| Curcumin is a polyphenolic compound originally from the turmeric rhizomes. Curcumin has been shown to possess multiple biological and therapeutical properties towards anti-inflammation, anti-oxidation, lipid regulation, anti-tumor, and other pharmacological activities, while it is quite low in toxicity and adverse reactions. Furthermore, recent studies demonstrated that curcumin also exhibits a potent role in alleviating cognitive dysfunctions. Despite the benefitial effects on various physiological or pathophysiological processes, molecular foundations underlying these effects of curcumin, especially on modulation of gene expression in the brain during normal aging, are still poorly understood. In this study, we firstly assessed the behavioral changes relavent to cognitive improvement in the aged rats (18-month old) after a prolonged (6-or12-week) treatment of curcumin. To provide with molecular explanation for the cognitive benefit of curcumin, we performed a genome-wide profiling of hippocampus and cortex in the rats. To further investige the functional changes in response to curcumin treatment as well as curcumin-mediated modulation of gene expressions in the brain, we then examined a series of risk factors for aging-related cognitive decline, such as neurogenesis, oxidative and inflammatory statuses. The main findings are summarized as follows:1. Performance of the rats in behavioural tasks showed that curcumin did not influence the anxiety and motor coordination in aged rats. Curcumin improved the spatial memory after both6-and12-week treatment in social recognition test. There was a significant improvement of spatial memory in water maze task after12-week but not6-week curcumin treatments. These results suggested that prolonged curcumin consumption might prevent or slow down the decline of cognitive function with aging.2. Gene chip results showed that curcumin treatment caused significant changes in expressions of many genes in the hippocampus and cortex. Functional analysis revealed that majority of these differentially expressed genes, such as Neurod1, Neurod6, Cplx3, Syt9, Met, Nts, Stx1a, Rnf39, Fezf2, Robo3, Cip98, Agrn, Wnt2, Nr4a2, Tiam1, Unc5d, Shank3, Abba-1, Adcy1, CD74and Cav1, were associated with developmental and cognitive functions. There were also genes, such as Neurod1, Neurod6, Wnt2, Fezf2, Robo3, Nr4a2and Abba-1, that were found to be related to neurogenesis, and genes that exhibited important impacts on cognition-related risk factors during normal aging process, such as Met, Nts and ATP8(oxidative stress), Klf10(inflammation), Slc38a4(astrocytes function)。3. Curcumin treatment for12-week, but not6-week, could significantly enhance neurogenesis in the dentate gyrus of the aged rats, suggesting an important mechanistic pathway of the action of curcumin on cognition in the aged rats.4. The prolonged treatment of curcumin enhanced cognitive function and hippocampal neurogenesis in the aged rats, so we investigated the effects of12-week curcumin treatment on oxidative balance, inflammation and astrocytes functions in the aged rats. The results showed that curcumin could alleviate oxidative stress in brain of the aged rats. Although there were no alterarions in the total SOD, CuZn-SOD, CAT, GPx, GST and GR activity, both the lipid peroxidation marker (MDA) and DNA oxidation marker (8-OHdG) were significantly reduced, while the activity or level of the anti-oxidative emaymes GCS (the rate-limiting enzyme in GSH synthesis reaction) and GSH significantly elevated, in the brain tissues of the aged rats as compared with the control rats. Curcumin could inhibit excessive activation of astrocytes and GFAP expression in the brain of the aged rats. Although curcumin did not affect the expression of GS protein, it could significantly enhance the activity of GS. Curcumin reduced the IL-1beta and IL-6levels, and increased levels of GDNF, but has no effect on BDNF. Addition, Curcumin increased the content of D-serine.In summary, our study demonstrated a marked role of prolonged treatment of curcumin in improving cognitive function of aged rats under normal aging conditions. Genome-wide expression profiling of hippocampus and cortex revealed that such a beneficial effect of curcumin on cognition may be attributed to functional changes of genes related not only to neuronal growth and synaptic plasticity, but also to neurogenesis and several critical risk factors, such as oxidative stress, inflammation and the function of astrocytes for aging-related cognitive decline. We thus further showed that curcumin could promote neurogenesis, inhibit oxidative damage and inflammatory responses, and improve the function of astrocytes in the brain of aged rats. Collectively, the present study revealed that the prolonged treatment of curcumin might act as a mechanistic component in the aged brain that modulated the transcriptional network interactions and hereby enhanced neurogenesis and counteracted aging-related risk factors towards the improvment of cognitive function. |
PDF Full Text Request