Curcumin enhances neurogenesis and cognition in aged rats: implications for transcriptional interactions related to growth and synaptic plasticity

Suzhen Dong, Qingwen Zeng, E Siobhan Mitchell, Jin Xiu, Yale Duan, Chunxia Li, Jyoti K Tiwari, Yinghe Hu, Xiaohua Cao, Zheng Zhao, Suzhen Dong, Qingwen Zeng, E Siobhan Mitchell, Jin Xiu, Yale Duan, Chunxia Li, Jyoti K Tiwari, Yinghe Hu, Xiaohua Cao, Zheng Zhao

Abstract

Background: Curcumin has been demonstrated to have many neuroprotective properties, including improvement of cognition in humans and neurogenesis in animals, yet the mechanism of such effects remains unclear.

Methodology: We assessed behavioural performance and hippocampal cell proliferation in aged rats after 6- and 12-week curcumin-fortified diets. Curcumin enhanced non-spatial and spatial memory, as well as dentate gyrate cell proliferation as compared to control diet rats. We also investigated underlying mechanistic pathways that might link curcumin treatment to increased cognition and neurogenesis via exon array analysis of cortical and hippocampal mRNA transcription. The results revealed a transcriptional network interaction of genes involved in neurotransmission, neuronal development, signal transduction, and metabolism in response to the curcumin treatment.

Conclusions: The results suggest a neurogenesis- and cognition-enhancing potential of prolonged curcumin treatment in aged rats, which may be due to its diverse effects on genes related to growth and plasticity.

Conflict of interest statement

Competing Interests: ESM, JX and JKT are employees of Unilever R&D, the research arm of a food company which does sell products with very small amounts of curcumin. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. Experimental design of this study.
Figure 1. Experimental design of this study.
Curcumin was given to the aged rats in food for 6 (short-term) or 12 weeks (long-term). Behavioural tests were performed on the last two weeks of curcumin administration and BrdU were injected daily for ten days on the last ten days. Rats were killed for immunihistological and biochemical analysis at the end of curcumin treatment.
Figure 2. Social recognition ability and spatial…
Figure 2. Social recognition ability and spatial reference memory were enhanced after 6- or 12-week curcumin treatment.
A and C: In the first trial (Exposure, E1) of social recognition task, the curcumin group and control group had the same preference for the juvenile rats. In the second trial (Exposure 2, E2) of social recognition task, the time spent on exploring the novel and the familiar juvenile rats was expressed as E2(novel) and E2(familiar), respectively. 6- or 12-week curcumin treatment exhibited the significant lower exploration for the familiar juvenile rat during the second trial (E2). B and D: There was significance difference between curcumin and control groups in investigation index after 6- or 12-week treatment with curcumin treatment in aged rats (P<0.01). Investigation index = E2(novel)/(E2(familiar)+E2(novel)). E and G: Effects of 6- and 12-week curcumin treatment during Morris water maze training sessions. Latency to reach the platform and area under curve (AUC) of latencies are shown. Data are expressed as means (± SEM) of daily averages of 4 trials. The area under curve for latency was no significant difference between drug treatment and control for both 6- (Figure E) and 12-week (Figure G, p>0.05). F and H: Effects of 6- and 12-week curcumin treatment during the Morris water maze probe trial. Time spent in the target quadrants is shown. Curcumin group spent more time in the target quadrant than control group after 12-week drug treatment. *P<0.05.
Figure 3. 12-week but not 6-week curcumin…
Figure 3. 12-week but not 6-week curcumin treatment induced a significant increase of BrdU-positive cells in dentate gyrus.
A and B: BrdU immunhistology results from the representative slices of 6-week curcumin-treated rats and controls, respectively. C: the statistical results of 6-week curcumin treatment on hippocampal neurogenesis. D and E: BrdU immunhistology results from the representative slices of 12-week curcumin-treated rats and controls, respectively. F: the statistical results of 12-week curcumin treatment on hippocampal neurogenesis. The yellow arrows: the BrdU-positive cells. In C and F, data were expressed as mean ± SEM. *: P

Figure 4. Numbers of up-regulated and down-regulated…

Figure 4. Numbers of up-regulated and down-regulated genes in the hippocampus and cortex after curcumin…

Figure 4. Numbers of up-regulated and down-regulated genes in the hippocampus and cortex after curcumin treatment.
Number on the bar showed the number of genes whose expressions were up-regulated or down-regulated. 6 W: 6-week; 12 W:12-week.

Figure 5. Functional categories of genes affected…

Figure 5. Functional categories of genes affected by curcumin.

Percentages of genes whose expression levels…

Figure 5. Functional categories of genes affected by curcumin.
Percentages of genes whose expression levels are changed by curcumin were indicated.

Figure 6. Relative expression levels of relevant…

Figure 6. Relative expression levels of relevant genes in the hippocampus of the aged rats.

Figure 6. Relative expression levels of relevant genes in the hippocampus of the aged rats.
A, B: after 6-week curcumin treatment; C, D: after 12-week curcumin treatment;. A, C: the results of real time PCR; B, D: the comparisons of the relative gene expressions compared to control rats between the results of quantitative PCR and microarray experiments. Student t-test, *P<0.05, **P<0.01 compared to control rats.
Figure 4. Numbers of up-regulated and down-regulated…
Figure 4. Numbers of up-regulated and down-regulated genes in the hippocampus and cortex after curcumin treatment.
Number on the bar showed the number of genes whose expressions were up-regulated or down-regulated. 6 W: 6-week; 12 W:12-week.
Figure 5. Functional categories of genes affected…
Figure 5. Functional categories of genes affected by curcumin.
Percentages of genes whose expression levels are changed by curcumin were indicated.
Figure 6. Relative expression levels of relevant…
Figure 6. Relative expression levels of relevant genes in the hippocampus of the aged rats.
A, B: after 6-week curcumin treatment; C, D: after 12-week curcumin treatment;. A, C: the results of real time PCR; B, D: the comparisons of the relative gene expressions compared to control rats between the results of quantitative PCR and microarray experiments. Student t-test, *P<0.05, **P<0.01 compared to control rats.

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