姜黄素对老年鼠认知功能的影响及其分子基础研究
摘要
随着世界人口老龄化日益加重,老年人认知功能障碍的发病率也在不断上升。认知功能障碍的发展是个长期的过程,在出现临床表现前数十年即己开始,在疾病进展后期,特别是发生痴呆后再进行干预治疗,虽仍可能延缓认知功能衰退的进程,但已有的损害多不能逆转。因此寻找有效的治疗手段,并在认知功能障碍的最初阶段加以干预,不仅能为老年认知功能减退的防治提供切实可行的有效途径,且有助于改善老年人的生活质量,减轻家庭及社会的巨大压力。
姜黄素(curcumin)是一种多酚类化合物,最早从姜黄根茎中提取出来。大量体外体内(包括人和动物)研究表明,姜黄素在机体或生物系统内具有非常多的分子靶标,涉及多重分子信号途径,因而呈现出抗炎、抗氧化、调脂、抗病毒、抗感染、抗肿瘤、抗凝、抗肝纤维化、抗动脉粥样硬化等广泛的药理活性,且毒性低、不良反应小。近年来更有证据表明,姜黄素对老年认知功能障碍也具有很好的改善或治疗作用。尽管研究证明姜黄素对多种病理生理过程有不少益处,但人们对这些益处背后的分子机制,尤其是正常衰老过程中姜黄素对大脑基因表达的影响和调控及其带来的整个机体生物化学和生理学功能的改变并不清楚。本课题旨在研究长期服食姜黄素对正常衰老过程中SD大鼠的认知功能是否有改善作用,在此基础之上利用基因芯片技术研究这种改善作用的基因基础,并从正常衰老过程中逐渐出现的重要病生理危险因素,如神经细胞功能改变、氧化应激和炎症等角度,进一步了解姜黄素诱导的大脑基因表达变化与认知改善及衰老相关危险因素的作用关系。主要研究结果如下：
1.姜黄素对老年大鼠的焦虑及运动协调能力没有影响,但是经过6和12周的处理,姜黄素可以提高老年鼠在新异个体识别任务中的记忆能力；经过12周的处理,姜黄素可以改善老年鼠在水迷宫实验中的空间记忆能力(6周的姜黄素处理没有影响),这提示较长时间的姜黄素处理对老年鼠认知功能具有更好的改善作用。
2.利用基因芯片分析了老年SD大鼠皮层和海马的基因表达,结果表明姜黄素的作用涉及多种信号分子,且大多数与发育和认知功能有关,如：Neurodl、 Neurod6、Cplx3, Syt9、 Met、Nts、 Stx1a、Rnf39、Fezf2、Robo3、 Cip98、 Agrn、 Wnt2、 Nr4a2、 Tiam1、 Unc5d、 Shank3、 Abba-1、 Adcy1、 CD74和Cav1等,其中与神经发生有关的基因有Neurod1、 Neurod6、Wnt2、Fezf2、 Robo3、 Nr4a2和Abba-1等。此外,一些基因也与老年认知功能障碍的影响因素密切有关,如：Met、 Nts和ATP8(与氧化应激有关)、KIf10(与炎症有关)；Slc38a4(与星形胶质细胞功能有关)。
3.姜黄素处理6周对老年鼠的神经发生没有影响,但是姜黄素处理12周则可明显促进老年鼠的神经发生。
4.由于12周姜黄素处理对老年鼠认知功能和神经发生的效果更为明显,因此我们考察了姜黄素处理12周后,老年鼠皮层和海马的氧化性平衡、炎症以及星形胶质细胞功能的变化情况。结果表明姜黄素可以改善老年鼠的氧化应激状态,降低皮层和海马脂质过氧化产物MDA和核酸氧化产物8-OHdG的含量,提高抗氧化体系中γ-谷氨酰半胱氨酸合酶(GCS)活性,进而增加还原型谷胱甘肽(GSH)水平(GCS是GSH合成反应中的限速酶,决定着GSH生物合成的速率和量)。但对老年鼠脑内的其他抗氧化酶活性没有影响,包括：总超氧化物歧化酶(SOD)、 CuZn-超氧化物歧化酶(CuZn-SOD)、过氧化氢酶(CAT)、谷胱甘肽一过氧化物酶(GPx)、谷胱甘肽一S转移酶(GST)和谷胱甘肽还原酶(GR)等。姜黄素可以抑制老年鼠皮层和海马的星形胶质细胞过度活化和胶质纤维酸性蛋白(GFAP)的表达。虽然姜黄素对皮层和海马谷氨酰胺合成酶(GS)蛋白的表达没有影响,但可以增强GS的活性。姜黄素可以减少老年鼠皮层和海马白介素1-beta (IL-1beta)和白介素-6(IL-6)的水平,增加胶质细胞源性神经营养因子(GDNF)的水平,但对脑源性神经营养因子(BDNF)没有影响。此外,姜黄素可增加皮层D-丝氨酸(D-serine)的含量。
综上所述,本研究首先从行为学水平验证了姜黄素对正常衰老条件下老年鼠认知功能的改善作用,并在基因水平观察了姜黄素对老年鼠皮层和海马的基因表达的影响,以研究姜黄素改善老年鼠认知的大脑基因基础。基因功能分析结果显示姜黄素对皮层和海马功能基因的影响或调控主要涉及与发育和认知等有关的多种信号分子,并与大脑神经发生、氧化性平衡、炎症和星形胶质细胞功能有关,而这四方面都是正常生理或病理条件下老年认知功能障碍的重要影响因素。由此,我们进一步深入研究了姜黄素对这些因素的影响及与其改善认知的作用关系。结果显示姜黄素可以促进神经发生,抑制脑内氧化损伤和炎症反应,改善星形胶质细胞功能。姜黄素在大脑多种生物学功能的共同作用可能是其改善老年认知功能障碍的分子基础。
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.
姜黄素(curcumin)是一种多酚类化合物,最早从姜黄根茎中提取出来。大量体外体内(包括人和动物)研究表明,姜黄素在机体或生物系统内具有非常多的分子靶标,涉及多重分子信号途径,因而呈现出抗炎、抗氧化、调脂、抗病毒、抗感染、抗肿瘤、抗凝、抗肝纤维化、抗动脉粥样硬化等广泛的药理活性,且毒性低、不良反应小。近年来更有证据表明,姜黄素对老年认知功能障碍也具有很好的改善或治疗作用。尽管研究证明姜黄素对多种病理生理过程有不少益处,但人们对这些益处背后的分子机制,尤其是正常衰老过程中姜黄素对大脑基因表达的影响和调控及其带来的整个机体生物化学和生理学功能的改变并不清楚。本课题旨在研究长期服食姜黄素对正常衰老过程中SD大鼠的认知功能是否有改善作用,在此基础之上利用基因芯片技术研究这种改善作用的基因基础,并从正常衰老过程中逐渐出现的重要病生理危险因素,如神经细胞功能改变、氧化应激和炎症等角度,进一步了解姜黄素诱导的大脑基因表达变化与认知改善及衰老相关危险因素的作用关系。主要研究结果如下：
1.姜黄素对老年大鼠的焦虑及运动协调能力没有影响,但是经过6和12周的处理,姜黄素可以提高老年鼠在新异个体识别任务中的记忆能力；经过12周的处理,姜黄素可以改善老年鼠在水迷宫实验中的空间记忆能力(6周的姜黄素处理没有影响),这提示较长时间的姜黄素处理对老年鼠认知功能具有更好的改善作用。
2.利用基因芯片分析了老年SD大鼠皮层和海马的基因表达,结果表明姜黄素的作用涉及多种信号分子,且大多数与发育和认知功能有关,如：Neurodl、 Neurod6、Cplx3, Syt9、 Met、Nts、 Stx1a、Rnf39、Fezf2、Robo3、 Cip98、 Agrn、 Wnt2、 Nr4a2、 Tiam1、 Unc5d、 Shank3、 Abba-1、 Adcy1、 CD74和Cav1等,其中与神经发生有关的基因有Neurod1、 Neurod6、Wnt2、Fezf2、 Robo3、 Nr4a2和Abba-1等。此外,一些基因也与老年认知功能障碍的影响因素密切有关,如：Met、 Nts和ATP8(与氧化应激有关)、KIf10(与炎症有关)；Slc38a4(与星形胶质细胞功能有关)。
3.姜黄素处理6周对老年鼠的神经发生没有影响,但是姜黄素处理12周则可明显促进老年鼠的神经发生。
4.由于12周姜黄素处理对老年鼠认知功能和神经发生的效果更为明显,因此我们考察了姜黄素处理12周后,老年鼠皮层和海马的氧化性平衡、炎症以及星形胶质细胞功能的变化情况。结果表明姜黄素可以改善老年鼠的氧化应激状态,降低皮层和海马脂质过氧化产物MDA和核酸氧化产物8-OHdG的含量,提高抗氧化体系中γ-谷氨酰半胱氨酸合酶(GCS)活性,进而增加还原型谷胱甘肽(GSH)水平(GCS是GSH合成反应中的限速酶,决定着GSH生物合成的速率和量)。但对老年鼠脑内的其他抗氧化酶活性没有影响,包括：总超氧化物歧化酶(SOD)、 CuZn-超氧化物歧化酶(CuZn-SOD)、过氧化氢酶(CAT)、谷胱甘肽一过氧化物酶(GPx)、谷胱甘肽一S转移酶(GST)和谷胱甘肽还原酶(GR)等。姜黄素可以抑制老年鼠皮层和海马的星形胶质细胞过度活化和胶质纤维酸性蛋白(GFAP)的表达。虽然姜黄素对皮层和海马谷氨酰胺合成酶(GS)蛋白的表达没有影响,但可以增强GS的活性。姜黄素可以减少老年鼠皮层和海马白介素1-beta (IL-1beta)和白介素-6(IL-6)的水平,增加胶质细胞源性神经营养因子(GDNF)的水平,但对脑源性神经营养因子(BDNF)没有影响。此外,姜黄素可增加皮层D-丝氨酸(D-serine)的含量。
综上所述,本研究首先从行为学水平验证了姜黄素对正常衰老条件下老年鼠认知功能的改善作用,并在基因水平观察了姜黄素对老年鼠皮层和海马的基因表达的影响,以研究姜黄素改善老年鼠认知的大脑基因基础。基因功能分析结果显示姜黄素对皮层和海马功能基因的影响或调控主要涉及与发育和认知等有关的多种信号分子,并与大脑神经发生、氧化性平衡、炎症和星形胶质细胞功能有关,而这四方面都是正常生理或病理条件下老年认知功能障碍的重要影响因素。由此,我们进一步深入研究了姜黄素对这些因素的影响及与其改善认知的作用关系。结果显示姜黄素可以促进神经发生,抑制脑内氧化损伤和炎症反应,改善星形胶质细胞功能。姜黄素在大脑多种生物学功能的共同作用可能是其改善老年认知功能障碍的分子基础。
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.
