOVA revealed a significant effect of drug treatments on [Ftreatment (4, 159) = 10.95, P < 0.0001], time [Ftime (4, 159) = 110.7, P < 0.0001] and an interaction [F (16, 159) = 2.583, P = 0.0013] with the escape latency (Fig 6B). In the probe trial, the rats in the Aβ1–42+Cur, Aβ1–42+Cur+wortmannin and sham groups spent increased amounts of time in the quadrant (Fig 6C) and crossed the platform at similar frequencies (Fig 5D) compared with the Aβ1–42+saline group. However, the Aβ1–42+Cur+PD98059 group showed no difference in both the time spent in the quadrant and platform crossing frequency compared with the Aβ1–42+saline rats. The Aβ1–42+Cur (P < 0.0001), Aβ1–42+Cur+wort (P < 0.01) and the sham group (P < 0.01) were significantly higher vs the 25% hazard level. These results suggest that an intra-hippocampus infusion of ERK inhibitors, but not GSK3 activator, blocks the curcumin-induced cognitive improvement.


Curcumin Improves Amyloid β-Peptide (1-42) Induced Spatial Memory Deficits through BDNF-ERK Signaling Pathway.

Zhang L, Fang Y, Xu Y, Lian Y, Xie N, Wu T, Zhang H, Sun L, Zhang R, Wang Z - PLoS ONE (2015)

Effect of intra-hippocampal injections of ERK inhibitor or GSK3 activator on spatial learning function in the rat model of Alzheimer's disease.The ERK inhibitor PD98059 (20 μM) or GSK3 activator wortmannin (100 μM) (combined with chronic curcumin i.p. injection) was injected bilaterally into the hippocampus 30 min before the water-maze training trial. (A) Swim speed in each training trial. (B) The escape latency during the water maze training trials. (C) The time spent in the target quadrant and (D) the number of times crossing the platform in the probe task. n = 8/group. For panel B, *P < 0.05, **P < 0.01, Aβ1–42 + saline vs. sham control group; # P < 0.05, Aβ1–42 + Cur vs. Aβ1–42 + saline group; ^ P < 0.05, Aβ1–42 + Cur + wortmannin vs. Aβ1–42 + saline group. For other panels, * P < 0.05, ** P < 0.01, *** P < 0.0001 compared with Aβ1–42 + saline.
© Copyright Policy
Related In: Results  -  Collection

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pone.0131525.g006: Effect of intra-hippocampal injections of ERK inhibitor or GSK3 activator on spatial learning function in the rat model of Alzheimer's disease.The ERK inhibitor PD98059 (20 μM) or GSK3 activator wortmannin (100 μM) (combined with chronic curcumin i.p. injection) was injected bilaterally into the hippocampus 30 min before the water-maze training trial. (A) Swim speed in each training trial. (B) The escape latency during the water maze training trials. (C) The time spent in the target quadrant and (D) the number of times crossing the platform in the probe task. n = 8/group. For panel B, *P < 0.05, **P < 0.01, Aβ1–42 + saline vs. sham control group; # P < 0.05, Aβ1–42 + Cur vs. Aβ1–42 + saline group; ^ P < 0.05, Aβ1–42 + Cur + wortmannin vs. Aβ1–42 + saline group. For other panels, * P < 0.05, ** P < 0.01, *** P < 0.0001 compared with Aβ1–42 + saline.
Mentions: Because chronic curcumin affected both hippocampal ERK and GSK3β phosphorylation, we next investigated which of these factors plays a larger role in curcumin-induced hippocampus-dependent spatial memory enhancement. The ERK inhibitor PD98059 (20 μM) or GSK3 activator wortmannin (100 μM) (combined with chronic curcumin i.p. injection) was injected bilaterally into the hippocampus 30 min before the water-maze training trial. Thirty-six animals total were included in the final analyses (sham group, n = 8; Aβ1–42+saline group, n = 6; Aβ1–42+Cur group, n = 8; Aβ1–42+Cur+PD98059 group, n = 6; Aβ1–42+Cur+wortmannin group, n = 8). Four rats were discarded due to misplaced injection sites. No changes in swimming speed were observed in these rats during the entire water maze training period [Ftreatment (4, 159) = 0.02157, P = 0.9991; Ftime (4, 159) = 0.1366, P = 0.9686] (Fig 6A). A two-way ANOVA revealed a significant effect of drug treatments on [Ftreatment (4, 159) = 10.95, P < 0.0001], time [Ftime (4, 159) = 110.7, P < 0.0001] and an interaction [F (16, 159) = 2.583, P = 0.0013] with the escape latency (Fig 6B). In the probe trial, the rats in the Aβ1–42+Cur, Aβ1–42+Cur+wortmannin and sham groups spent increased amounts of time in the quadrant (Fig 6C) and crossed the platform at similar frequencies (Fig 5D) compared with the Aβ1–42+saline group. However, the Aβ1–42+Cur+PD98059 group showed no difference in both the time spent in the quadrant and platform crossing frequency compared with the Aβ1–42+saline rats. The Aβ1–42+Cur (P < 0.0001), Aβ1–42+Cur+wort (P < 0.01) and the sham group (P < 0.01) were significantly higher vs the 25% hazard level. These results suggest that an intra-hippocampus infusion of ERK inhibitors, but not GSK3 activator, blocks the curcumin-induced cognitive improvement.

Bottom Line: Curcumin, the most active component of turmeric, has various beneficial properties, such as antioxidant, anti-inflammatory, and antitumor effects.In addition, the beneficial effect of curcumin is accompanied by increased BDNF levels and elevated levels of phosphorylated ERK in the hippocampus.Furthermore, the cognition enhancement effect of curcumin could be mimicked by the overexpression of BDNF in the hippocampus and blocked by either bilateral hippocampal injections with lentiviruses that express BDNF shRNA or a microinjection of ERK inhibitor.

View Article: PubMed Central - PubMed

Affiliation: Key-Disciplines Laboratory Clinical-Medicine of Henan, Zhengzhou, Henan, PR China; Department of Neurology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China.

ABSTRACT
Curcumin, the most active component of turmeric, has various beneficial properties, such as antioxidant, anti-inflammatory, and antitumor effects. Previous studies have suggested that curcumin reduces the levels of amyloid and oxidized proteins and prevents memory deficits and thus is beneficial to patients with Alzheimer's disease (AD). However, the molecular mechanisms underlying curcumin's effect on cognitive functions are not well-understood. In the present study, we examined the working memory and spatial reference memory in rats that received a ventricular injection of amyloid-β1-42 (Aβ1-42), representing a rodent model of Alzheimer's disease (AD). The rats treated with Aβ1-42 exhibited obvious cognitive deficits in behavioral tasks. Chronic (seven consecutive days, once per day) but not acute (once a day) curcumin treatments (50, 100, and 200 mg/kg) improved the cognitive functions in a dose-dependent manner. In addition, the beneficial effect of curcumin is accompanied by increased BDNF levels and elevated levels of phosphorylated ERK in the hippocampus. Furthermore, the cognition enhancement effect of curcumin could be mimicked by the overexpression of BDNF in the hippocampus and blocked by either bilateral hippocampal injections with lentiviruses that express BDNF shRNA or a microinjection of ERK inhibitor. These findings suggest that chronic curcumin ameliorates AD-related cognitive deficits and that upregulated BDNF-ERK signaling in the hippocampus may underlie the cognitive improvement produced by curcumin.

No MeSH data available.


Related in: MedlinePlus