引文
1. Peinado MA: Histology and histochemistry of the aging cerebral cortex:an overview. Microsc Res Tech 1998,43(1):1-7.
2. Bishop NA, Lu T, Yankner BA:Neural mechanisms of ageing and cognitive decline. Nature 2010,464(7288)529-535.
3. Adair JC, Williamson DJ, Knoefel JE:Cognitive impairment in elderly who are not yet demented. Compr Ther 1999,25(8-10):390-396.
4. Collie A, Maruff P:The neuropsychology of preclinical Alzheimer's disease and mild cognitive impairment. Neurosci Biobehav Rev 2000,24(3):365-374.
5. Sherwin BB:Mild cognitive impairment: potential pharmacological treatment options. J Am Geriatr Soc 2000,48(4):431-441.
6. Vandewoude MF: The pharmacological management of cognitive dysfunction in Alzheimer's disease. Acta Clin Belg 1999,54(5):306-311.
7. Schraufstatter E, Bernt H:Antibacterial action of curcumin and related compounds. Nature 1949,164(4167):456.
8. Esatbeyoglu T, Huebbe P, Ernst IM, Chin D, Wagner AE, Rimbach G:Curcumin-from molecule to biological function. Angew Chem Int Ed Engl 2012,51(22):5308-5332.
9. Mythri RB, Bharath MM:Curcumin:a potential neuroprotective agent in Parkinson's disease. Curr Pharm Des 2012,18(1):91-99.
10. Gupta SC, Patchva S, Koh W, Aggarwal BB: Discovery of curcumin, a component of golden spice, and its miraculous biological activities. Clin Exp Pharmacol Physiol 2012, 39(3):283-299.
11. Belkacemi A, Doggui S, Dao L, Ramassamy C: Challenges associated with curcumin therapy in Alzheimer disease. Expert Rev Mol Med 2011,13:e34.
12. Kulkarni S, Dhir A, Akula KK:Potentials of curcumin as an antidepressant. ScientificWorldJournal 2009,9:1233-1241.
13. Ovbiagele B:Potential role of curcumin in stroke prevention. Expert Rev Neurother 2008,8(8):1175-1176.
14. Hamaguchi T, Ono K, Yamada M:REVIEW: Curcumin and Alzheimer's disease. CNS Neurosci Ther 2010,16(5):285-297.
15. Zhao J, Zhao Y, Zheng W, Lu Y, Feng G, Yu S: Neuroprotective effect of curcumin on transient focal cerebral ischemia in rats. Brain Res 2008,1229:224-232.
16. Shen LR, Parnell LD, Ordovas JM, Lai CQ: Curcumin and aging. Biofactors 2013, 39(1):133-140.
17. Wu A, Ying Z, Schubert D, Gomez-Pinilla F:Brain and spinal cord interaction: a dietary curcumin derivative counteracts locomotor and cognitive deficits after brain trauma. Neurorehabil Neural Repair 2011,25(4):332-342.
18. Ng TP, Chiam PC, Lee T, Chua HC, Lim L, Kua EH:Curry consumption and cognitive function in the elderly. Am J Epidemiol 2006,164(9):898-906.
19. Brodaty H, Heffernan M, Kochan NA, Draper B, Trollor JN, Reppermund S, Slavin MJ, Sachdev PS: Mild cognitive impairment in a community sample:The Sydney Memory and Ageing Study. Alzheimers Dement 2012.
20. Dodson JA, Truong TT, Towle VR, Kerins G, Chaudhry SI:Cognitive impairment in older adults with heart failure: prevalence, documentation, and impact on outcomes. Am J Med 2013,126(2):120-126.
21.张健,李华：社区脑卒中危险因素及认知状态流行病学研究.农垦医学2012,第34卷第3期：269-273.
22. Frautschy SA, Hu W, Kim P, Miller SA, Chu T, Harris-White ME, Cole GM:Phenolic anti-inflammatory antioxidant reversal of Abeta-induced cognitive deficits and neuropathology. NeurobiolAging 2001,22(6):993-1005.
23. Wu A, Ying Z, Gomez-Pinilla F:Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition. Exp Neurol 2006, 197(2):309-317.
24. Ishrat T, Hoda MN, Khan MB, Yousuf S, Ahmad M, Khan MM, Ahmad A, Islam F: Amelioration of cognitive deficits and neurodegeneration by curcumin in rat model of sporadic dementia of Alzheimer's type (SDAT). Eur Neuropsychopharmacol 2009, 19(9):636-647.
25. Steffener J, Stern Y:Exploring the neural basis of cognitive reserve in aging. Biochim Biophys Acta 2012,1822(3):467-473.
26. Kraft E:Cognitive function, physical activity, and aging:possible biological links and implications for multimodal interventions. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn 2012,19(1-2):248-263.
27. Dekeyne A: Behavioural models for the characterisation of established and innovative antidepressant agents. Therapie 2005,60(5):477-484.
28. Morris R: Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 1984, 11(1):47-60.
29. Shen LR, Xiao F, Yuan P, Chen Y, Gao QK, Panell LD, Meydani M, Ordovas JM, Li D, Lai CQ: Curcumin-supplemented diets increase superoxide dismutase activity and mean lifespan in Drosophila. Age (Dordr) 2012.
30. Eckert GP, Schiborr C, Hagl S, Abdel-Kader R, Muller WE, Rimbach G, Frank J:Curcumin prevents mitochondrial dysfunction in the brain of the senescence-accelerated mouse-prone 8. Neurochem Int 2013.
31. Zhang C, Browne A, Child D, Tanzi RE:Curcumin decreases amyloid-beta peptide levels by attenuating the maturation of amyloid-beta precursor protein. J Biol Chem 2010, 285(37):28472-28480.
32. Akazawa N, Choi Y, Miyaki A, Tanabe Y, Sugawara J, Ajisaka R, Maeda S:Curcumin ingestion and exercise training improve vascular endothelial function in postmenopausal women. Nutr Res 2012,32(10):795-799.
33. Evsen L, Sugahara S, Uchikawa M, Kondoh H, Wu DK:Progression of neurogenesis in the inner ear requires inhibition of sox2 transcription by neurogeninl and neurodl. J Neurosci 2013,33(9):3879-3890.
34. Packard A, Giel-Moloney M, Leiter A, Schwob JE:Progenitor cell capacity of NeuroDl-expressing globose basal cells in the mouse olfactory epithelium. J Comp Neurol 2011,519(17):3580-3596.
35. Uittenbogaard M, Baxter KK, Chiaramello A:NeuroD6 genomic signature bridging neuronal differentiation to survival via the molecular chaperone network. J Neurosci Res 2010,88(1):33-54.
36. Baxter KK, Uittenbogaard M, Chiaramello A:The neurogenic basic helix-loop-helix transcription factor NeuroD6 enhances mitochondrial biogenesis and bioenergetics to confer tolerance of neuronal PC12-NeuroD6 cells to the mitochondrial stressor rotenone. Exp Cell Res 2012,318(17):2200-2214.
37. Reim K, Regus-Leidig H, Ammermuller J, EI-Kordi A, Radyushkin K, Ehrenreich H, Brandstatter JH, Brose N:Aberrant function and structure of retinal ribbon synapses in the absence of complexin 3 and complexin 4. J Cell Sci 2009,122(Pt 9):1352-1361.
38. McCue HV, Haynes LP, Burgoyne RD:The diversity of calcium sensor proteins in the regulation of neuronal function. Cold Spring Harb Perspect Biol 2010,2(8):a004085.
39. leraci A, Forni PE, Ponzetto C: Viable hypomorphic signaling mutant of the Met receptor reveals a role for hepatocyte growth factor in postnatal cerebellar development. Proc NatlAcad Sci U S A 2002,99(23):15200-15205.
40. Takeo S, Takagi N, Takagi K: [Ischemic brain injury and hepatocyte growth factor]. Yakugaku Zasshi 2007,127(11):1813-1823.
41. Kitta K, Day RM, Ikeda T, Suzuki YJ:Hepatocyte growth factor protects cardiac myocytes against oxidative stress-induced apoptosis. Free Radic Biol Med 2001,31(7):902-910.
42. Mizhorkova Z, Chernaeva L, Papasova M:Effect of neurotensin on contractile activity and [3H]acetylcholine release in cat terminal ileum during different postnatal periods. Mech Ageing Dev 1992,63(2):147-155.
43. Assimakopoulos SF, Scopa CD, Zervoudakis G, Mylonas PG, Georgiou C, Nikolopoulou V, Vagianos CE:Bombesin and neurotensin reduce endotoxemia, intestinal oxidative stress, and apoptosis in experimental obstructive jaundice. Ann Surg 2005, 241(1):159-167.
44. Chua JJ, Butkevich E, Worseck JM, Kittelmann M, Gronborg M, Behrmann E, Stelzl U, Pavlos NJ, Lalowski MM, Eimer S etal:Phosphorylation-regulated axonal dependent transport of syntaxin 1 is mediated by a Kinesin-1 adapter. Proc NatlAcad Sci U S A 2012,109(15):5862-5867.
45. Fan HP, Fan FJ, Bao L, Pei G:SNAP-25/syntaxin 1A complex functionally modulates neurotransmitter gamma-aminobutyric acid reuptake. J Biol Chem 2006, 281(38):28174-28184.
46. Mishima T, Fujiwara T, Kofuji T, Akagawa K:Impairment of catecholamine systems during induction of long-term potentiation at hippocampal CA1 synapses in HPC-1/syntaxin 1A knock-out mice. J Neurosci 2012,32(1):381-389.
47. Matsuo R, Asada A, Fujitani K, Inokuchi K:LIRF, a gene induced during hippocampal long-term potentiation as an immediate-early gene, encodes a novel RING finger protein. Biochem Biophys Res Commun 2001,289(2):479-484.
48. Shimizu T, Nakazawa M, Kani S, Bae YK, Kageyama R, Hibi M:Zinc finger genes Fezfl and Fezf2 control neuronal differentiation by repressing Hes5 expression in the forebrain. Development 2010,137(11):1875-1885.
49. Cariboni A, Andrews WD, Memi F, Ypsilanti AR, Zelina P, Chedotal A, Parnavelas JG:Slit2 and Robo3 modulate the migration of GnRH-secreting neurons. Development 2012, 139(18):3326-3331.
50. Pappu KS, Morey M, Nern A, Spitzweck B, Dickson BJ, Zipursky SL:Robo-3-mediated repulsive interactions guide R8 axons during Drosophila visual system development. Proc Natl Acad Sci U S A 2011,108(18):7571-7576.
51. Yap CC, Liang F, Yamazaki Y, Muto Y, Kishida H, Hayashida T, Hashikawa T, Yano R:CIP98, a novel PDZ domain protein, is expressed in the central nervous system and interacts with calmodulin-dependent serine kinase. J Neurochem 2003,85(1):123-134.
52. Wayman GA, Bose DD, Yang D, Lesiak A, Bruun D, Impey S, Ledoux V, Pessah IN, Lein PJ: PCB-95 modulates the calcium-dependent signaling pathway responsible for activity-dependent dendritic growth. Environ Health Perspect 2012,120(7):1003-1009.
53. Madsen TM, Newton SS, Eaton ME, Russell DS, Duman RS:Chronic electroconvulsive seizure up-regulates beta-catenin expression in rat hippocampus: role in adult neurogenesis. Biol Psychiatry 2003,54(10):1006-1014.
54. Blin M, Norton W, Bally-Cuif L, Vernier P:NR4A2 controls the differentiation of selective dopaminergic nuclei in the zebrafish brain. Mol Cell Neurosci 2008,39(4):592-604.
55. Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, Gage FH, Glass CK:A Nurrl/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 2009,137(1):47-59.
56. Holla VR, Wu H, Shi Q, Menter DG, DuBois RN:Nuclear orphan receptor NR4A2 modulates fatty acid oxidation pathways in colorectal cancer. J Biol Chem 2011, 286(34):30003-30009.
57. Tanaka M, Ohashi R, Nakamura R, Shinmura K, Kamo T, Sakai R, Sugimura H:Tiaml mediates neurite outgrowth induced by ephrin-B1 and EphA2. EMBO J 2004, 23(5):1075-1088.
58. Tolias KF, Bikoff JB, Kane CG, Tolias CS, Hu L, Greenberg ME:The Racl guanine nucleotide exchange factor Tiaml mediates EphB receptor-dependent dendritic spine development. Proc Natl Acad Sci U S A 2007,104(17):7265-7270.
59. Zhuang B, Su YS, Sockanathan S:FARP1 promotes the dendritic growth of spinal motor neuron subtypes through transmembrane Semaphorin6A and PlexinA4 signaling. Neuron 2009,61(3):359-372.
60. Takemoto M, Hattori Y, Zhao H, Sato H, Tamada A, Sasaki S, Nakajima K, Yamamoto N: Laminar and areal expression of unc5d and its role in cortical cell survival. Cereb Cortex 2011,21(8):1925-1934.
61. Bozdagi 0, Sakurai T, Papapetrou D, Wang X, Dickstein DL, Takahashi N, Kajiwara Y, Yang M, Katz AM, Scattoni ML et al: Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Mot Autism 2010,1(1):15.
62. Dai J, Kumar J, Feng Y, Asrican R, Kim J, Fofonoff T, Russakovsky V, Churchill R, Roy N, Bell E:The specificity of phenotypic induction of mouse and human stem cells by signaling complexes. In Vitro Cell Dev Biol Anim 2002,38(4):198-204.
63. Ago Y, Hiramatsu N, Ishihama T, Hazama K, Hayata-Takano A, Shibasaki Y, Shintani N, Hashimoto H, Kawasaki T, Onoe H et al: The selective metabotropic glutamate 2/3 receptor agonist MGS0028 reverses psychomotor abnormalities and recognition memory deficits in mice lacking the pituitary adenylate cyclase-activating polypeptide. Behav Pharmacol 2013,24(1):74-77.
64. Xia Z, Storm DR: Role of signal transduction crosstalk between adenylyl cyclase and MAP kinase in hippocampus-dependent memory. Learn Mem 2012,19(9):369-374.
65. Matsuda S, Matsuda Y, D'Adamio L:CD74 interacts with APP and suppresses the production of Abeta. Mol Neurodegener 2009,4:41.
66. Gaudreault SB, Dea D, Poirier J:Increased caveolin-1 expression in Alzheimer's disease brain. Neurobiol Aging 2004,25(6):753-759.
67. Rauch SM, Huen K, Miller MC, Chaudry H, Lau M, Sanes JR, Johanson CE, Stopa EG, Burgess RW: Changes in brain beta-amyloid deposition and aquaporin 4 levels in response to altered agrin expression in mice. J Neuropathol Exp Neurol 2011, 70(12):1124-1137.
68. Weiss H, Wester-Rosenloef L, Koch C, Koch F, Baltrusch S, Tiedge M, Ibrahim S;The mitochondrial Atp8 mutation induces mitochondrial ROS generation, secretory dysfunction, and beta-cell mass adaptation in conplastic B6-mtFVB mice. Endocrinology 2012,153(10):4666-4676.
69. Cao Z, Wara AK, Icli B, Sun X, Packard RR, Esen F, Stapleton CJ, Subramaniam M, Kretschmer K, Apostolou I et al: Kruppel-like factor KLF10 targets transforming growth factor-betal to regulate CD4(+)CD25(-) T cells and T regulatory cells. J Biol Chem 2009, 284(37):24914-24924.
70. Shi Q, Padmanabhan R, Villegas CJ, Gu S, Jiang JX: Membrane topological structure of neutral system N/A amino acid transporter 4 (SNAT4) protein. J Biol Chem 2011, 286(44)38086-38094.
71. Gonzalez-Renteria SM, Loera-Castaneda V, Chairez-Hernandez I, Sosa-Macias M, Paniagua-Castro N, Lares-Aseff I, Rodriguez-Moran M, Guerrero-Romero F, Galaviz-Hernandez C: Association of the polymorphisms 292 C>T and 1304 G>A in the SLC38A4 gene with hyperglycaemia. Diabetes Metab Res Rev 2013,29(1):39-43.
72. Driskell OJ, Mironov A, Allan VJ, Woodman PG:Dynein is required for receptor sorting and the morphogenesis of early endosomes. Nat Cell Biol 2007,9(1):113-120.
73. Lechtreck KF, Delmotte P, Robinson ML, Sanderson MJ, Witman GB:Mutations in Hydin impair ciliary motility in mice. J Cell Biol 2008,180(3):633-643.
74. Ogasawara K, Iwabuchi K, Kobayashi S, Ishikawa N, Ikeda H, Natori T, Ogasawara M, Geng L, Good RA, Onoe K:An epitope on class II antigens that is maintained across species barriers and important in immunologic functions. Transplantation 1987, 43(3):427-432.
75. Altman J, Das GD:Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 1965,124(3):319-335.
76. Kaplan MS, Hinds JW: Neurogenesis in the adult rat:electron microscopic analysis of light radioautographs. Science 1977,197(4308):1092-1094.
77. Kaplan MS:Neurogenesis in the 3-month-old rat visual cortex. J Comp Neurol 1981, 195(2):323-338.
78. Gould E, McEwen BS, Tanapat P, Galea LA, Fuchs E:Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci 1997,17(7):2492-2498.
79. Kornack DR, Rakic P:Continuation of neurogenesis in the hippocampus of the adult macaque monkey. Proc Natl Acad Sci U S A 1999,96(10):5768-5773.
80. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH: Neurogenesis in the adult human hippocampus. Nat Med 1998,4(11):1313-1317.
81. Ben Abdallah NM, Slomianka L, Vyssotski AL, Lipp HP:Early age-related changes in adult hippocampal neurogenesis in C57 mice. Neurobiol Aging 2010,31(1):151-161.
82. Kuhn HG, Dickinson-Anson H, Gage FH:Neurogenesis in the dentate gyrus of the adult rat:age-related decrease of neuronal progenitor proliferation. J Neurosci 1996, 16(6):2027-2033.
83. Kang SK, Cha SH, Jeon HG:Curcumin-induced histone hypoacetylation enhances caspase-3-dependent glioma cell death and neurogenesis of neural progenitor cells. Stem Cells Dev 2006,15(2):165-174.
84. Kim SJ, Son TG, Park HR, Park M, Kim MS, Kim HS, Chung HY, Mattson MP, Lee J: Curcumin stimulates proliferation of embryonic neural progenitor cells and neurogenesis in the adult hippocampus. J Biol Chem 2008,283(21):14497-14505.
85. Xu Y, Ku B, Cui L, Li X, Barish PA, Foster TC, Ogle WO:Curcumin reverses impaired hippocampal neurogenesis and increases serotonin receptor 1A mRNA and brain-derived neurotrophic factor expression in chronically stressed rats. Brain Res 2007,1162:9-18.
86. Zhao C, Deng W, Gage FH:Mechanisms and functional implications of adult neurogenesis. Cell 2008,132(4):645-660.
87. Ge S, Yang CH, Hsu KS, Ming GL, Song H:A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain. Neuron 2007,54(4):559-566.
88. Drapeau E, Mayo W, Aurousseau C, Le Moal M, Piazza PV, Abrous DN:Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc Natl Acad Sci U S A 2003,100(24):14385-14390.
89. Harman D:Aging:a theory based on free radical and radiation chemistry. J Gerontol 1956, 11(3):298-300.
90. Maugeri D, Santangelo A, Bonanno MR, Testai M, Abbate S, Lo Giudice F, Mamazza C, Pugllsi N, Panebianco P:Oxidative stress and aging:studies on an East-Sicilian, ultraoctagenarian population living in institutes or at home. Arch Gerontol Geriatr Suppl 2004(9):271-277.
91. Fukui K, Omoi NO, Hayasaka T, Shinnkai T, Suzuki S, Abe K, Urano S:Cognitive impairment of rats caused by oxidative stress and aging, and its prevention by vitamin E. Ann N Y Acad Sci 2002,959:275-284.
92. Zhu M, Gu F, Shi J, Hu J, Hu Y, Zhao Z:Increased oxidative stress and astrogliosis responses in conditional double-knockout mice of Alzheimer-like presenilin-1 and presenilin-2. Free Radic Biol Med 2008,45(10):1493-1499.
93. Nagai T, Yamada K, Kim HC, Noda Y, Nabeshima Y, Nabeshima T:[Cognition impairment in the klotho gene mutant mice and oxidative stress]. Nihon Shinkei Seishin Yakurigaku Zasshi 2003,23(5):211-217.
94. Fernandez-Fernandez S, Almeida A, Bolanos JP:Antioxidant and bioenergetic coupling between neurons and astrocytes. Biochem J 2012,443(1):3-11.
95. Blackburn D, Sargsyan S, Monk PN, Shaw PJ:Astrocyte function and role in motor neuron disease:a future therapeutic target? Glia 2009,57(12):1251-1264.
96. Limon-Pacheco JH, Gonsebatt ME:The glutathione system and its regulation by neurohormone melatonin in the central nervous system. Cent Nerv Syst Agents Med Chem 2010,10(4):287-297.
97. Titler AM, Posimo JM, Leak RK:Astrocyte plasticity revealed by adaptations to severe proteotoxic stress. Cell Tissue Res 2013.
98. Lane DJ, Lawen A:The Glutamate Aspartate Transporter (GLAST) Mediates L-Glutamate-Stimulated Ascorbate-Release Via Swelling-Activated Anion Channels in Cultured Neonatal Rodent Astrocytes. Cell Biochem Biophys 2013,65(2):107-119.
99. Hama H, Hara C, Yamaguchi K, Miyawaki A:PKC signaling mediates global enhancement of excitatory synaptogenesis in neurons triggered by local contact with astrocytes. Neuron 2004,41(3):405-415.
100. Micevych P, Christensen A:Membrane-initiated estradiol actions mediate structural plasticity and reproduction. Front Neuroendocrinol 2012,33(4):331-341.
101. Pfrieger FW, Ungerer N:Cholesterol metabolism in neurons and astrocytes. Prog Lipid Res 2011,50(4):357-371.
102. Beierlein M:Imaging calcium waves in cerebellar Bergmann glia. Cold Spring Harb Protoc 2013,2013(1).
103. Cirillo G, De Luca D, Papa M:Calcium imaging of living astrocytes in the mouse spinal cord following sensory stimulation. Neural Plast 2012,2012:425818.
104. Song HJ, Stevens CF, Gage FH:Neural stem cells from adult hippocampus develop essential properties of functional CNS neurons. Nat Neurosci 2002,5(5):438-445.
105. Shetty AK: Neural Stem Cell Therapy for Temporal Lobe Epilepsy.2012.
106. Okuyama S, Shimada N, Kaji M, Morita M, Miyoshi K, Minami S, Amakura Y, Yoshimura M, Yoshida T, Watanabe S et al:Heptamethoxyflavone, a citrus flavonoid, enhances brain-derived neurotrophic factor production and neurogenesis in the hippocampus following cerebral global ischemia in mice. Neurosci Lett 2012,528(2):190-195.
107. Yang Y, Ge W, Chen Y, Zhang Z, Shen W, Wu C, Poo M, Duan S:Contribution of astrocytes to hippocampal long-term potentiation through release of D-serine. Proc Natl Acad Sci U S A 2003,100(25):15194-15199.
108. Jin QH, Shen HX, Wang H, Shou QY, Liu Q:Curcumin improves expression of SCF/c-kit through attenuating oxidative stress and NF-kappaB activation in gastric tissues of diabetic gastroparesis rats. Diabetol Metab Syndr 2013,5(1):12.
109. Tokac M, Taner G, Aydin S, Ozkardes AB, Dundar HZ, Taslipinar MY, Arikok AT, Kilic M, Basaran AA, Basaran N:Protective effects of curcumin against oxidative stress parameters and DNA damage in the livers and kidneys of rats with biliary obstruction. Food Chem Toxicol 2013.
110. Chhunchha B, Fatma N, Kubo E, Rai P, Singh SP, Singh DP:Curcumin abates hypoxia-induced oxidative stress based-ER stress-mediated cell death in mouse hippocampal cells (HT22) by controlling Prdx6 and NF-kappaB regulation. Am J Physiol Cell Physiol 2013.
111. Flora G, Gupta D, Tiwari A:Preventive efficacy of bulk and nanocurcumin against lead-induced oxidative stress in mice. Biol Trace Elem Res 2013,152(1):31-40.
112. Yang Y, Duan W, Liang Z, Yi W, Yan J, Wang N, Li Y, Chen W, Yu S, Jin Z et al:Curcumin attenuates endothelial cell oxidative stress injury through Notch signaling inhibition. Cell Signal 2013,25(3):615-629.
113. Soetikno V, Sari FR, Lakshmanan AP, Arumugam S, Harima M, Suzuki K, Kawachi H, Watanabe K:Curcumin alleviates oxidative stress, inflammation, and renal fibrosis in remnant kidney through the Nrf2-keapl pathway. Mol Nutr Food Res 2012.
114. Jiang H, Tian X, Guo Y, Duan W, Bu H, Li C:Activation of nuclear factor erythroid 2-related factor 2 cytoprotective signaling by curcumin protect primary spinal cord astrocytes against oxidative toxicity. Biol Pharm Bull 2011,34(8):1194-1197.
115. Wang Y, Yin H, Wang L, Shuboy A, Lou J, Han B, Zhang X, Li J:Curcumin as a potential treatment for Alzheimer's disease:a study of the effects of curcumin on hippocampal expression of glial fibrillary acidic protein. Am J Chin Med 2013,41(l):59-70.
116. Karpinska A, Gromadzka G:Oxidative stress and natural antioxidant mechanisms:the role in neurodegeneration. From molecular mechanisms to therapeutic strategies. Postepy Hig Med Dosw (Online) 2013,67(0):43-53.
117. Feng Y, Wang X: Antioxidant therapies for Alzheimer's disease. Oxid Med Cell Longev 2012,2012:472932.
118. Fujita K, Yamafuji M, Nakabeppu Y, Noda M:Therapeutic approach to neurodegenerative diseases by medical gases:focusing on redox signaling and related antioxidant enzymes. Oxid Med Cell Longev 2012,2012:324256.
119. Sutachan JJ, Casas Z, Albarracin SL, Stab BR,2nd, Samudio I, Gonzalez J, Morales L, Barreto GE:Cellular and molecular mechanisms of antioxidants in Parkinson's disease. Nutr Neurosci 2012,15(3):120-126.
120. Aoyama K, Watabe M, Nakaki T:Regulation of neuronal glutathione synthesis. J Pharmacol Sci 2008,108(3):227-238.
121. Dringen R, Hirrlinger J:Glutathione pathways in the brain. Biol Chem 2003, 384(4):505-516.
122. Currais A, Maher P:Functional Consequences of Age-Dependent Changes in Glutathione Status in the Brain. Antioxid Redox Signal 2013.
123. Aschner M:Neuron-astrocyte interactions:implications for cellular energetics and antioxidant levels. Neurotoxicology 2000,21(6):1101-1107.
124. Raps SP, Lai JC, Hertz L, Cooper AJ:Glutathione is present in high concentrations in cultured astrocytes but not in cultured neurons. Brain Res 1989,493(2):398-401.
125. Langeveld CH, Schepens E, Jongenelen CA, Stoof JC, Hjelle OP, Ottersen OP, Drukarch B: Presence of glutathione immunoreactivity in cultured neurones and astrocytes. Neuroreport 1996,7(11):1833-1836.
126. Shih AY, Johnson DA, Wong G, Kraft AD, Jiang L, Erb H, Johnson JA, Murphy TH: Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci 2003,23(8):3394-3406.
127. Brown-Borg HM, Rakoczy SG:Glutathione metabolism in long-living Ames dwarf mice. Exp Gerontol 2005,40(1-2):115-120.
128. Sasaki T, Unno K, Tahara S, Kaneko T:Age-related increase of reactive oxygen generation in the brains of mammals and birds:is reactive oxygen a signaling molecule to determine the aging process and life span? Geriatr Gerontol Int 2010,10 Suppl 1:S10-24.
129. Sozmen EY, Kanit L, Kutay FZ, Hariri NI:Possible supportive effects of co-dergocrine mesylate on antioxidant enzyme systems in aged rat brain. Eur Neuropsychopharmacol 1998,8(1):13-16.
130. Ozturk G, Akbulut KG, Guney S, Acuna-Castroviejo D:Age-related changes in the rat brain mitochondrial antioxidative enzyme ratios:modulation by melatonin. Exp Gerontol 2012,47(9):706-711.
131. Cerbai F, Lana D, Nosi D, Petkova-Kirova P, Zecchi S, Brothers HM, Wenk GL, Giovannini MG:The neuron-astrocyte-microglia triad in normal brain ageing and in a model of neuroinflammation in the rat hippocampus. PLoS One 2012,7(9):e45250.
132. Berciano MT, Andres MA, Calle E, Lafarga M:Age-induced hypertrophy of astrocytes in rat supraoptic nucleus:a cytological, morphometric, and immunocytochemical study. Anat Rec 1995,243(1):129-144.
133. Itoh Y, Yamada M, Suematsu N, Matsushita M, Otomo E:An immunohistochemical study of centenarian brains:a comparison. J Neurol Sci 1998,157(1):73-81.
134. Zhang R, Kadar T, Sirimanne E, MacGibbon A, Guan J:Age-related memory decline is associated with vascular and microglial degeneration in aged rats. Behav Brain Res 2012,235(2):210-217.
135. Lively S, Schlichter LC:Age-Related Comparisons of Evolution of the Inflammatory Response After Intracerebral Hemorrhage in Rats. Transl Stroke Res 2012,3(Suppl 1):132-146.
136. Enongene EN, Sun PN, Mehta CS: Sodium thiosulfate protects against acrylonitrile-induced elevation of glial fibrillary acidic protein levels by replenishing glutathione. Environ Toxicol Pharmacol 2000,8(2):153-161.
137. Javed H, Khan MM, Ahmad A, Vaibhav K, Ahmad ME, Khan A, Ashafaq M, Islam F, Siddiqui MS, Safhi MM:Rutin prevents cognitive impairments by ameliorating oxidative stress and neuroinflammation in rat model of sporadic dementia of Alzheimer type. Neuroscience 2012,210:340-352.
138. Ghoddoussi F, Galloway MP, Jambekar A, Bame M, Needleman R, Brusilow WS: Methionine sulfoximine, an inhibitor of glutamine synthetase, lowers brain glutamine and glutamate in a mouse model of ALS. J Neurol Sci 2010,290(1-2):41-47.
139. Castegna A, Palmieri L, Spera I, Porcelli V, Palmieri F, Fabis-Pedrini MJ, Kean RB, Barkhouse DA, Curtis MT, Hooper DC:Oxidative stress and reduced glutamine synthetase activity in the absence of inflammation in the cortex of mice with experimental allergic encephalomyelitis. Neuroscience 2011,185:97-105.
140. Smith CD, Carney JM, Starke-Reed PE, Oliver CN, Stadtman ER, Floyd RA, Markesbery WR: Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci U S A 1991,88(23):10540-10543.
141. Head E, Liu J, Hagen TM, Muggenburg BA, Milgram NW, Ames BN, Cotman CW: Oxidative damage increases with age in a canine model of human brain aging. J Neurochem 2002,82(2):375-381.
142. Poon HF, Vaishnav RA, Getchell TV, Getchell ML, Butterfield DA:Quantitative proteomics analysis of differential protein expression and oxidative modification of specific proteins in the brains of old mice. Neurobiol Aging 2006,27(7):1010-1019.
143. Nichols NR, Day JR, Laping NJ, Johnson SA, Finch CE:GFAP mRNA increases with age in rat and human brain. Neurobiol Aging 1993,14(5):421-429.
144. Wu Y, Zhang AQ, Yew DT:Age related changes of various markers of astrocytes in senescence-accelerated mice hippocampus. Neurochem Int 2005,46(7):565-574.
145. Carrette O, Burkhard PR, Hochstrasser DF, Sanchez JC:Age-related proteome analysis of the mouse brain:a 2-DE study. Proteomics 2006,6(18):4940-4949.
146. Chen Y, Ai Y, Slevin JR, Maley BE, Gash DM:Progenitor proliferation in the adult hippocampus and substantia nigra induced by glial cell line-derived neurotrophic factor. Exp Neurol 2005,196(1):87-95.
147. Islam O, Loo TX, Heese K: Brain-derived neurotrophic factor (BDNF) has proliferative effects on neural stem cells through the truncated TRK-B receptor, MAP kinase, AKT, and STAT-3 signaling pathways. Curr Neurovasc Res 2009,6(1):42-53.
148. Perez-Martin M, Cifuentes M, Grondona JM, Lopez-Avalos MD, Gomez-Pinedo U, Garcia-Verdugo JM, Fernandez-Llebrez P:IGF-I stimulates neurogenesis in the hypothalamus of adult rats. Eur J Neurosci 2010,31(9):1533-1548.
149. Vallieres L, Campbell IL, Gage FH, Sawchenko PE:Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci 2002,22(2):486-492.
150. Wu MD, Hein AM, Moravan MJ, Shaftel SS, Olschowka JA, O'Banion MK:Adult murine hippocampal neurogenesis is inhibited by sustained IL-lbeta and not rescued by voluntary running. Brain Behav Immun 2012,26(2):292-300.
151. Godbout JP, Johnson RW:Interleukin-6 in the aging brain. J Neuroimmunol 2004, 147(1-2):141-144.
152. Liu X, Wu Z, Hayashi Y, Nakanishi H:Age-dependent neuroinflammatory responses and deficits in long-term potentiation in the hippocampus during systemic inflammation. Neuroscience 2012,216:133-142.
153. Muto Y, Hayashi T, Higashi Y, Endo T, Yamamoto T, Sato K:Age-related decrease in brain-derived neurotrophic factor gene expression in the brain of the zitter rat with genetic spongiform encephalopathy. Neurosci Lett 1999,271(2):69-72.
154. Miyazaki H, Okuma Y, Nomura J, Nagashima K, Nomura Y:Age-related alterations in the expression of glial cell line-derived neurotrophic factor in the senescence-accelerated mouse brain. J Pharmacol Sci 2003,92(1):28-34.
155. Tiwari V, Chopra K: Attenuation of oxidative stress, neuroinflammation, and apoptosis by curcumin prevents cognitive deficits in rats postnatally exposed to ethanol. Psychopharmacology (Berl) 2012,224(4):519-535.
156. King MD, McCracken DJ, Wade FM, Meiler SE, Alleyne CH, Jr., Dhandapani KM: Attenuation of hematoma size and neurological injury with curcumin following intracerebral hemorrhage in mice. J Neurosurg 2011,115(1):116-123.
157. Hurley LL, Akinfiresoye L, Nwulia E, Kamiya A, Kulkarni AA, Tizabi Y:Antidepressant-like effects of curcumin in WKY rat model of depression is associated with an increase in hippocampal BDNF. Behav Brain Res 2013,239:27-30.
158. Zhang L, Xu T, Wang S, Yu L, Liu D, Zhan R, Yu SY:Curcumin produces antidepressant effects via activating MAPK/ERK-dependent brain-derived neurotrophic factor expression in the amygdala of mice. Behav Brain Res 2012,235(1):67-72.
159.Steele ML, Fuller S, Maczurek AE, Kersaitis C, Ooi L, Munch G:Chronic inflammation alters production and release of glutathione and related thiols in human U373 astroglial cells. Cell Mol Neurobiol 2013,33(1):19-30.
160. Schell MJ:The N-methyl D-aspartate receptor glycine site and D-serine metabolism:an evolutionary perspective. Philos Trans R Soc Lond B Biol Sci 2004,359(1446):943-964.
161. Billard JM:D-serine signalling as a prominent determinant of neuronal-glial dialogue in the healthy and diseased brain. J Cell Mol Med 2008,12(5B):1872-1884.
162. Nagai T, Yu J, Kitahara Y, Nabeshima T, Yamada K:D-Serine ameliorates neonatal Polyl:C treatment-induced emotional and cognitive impairments in adult mice. J Pharmacol Sci 2012,120(3):213-227.
163. Fossat P, Turpin FR, Sacchi S, Dulong J, Shi T, Rivet JM, Sweedler JV, Pollegioni L, Millan MJ, Oliet SH et al:Glial D-serine gates NMDA receptors at excitatory synapses in prefrontal cortex. Cereb Cortex 2012,22(3):595-606.
164. Turpin FR, Potier B, Dulong JR, Sinet PM, Alliot J, Oliet SH, Dutar P, Epelbaum J, Mothet JP, Billard JM:Reduced serine racemase expression contributes to age-related deficits in hippocampal cognitive function. Neurobiol Aging 2011,32(8):1495-1504.
165. Haxaire C, Turpin FR, Potier B, Kervern M, Sinet PM, Barbanel G, Mothet JP, Dutar P, Billard JM:Reversal of age-related oxidative stress prevents hippocampal synaptic plasticity deficits by protecting D-serine-dependent NMDA receptor activation. Aging Cell 2012, 11(2):336-344.
166. Ullian EM, Sapperstein SK, Christopherson KS, Barres BA:Control of synapse number by glia. Science 2001,291(5504):657-661.
167. Tanaka M, Shih PY, Gomi H, Yoshida T, Nakai J, Ando R, Furuichi T, Mikoshiba K, Semyanov A, Itohara S:Astrocytic Ca2+ signals are required for the functional integrity of tripartite synapses. Mol Brain 2013,6:6.
168. Nakayama T, Momoki-Soga T, Inoue N:Astrocyte-derived factors instruct differentiation of embryonic stem cells into neurons. Neurosci Res 2003,46(2):241-249.
169. Kuzumaki N, Ikegami D, Imai S, Narita M, Tamura R, Yajima M, Suzuki A, Miyashita K, Niikura K, Takeshima H et al:Enhanced IL-lbeta production in response to the activation of hippocampal glial cells impairs neurogenesis in aged mice. Synapse 2010, 64(9):721-728.
170. Ueki T, Tanaka M, Yamashita K, Mikawa S, Qiu Z, Maragakis NJ, Hevner RF, Miura N, Sugimura H, Sato K: A novel secretory factor, Neurogenesin-1, provides neurogenic environmental cues for neural stem cells in the adult hippocampus. J Neurosci 2003, 23(37):11732-11740.
171. Panatier A, Theodosis DT, Mothet JP, Touquet B, Pollegioni L, Poulain DA, Oliet SH: Glia-derived D-serine controls NMDA receptor activity and synaptic memory. Cell 2006, 125(4):775-784.
172. Yang S, Qiao H, Wen L, Zhou W, Zhang Y:D-serine enhances impaired long-term potentiation in CAl subfield of hippocampal slices from aged senescence-accelerated mouse prone/8. Neurosci Lett 2005,379(1):7-12.
173. Suzuki A, Stern SA, Bozdagi O, Huntley GW, Walker RH, Magistretti PJ, Alberini CM: Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 2011,144(5):810-823.
174. Toescu EC, Verkhratsky A:Neuronal ageing from an intraneuronal perspective:roles of endoplasmic reticulum and mitochondria. Cell Calcium 2003,34(4-5):311-323.
175. Dringen R, Gutterer JM, Hirrlinger J:Glutathione metabolism in brain metabolic interaction between astrocytes and neurons in the defense against reactive oxygen species. EurJ Biochem 2000,267(16):4912-4916.
176. Marosi K, Bori Z, Hart N, Sarga L, Koltai E, Radak Z, Nyakas C:Long-term exercise treatment reduces oxidative stress in the hippocampus of aging rats. Neuroscience 2012,226:21-28.
177. El-Sawalhi MM, Darwish HA, Mausouf MN, Shaheen AA:Modulation of age-related changes in oxidative stress markers and energy status in the rat heart and hippocampus:a significant role for ozone therapy. Cell Biochem Funct 2012.
178. Sakul A, Cumaoglu A, Aydin E, Ari N, Dilsiz N, Karasu C:Age- and diabetes-induced regulation of oxidative protein modification in rat brain and peripheral tissues: Consequences of treatment with antioxidant pyridoindole. Exp Gerontol 2013.
179. Siqueira IR, Fochesatto C, de Andrade A, Santos M, Hagen M, Bello-Klein A, Netto CA: Total antioxidant capacity is impaired in different structures from aged rat brain. Int J Dev Neurosci 2005,23(8):663-671.
180. Benzi G, Moretti A:Age- and peroxidative stress-related modifications of the cerebral enzymatic activities linked to mitochondria and the glutathione system. Free Radic Biol Med1995,19(1):77-101.
181. Leutner S, Eckert A, Muller WE:ROS generation, lipid peroxidation and antioxidant enzyme activities in the aging brain. J Neural Transm 2001,108(8-9):955-967.
182. Gottfried C, Tramontina F, Goncalves D, Goncalves CA, Moriguchi E, Dias RD, Wofchuk ST, Souza DO:Glutamate uptake in cultured astrocytes depends on age:a study about the effect of guanosine and the sensitivity to oxidative stress induced by H(2)O(2). Mech Ageing Dev 2002,123(10):1333-1340.
183. Klamt F, Gottfried C, Tramontina F, Dal-Pizzol F, Da Frota ML, Jr., Moreira JC, Dias RD, Moriguchi E, Wofchuk S, Souza DO:Time-related increase in mitochondrial superoxide production, biomolecule damage and antioxidant enzyme activities in cortical astrocyte cultures. Neuroreport 2002,13(12):1515-1518.
184. Tucker AM, Stern Y:Cognitive reserve in aging. Curr Alzheimer Res 2011,8(4):354-360.
185. Ding J, Strachan MW, Reynolds RM, Frier BM, Deary IJ, Fowkes FG, Lee AJ, McKnight J, Halpin P, Swa K et al Diabetic retinopathy and cognitive decline in older people with type 2 diabetes:the Edinburgh Type 2 Diabetes Study. Diabetes 2010, 59(11):2883-2889.
186. Kuo CK, Lin LY, Yu YH, Wu KH, Kuo HK:Inverse association between insulin resistance and gait speed in nondiabetic older men:results from the U.S. National Health and Nutrition Examination Survey (NHANES) 1999-2002. BMC Geriatr 2009,9:49.
187. Doucet J, Druesne L, Capet C, Greboval E, Landrin I, Moirot P, Micaud G:Risk factors and management of diabetes in elderly French patients. Diabetes Metab 2008,34(6 Pt 1):574-580.
188. Okereke OI, Kurth T, Pollak MN, Gaziano JM, Grodstein F:Fasting plasma insulin, C-peptide and cognitive change in older men without diabetes:results from the Physicians' Health Study II. Neuroepidemiology 2010,34(4):200-207.
189. Peila R, Rodriguez BL, White LR, Launer U:Fasting insulin and incident dementia in an elderly population of Japanese-American men. Neurology 2004,63(2):228-233.
190. van Elderen SG, de Roos A, de Craen AJ, Westendorp RG, Blauw GJ, Jukema JW, Bollen EL, Middelkoop HA, van Buchem MA, van der Grond J:Progression of brain atrophy and cognitive decline in diabetes mellitus: a 3-year follow-up. Neurology 2010, 75(11):997-1002.
191. Yaffe K, Falvey C, Hamilton N, Schwartz AV, Simonsick EM, Satterfield S, Cauley JA, Rosano C, Launer U, Strotmeyer ES et al: Diabetes, glucose control, and 9-year cognitive decline among older adults without dementia. Arch Neurol 2012, 69(9):1170-1175.
192. Bialecka M, Kurzawski M, Roszmann A, Robowski P, Sitek EJ, Honczarenko K, Gorzkowska A, Budrewicz S, Mak M, Jarosz M et al:Association of COMT, MTHFR, and SLC19A1(RFC-1) polymorphisms with homocysteine blood levels and cognitive impairment in Parkinson's disease. Pharmacogenet Genomics 2012,22(10):716-724.
193. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA:Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 2002,346(7):476-483.
194. Schafer JH, Glass TA, Bolla Kl, Mintz M, Jedlicka AE, Schwartz BS:Homocysteine and cognitive function in a population-based study of older adults. J Am Geriatr Soc 2005, 53(3):381-388.
195.胡晓舟,王少亭,刘章锁,刘东伟：郑州市社区老年人群血脂异常分布与慢性肾脏病 的相关性.中国老年学杂志2011,31(18)：3584-3586.
196. Hilal S, Ikram MK, Saini M, Tan CS, Catindig JA, Dong YH, Lim LB, Ting EY, Koo EH, Cheung CY et al: Prevalence of cognitive impairment in Chinese: Epidemiology of Dementia in Singapore study. J Neurol Neurosurg Psychiatry 2013.
197. Solomon A, Sippola R, Soininen H, Wolozin B, Tuomilehto J, Laatikainen T, Kivipelto M: Lipid-lowering treatment is related to decreased risk of dementia:a population-based study (FINRISK). Neurodegener Dis 2010,7(1-3):180-182.
198. Asha Devi S:Aging brain:prevention of oxidative stress by vitamin E and exercise. ScientificWorldJournal 2009,9:366-372.
2. Bishop NA, Lu T, Yankner BA:Neural mechanisms of ageing and cognitive decline. Nature 2010,464(7288)529-535.
3. Adair JC, Williamson DJ, Knoefel JE:Cognitive impairment in elderly who are not yet demented. Compr Ther 1999,25(8-10):390-396.
4. Collie A, Maruff P:The neuropsychology of preclinical Alzheimer's disease and mild cognitive impairment. Neurosci Biobehav Rev 2000,24(3):365-374.
5. Sherwin BB:Mild cognitive impairment: potential pharmacological treatment options. J Am Geriatr Soc 2000,48(4):431-441.
6. Vandewoude MF: The pharmacological management of cognitive dysfunction in Alzheimer's disease. Acta Clin Belg 1999,54(5):306-311.
7. Schraufstatter E, Bernt H:Antibacterial action of curcumin and related compounds. Nature 1949,164(4167):456.
8. Esatbeyoglu T, Huebbe P, Ernst IM, Chin D, Wagner AE, Rimbach G:Curcumin-from molecule to biological function. Angew Chem Int Ed Engl 2012,51(22):5308-5332.
9. Mythri RB, Bharath MM:Curcumin:a potential neuroprotective agent in Parkinson's disease. Curr Pharm Des 2012,18(1):91-99.
10. Gupta SC, Patchva S, Koh W, Aggarwal BB: Discovery of curcumin, a component of golden spice, and its miraculous biological activities. Clin Exp Pharmacol Physiol 2012, 39(3):283-299.
11. Belkacemi A, Doggui S, Dao L, Ramassamy C: Challenges associated with curcumin therapy in Alzheimer disease. Expert Rev Mol Med 2011,13:e34.
12. Kulkarni S, Dhir A, Akula KK:Potentials of curcumin as an antidepressant. ScientificWorldJournal 2009,9:1233-1241.
13. Ovbiagele B:Potential role of curcumin in stroke prevention. Expert Rev Neurother 2008,8(8):1175-1176.
14. Hamaguchi T, Ono K, Yamada M:REVIEW: Curcumin and Alzheimer's disease. CNS Neurosci Ther 2010,16(5):285-297.
15. Zhao J, Zhao Y, Zheng W, Lu Y, Feng G, Yu S: Neuroprotective effect of curcumin on transient focal cerebral ischemia in rats. Brain Res 2008,1229:224-232.
16. Shen LR, Parnell LD, Ordovas JM, Lai CQ: Curcumin and aging. Biofactors 2013, 39(1):133-140.
17. Wu A, Ying Z, Schubert D, Gomez-Pinilla F:Brain and spinal cord interaction: a dietary curcumin derivative counteracts locomotor and cognitive deficits after brain trauma. Neurorehabil Neural Repair 2011,25(4):332-342.
18. Ng TP, Chiam PC, Lee T, Chua HC, Lim L, Kua EH:Curry consumption and cognitive function in the elderly. Am J Epidemiol 2006,164(9):898-906.
19. Brodaty H, Heffernan M, Kochan NA, Draper B, Trollor JN, Reppermund S, Slavin MJ, Sachdev PS: Mild cognitive impairment in a community sample:The Sydney Memory and Ageing Study. Alzheimers Dement 2012.
20. Dodson JA, Truong TT, Towle VR, Kerins G, Chaudhry SI:Cognitive impairment in older adults with heart failure: prevalence, documentation, and impact on outcomes. Am J Med 2013,126(2):120-126.
21.张健,李华：社区脑卒中危险因素及认知状态流行病学研究.农垦医学2012,第34卷第3期：269-273.
22. Frautschy SA, Hu W, Kim P, Miller SA, Chu T, Harris-White ME, Cole GM:Phenolic anti-inflammatory antioxidant reversal of Abeta-induced cognitive deficits and neuropathology. NeurobiolAging 2001,22(6):993-1005.
23. Wu A, Ying Z, Gomez-Pinilla F:Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition. Exp Neurol 2006, 197(2):309-317.
24. Ishrat T, Hoda MN, Khan MB, Yousuf S, Ahmad M, Khan MM, Ahmad A, Islam F: Amelioration of cognitive deficits and neurodegeneration by curcumin in rat model of sporadic dementia of Alzheimer's type (SDAT). Eur Neuropsychopharmacol 2009, 19(9):636-647.
25. Steffener J, Stern Y:Exploring the neural basis of cognitive reserve in aging. Biochim Biophys Acta 2012,1822(3):467-473.
26. Kraft E:Cognitive function, physical activity, and aging:possible biological links and implications for multimodal interventions. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn 2012,19(1-2):248-263.
27. Dekeyne A: Behavioural models for the characterisation of established and innovative antidepressant agents. Therapie 2005,60(5):477-484.
28. Morris R: Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 1984, 11(1):47-60.
29. Shen LR, Xiao F, Yuan P, Chen Y, Gao QK, Panell LD, Meydani M, Ordovas JM, Li D, Lai CQ: Curcumin-supplemented diets increase superoxide dismutase activity and mean lifespan in Drosophila. Age (Dordr) 2012.
30. Eckert GP, Schiborr C, Hagl S, Abdel-Kader R, Muller WE, Rimbach G, Frank J:Curcumin prevents mitochondrial dysfunction in the brain of the senescence-accelerated mouse-prone 8. Neurochem Int 2013.
31. Zhang C, Browne A, Child D, Tanzi RE:Curcumin decreases amyloid-beta peptide levels by attenuating the maturation of amyloid-beta precursor protein. J Biol Chem 2010, 285(37):28472-28480.
32. Akazawa N, Choi Y, Miyaki A, Tanabe Y, Sugawara J, Ajisaka R, Maeda S:Curcumin ingestion and exercise training improve vascular endothelial function in postmenopausal women. Nutr Res 2012,32(10):795-799.
33. Evsen L, Sugahara S, Uchikawa M, Kondoh H, Wu DK:Progression of neurogenesis in the inner ear requires inhibition of sox2 transcription by neurogeninl and neurodl. J Neurosci 2013,33(9):3879-3890.
34. Packard A, Giel-Moloney M, Leiter A, Schwob JE:Progenitor cell capacity of NeuroDl-expressing globose basal cells in the mouse olfactory epithelium. J Comp Neurol 2011,519(17):3580-3596.
35. Uittenbogaard M, Baxter KK, Chiaramello A:NeuroD6 genomic signature bridging neuronal differentiation to survival via the molecular chaperone network. J Neurosci Res 2010,88(1):33-54.
36. Baxter KK, Uittenbogaard M, Chiaramello A:The neurogenic basic helix-loop-helix transcription factor NeuroD6 enhances mitochondrial biogenesis and bioenergetics to confer tolerance of neuronal PC12-NeuroD6 cells to the mitochondrial stressor rotenone. Exp Cell Res 2012,318(17):2200-2214.
37. Reim K, Regus-Leidig H, Ammermuller J, EI-Kordi A, Radyushkin K, Ehrenreich H, Brandstatter JH, Brose N:Aberrant function and structure of retinal ribbon synapses in the absence of complexin 3 and complexin 4. J Cell Sci 2009,122(Pt 9):1352-1361.
38. McCue HV, Haynes LP, Burgoyne RD:The diversity of calcium sensor proteins in the regulation of neuronal function. Cold Spring Harb Perspect Biol 2010,2(8):a004085.
39. leraci A, Forni PE, Ponzetto C: Viable hypomorphic signaling mutant of the Met receptor reveals a role for hepatocyte growth factor in postnatal cerebellar development. Proc NatlAcad Sci U S A 2002,99(23):15200-15205.
40. Takeo S, Takagi N, Takagi K: [Ischemic brain injury and hepatocyte growth factor]. Yakugaku Zasshi 2007,127(11):1813-1823.
41. Kitta K, Day RM, Ikeda T, Suzuki YJ:Hepatocyte growth factor protects cardiac myocytes against oxidative stress-induced apoptosis. Free Radic Biol Med 2001,31(7):902-910.
42. Mizhorkova Z, Chernaeva L, Papasova M:Effect of neurotensin on contractile activity and [3H]acetylcholine release in cat terminal ileum during different postnatal periods. Mech Ageing Dev 1992,63(2):147-155.
43. Assimakopoulos SF, Scopa CD, Zervoudakis G, Mylonas PG, Georgiou C, Nikolopoulou V, Vagianos CE:Bombesin and neurotensin reduce endotoxemia, intestinal oxidative stress, and apoptosis in experimental obstructive jaundice. Ann Surg 2005, 241(1):159-167.
44. Chua JJ, Butkevich E, Worseck JM, Kittelmann M, Gronborg M, Behrmann E, Stelzl U, Pavlos NJ, Lalowski MM, Eimer S etal:Phosphorylation-regulated axonal dependent transport of syntaxin 1 is mediated by a Kinesin-1 adapter. Proc NatlAcad Sci U S A 2012,109(15):5862-5867.
45. Fan HP, Fan FJ, Bao L, Pei G:SNAP-25/syntaxin 1A complex functionally modulates neurotransmitter gamma-aminobutyric acid reuptake. J Biol Chem 2006, 281(38):28174-28184.
46. Mishima T, Fujiwara T, Kofuji T, Akagawa K:Impairment of catecholamine systems during induction of long-term potentiation at hippocampal CA1 synapses in HPC-1/syntaxin 1A knock-out mice. J Neurosci 2012,32(1):381-389.
47. Matsuo R, Asada A, Fujitani K, Inokuchi K:LIRF, a gene induced during hippocampal long-term potentiation as an immediate-early gene, encodes a novel RING finger protein. Biochem Biophys Res Commun 2001,289(2):479-484.
48. Shimizu T, Nakazawa M, Kani S, Bae YK, Kageyama R, Hibi M:Zinc finger genes Fezfl and Fezf2 control neuronal differentiation by repressing Hes5 expression in the forebrain. Development 2010,137(11):1875-1885.
49. Cariboni A, Andrews WD, Memi F, Ypsilanti AR, Zelina P, Chedotal A, Parnavelas JG:Slit2 and Robo3 modulate the migration of GnRH-secreting neurons. Development 2012, 139(18):3326-3331.
50. Pappu KS, Morey M, Nern A, Spitzweck B, Dickson BJ, Zipursky SL:Robo-3-mediated repulsive interactions guide R8 axons during Drosophila visual system development. Proc Natl Acad Sci U S A 2011,108(18):7571-7576.
51. Yap CC, Liang F, Yamazaki Y, Muto Y, Kishida H, Hayashida T, Hashikawa T, Yano R:CIP98, a novel PDZ domain protein, is expressed in the central nervous system and interacts with calmodulin-dependent serine kinase. J Neurochem 2003,85(1):123-134.
52. Wayman GA, Bose DD, Yang D, Lesiak A, Bruun D, Impey S, Ledoux V, Pessah IN, Lein PJ: PCB-95 modulates the calcium-dependent signaling pathway responsible for activity-dependent dendritic growth. Environ Health Perspect 2012,120(7):1003-1009.
53. Madsen TM, Newton SS, Eaton ME, Russell DS, Duman RS:Chronic electroconvulsive seizure up-regulates beta-catenin expression in rat hippocampus: role in adult neurogenesis. Biol Psychiatry 2003,54(10):1006-1014.
54. Blin M, Norton W, Bally-Cuif L, Vernier P:NR4A2 controls the differentiation of selective dopaminergic nuclei in the zebrafish brain. Mol Cell Neurosci 2008,39(4):592-604.
55. Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, Gage FH, Glass CK:A Nurrl/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 2009,137(1):47-59.
56. Holla VR, Wu H, Shi Q, Menter DG, DuBois RN:Nuclear orphan receptor NR4A2 modulates fatty acid oxidation pathways in colorectal cancer. J Biol Chem 2011, 286(34):30003-30009.
57. Tanaka M, Ohashi R, Nakamura R, Shinmura K, Kamo T, Sakai R, Sugimura H:Tiaml mediates neurite outgrowth induced by ephrin-B1 and EphA2. EMBO J 2004, 23(5):1075-1088.
58. Tolias KF, Bikoff JB, Kane CG, Tolias CS, Hu L, Greenberg ME:The Racl guanine nucleotide exchange factor Tiaml mediates EphB receptor-dependent dendritic spine development. Proc Natl Acad Sci U S A 2007,104(17):7265-7270.
59. Zhuang B, Su YS, Sockanathan S:FARP1 promotes the dendritic growth of spinal motor neuron subtypes through transmembrane Semaphorin6A and PlexinA4 signaling. Neuron 2009,61(3):359-372.
60. Takemoto M, Hattori Y, Zhao H, Sato H, Tamada A, Sasaki S, Nakajima K, Yamamoto N: Laminar and areal expression of unc5d and its role in cortical cell survival. Cereb Cortex 2011,21(8):1925-1934.
61. Bozdagi 0, Sakurai T, Papapetrou D, Wang X, Dickstein DL, Takahashi N, Kajiwara Y, Yang M, Katz AM, Scattoni ML et al: Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Mot Autism 2010,1(1):15.
62. Dai J, Kumar J, Feng Y, Asrican R, Kim J, Fofonoff T, Russakovsky V, Churchill R, Roy N, Bell E:The specificity of phenotypic induction of mouse and human stem cells by signaling complexes. In Vitro Cell Dev Biol Anim 2002,38(4):198-204.
63. Ago Y, Hiramatsu N, Ishihama T, Hazama K, Hayata-Takano A, Shibasaki Y, Shintani N, Hashimoto H, Kawasaki T, Onoe H et al: The selective metabotropic glutamate 2/3 receptor agonist MGS0028 reverses psychomotor abnormalities and recognition memory deficits in mice lacking the pituitary adenylate cyclase-activating polypeptide. Behav Pharmacol 2013,24(1):74-77.
64. Xia Z, Storm DR: Role of signal transduction crosstalk between adenylyl cyclase and MAP kinase in hippocampus-dependent memory. Learn Mem 2012,19(9):369-374.
65. Matsuda S, Matsuda Y, D'Adamio L:CD74 interacts with APP and suppresses the production of Abeta. Mol Neurodegener 2009,4:41.
66. Gaudreault SB, Dea D, Poirier J:Increased caveolin-1 expression in Alzheimer's disease brain. Neurobiol Aging 2004,25(6):753-759.
67. Rauch SM, Huen K, Miller MC, Chaudry H, Lau M, Sanes JR, Johanson CE, Stopa EG, Burgess RW: Changes in brain beta-amyloid deposition and aquaporin 4 levels in response to altered agrin expression in mice. J Neuropathol Exp Neurol 2011, 70(12):1124-1137.
68. Weiss H, Wester-Rosenloef L, Koch C, Koch F, Baltrusch S, Tiedge M, Ibrahim S;The mitochondrial Atp8 mutation induces mitochondrial ROS generation, secretory dysfunction, and beta-cell mass adaptation in conplastic B6-mtFVB mice. Endocrinology 2012,153(10):4666-4676.
69. Cao Z, Wara AK, Icli B, Sun X, Packard RR, Esen F, Stapleton CJ, Subramaniam M, Kretschmer K, Apostolou I et al: Kruppel-like factor KLF10 targets transforming growth factor-betal to regulate CD4(+)CD25(-) T cells and T regulatory cells. J Biol Chem 2009, 284(37):24914-24924.
70. Shi Q, Padmanabhan R, Villegas CJ, Gu S, Jiang JX: Membrane topological structure of neutral system N/A amino acid transporter 4 (SNAT4) protein. J Biol Chem 2011, 286(44)38086-38094.
71. Gonzalez-Renteria SM, Loera-Castaneda V, Chairez-Hernandez I, Sosa-Macias M, Paniagua-Castro N, Lares-Aseff I, Rodriguez-Moran M, Guerrero-Romero F, Galaviz-Hernandez C: Association of the polymorphisms 292 C>T and 1304 G>A in the SLC38A4 gene with hyperglycaemia. Diabetes Metab Res Rev 2013,29(1):39-43.
72. Driskell OJ, Mironov A, Allan VJ, Woodman PG:Dynein is required for receptor sorting and the morphogenesis of early endosomes. Nat Cell Biol 2007,9(1):113-120.
73. Lechtreck KF, Delmotte P, Robinson ML, Sanderson MJ, Witman GB:Mutations in Hydin impair ciliary motility in mice. J Cell Biol 2008,180(3):633-643.
74. Ogasawara K, Iwabuchi K, Kobayashi S, Ishikawa N, Ikeda H, Natori T, Ogasawara M, Geng L, Good RA, Onoe K:An epitope on class II antigens that is maintained across species barriers and important in immunologic functions. Transplantation 1987, 43(3):427-432.
75. Altman J, Das GD:Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 1965,124(3):319-335.
76. Kaplan MS, Hinds JW: Neurogenesis in the adult rat:electron microscopic analysis of light radioautographs. Science 1977,197(4308):1092-1094.
77. Kaplan MS:Neurogenesis in the 3-month-old rat visual cortex. J Comp Neurol 1981, 195(2):323-338.
78. Gould E, McEwen BS, Tanapat P, Galea LA, Fuchs E:Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci 1997,17(7):2492-2498.
79. Kornack DR, Rakic P:Continuation of neurogenesis in the hippocampus of the adult macaque monkey. Proc Natl Acad Sci U S A 1999,96(10):5768-5773.
80. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH: Neurogenesis in the adult human hippocampus. Nat Med 1998,4(11):1313-1317.
81. Ben Abdallah NM, Slomianka L, Vyssotski AL, Lipp HP:Early age-related changes in adult hippocampal neurogenesis in C57 mice. Neurobiol Aging 2010,31(1):151-161.
82. Kuhn HG, Dickinson-Anson H, Gage FH:Neurogenesis in the dentate gyrus of the adult rat:age-related decrease of neuronal progenitor proliferation. J Neurosci 1996, 16(6):2027-2033.
83. Kang SK, Cha SH, Jeon HG:Curcumin-induced histone hypoacetylation enhances caspase-3-dependent glioma cell death and neurogenesis of neural progenitor cells. Stem Cells Dev 2006,15(2):165-174.
84. Kim SJ, Son TG, Park HR, Park M, Kim MS, Kim HS, Chung HY, Mattson MP, Lee J: Curcumin stimulates proliferation of embryonic neural progenitor cells and neurogenesis in the adult hippocampus. J Biol Chem 2008,283(21):14497-14505.
85. Xu Y, Ku B, Cui L, Li X, Barish PA, Foster TC, Ogle WO:Curcumin reverses impaired hippocampal neurogenesis and increases serotonin receptor 1A mRNA and brain-derived neurotrophic factor expression in chronically stressed rats. Brain Res 2007,1162:9-18.
86. Zhao C, Deng W, Gage FH:Mechanisms and functional implications of adult neurogenesis. Cell 2008,132(4):645-660.
87. Ge S, Yang CH, Hsu KS, Ming GL, Song H:A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain. Neuron 2007,54(4):559-566.
88. Drapeau E, Mayo W, Aurousseau C, Le Moal M, Piazza PV, Abrous DN:Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc Natl Acad Sci U S A 2003,100(24):14385-14390.
89. Harman D:Aging:a theory based on free radical and radiation chemistry. J Gerontol 1956, 11(3):298-300.
90. Maugeri D, Santangelo A, Bonanno MR, Testai M, Abbate S, Lo Giudice F, Mamazza C, Pugllsi N, Panebianco P:Oxidative stress and aging:studies on an East-Sicilian, ultraoctagenarian population living in institutes or at home. Arch Gerontol Geriatr Suppl 2004(9):271-277.
91. Fukui K, Omoi NO, Hayasaka T, Shinnkai T, Suzuki S, Abe K, Urano S:Cognitive impairment of rats caused by oxidative stress and aging, and its prevention by vitamin E. Ann N Y Acad Sci 2002,959:275-284.
92. Zhu M, Gu F, Shi J, Hu J, Hu Y, Zhao Z:Increased oxidative stress and astrogliosis responses in conditional double-knockout mice of Alzheimer-like presenilin-1 and presenilin-2. Free Radic Biol Med 2008,45(10):1493-1499.
93. Nagai T, Yamada K, Kim HC, Noda Y, Nabeshima Y, Nabeshima T:[Cognition impairment in the klotho gene mutant mice and oxidative stress]. Nihon Shinkei Seishin Yakurigaku Zasshi 2003,23(5):211-217.
94. Fernandez-Fernandez S, Almeida A, Bolanos JP:Antioxidant and bioenergetic coupling between neurons and astrocytes. Biochem J 2012,443(1):3-11.
95. Blackburn D, Sargsyan S, Monk PN, Shaw PJ:Astrocyte function and role in motor neuron disease:a future therapeutic target? Glia 2009,57(12):1251-1264.
96. Limon-Pacheco JH, Gonsebatt ME:The glutathione system and its regulation by neurohormone melatonin in the central nervous system. Cent Nerv Syst Agents Med Chem 2010,10(4):287-297.
97. Titler AM, Posimo JM, Leak RK:Astrocyte plasticity revealed by adaptations to severe proteotoxic stress. Cell Tissue Res 2013.
98. Lane DJ, Lawen A:The Glutamate Aspartate Transporter (GLAST) Mediates L-Glutamate-Stimulated Ascorbate-Release Via Swelling-Activated Anion Channels in Cultured Neonatal Rodent Astrocytes. Cell Biochem Biophys 2013,65(2):107-119.
99. Hama H, Hara C, Yamaguchi K, Miyawaki A:PKC signaling mediates global enhancement of excitatory synaptogenesis in neurons triggered by local contact with astrocytes. Neuron 2004,41(3):405-415.
100. Micevych P, Christensen A:Membrane-initiated estradiol actions mediate structural plasticity and reproduction. Front Neuroendocrinol 2012,33(4):331-341.
101. Pfrieger FW, Ungerer N:Cholesterol metabolism in neurons and astrocytes. Prog Lipid Res 2011,50(4):357-371.
102. Beierlein M:Imaging calcium waves in cerebellar Bergmann glia. Cold Spring Harb Protoc 2013,2013(1).
103. Cirillo G, De Luca D, Papa M:Calcium imaging of living astrocytes in the mouse spinal cord following sensory stimulation. Neural Plast 2012,2012:425818.
104. Song HJ, Stevens CF, Gage FH:Neural stem cells from adult hippocampus develop essential properties of functional CNS neurons. Nat Neurosci 2002,5(5):438-445.
105. Shetty AK: Neural Stem Cell Therapy for Temporal Lobe Epilepsy.2012.
106. Okuyama S, Shimada N, Kaji M, Morita M, Miyoshi K, Minami S, Amakura Y, Yoshimura M, Yoshida T, Watanabe S et al:Heptamethoxyflavone, a citrus flavonoid, enhances brain-derived neurotrophic factor production and neurogenesis in the hippocampus following cerebral global ischemia in mice. Neurosci Lett 2012,528(2):190-195.
107. Yang Y, Ge W, Chen Y, Zhang Z, Shen W, Wu C, Poo M, Duan S:Contribution of astrocytes to hippocampal long-term potentiation through release of D-serine. Proc Natl Acad Sci U S A 2003,100(25):15194-15199.
108. Jin QH, Shen HX, Wang H, Shou QY, Liu Q:Curcumin improves expression of SCF/c-kit through attenuating oxidative stress and NF-kappaB activation in gastric tissues of diabetic gastroparesis rats. Diabetol Metab Syndr 2013,5(1):12.
109. Tokac M, Taner G, Aydin S, Ozkardes AB, Dundar HZ, Taslipinar MY, Arikok AT, Kilic M, Basaran AA, Basaran N:Protective effects of curcumin against oxidative stress parameters and DNA damage in the livers and kidneys of rats with biliary obstruction. Food Chem Toxicol 2013.
110. Chhunchha B, Fatma N, Kubo E, Rai P, Singh SP, Singh DP:Curcumin abates hypoxia-induced oxidative stress based-ER stress-mediated cell death in mouse hippocampal cells (HT22) by controlling Prdx6 and NF-kappaB regulation. Am J Physiol Cell Physiol 2013.
111. Flora G, Gupta D, Tiwari A:Preventive efficacy of bulk and nanocurcumin against lead-induced oxidative stress in mice. Biol Trace Elem Res 2013,152(1):31-40.
112. Yang Y, Duan W, Liang Z, Yi W, Yan J, Wang N, Li Y, Chen W, Yu S, Jin Z et al:Curcumin attenuates endothelial cell oxidative stress injury through Notch signaling inhibition. Cell Signal 2013,25(3):615-629.
113. Soetikno V, Sari FR, Lakshmanan AP, Arumugam S, Harima M, Suzuki K, Kawachi H, Watanabe K:Curcumin alleviates oxidative stress, inflammation, and renal fibrosis in remnant kidney through the Nrf2-keapl pathway. Mol Nutr Food Res 2012.
114. Jiang H, Tian X, Guo Y, Duan W, Bu H, Li C:Activation of nuclear factor erythroid 2-related factor 2 cytoprotective signaling by curcumin protect primary spinal cord astrocytes against oxidative toxicity. Biol Pharm Bull 2011,34(8):1194-1197.
115. Wang Y, Yin H, Wang L, Shuboy A, Lou J, Han B, Zhang X, Li J:Curcumin as a potential treatment for Alzheimer's disease:a study of the effects of curcumin on hippocampal expression of glial fibrillary acidic protein. Am J Chin Med 2013,41(l):59-70.
116. Karpinska A, Gromadzka G:Oxidative stress and natural antioxidant mechanisms:the role in neurodegeneration. From molecular mechanisms to therapeutic strategies. Postepy Hig Med Dosw (Online) 2013,67(0):43-53.
117. Feng Y, Wang X: Antioxidant therapies for Alzheimer's disease. Oxid Med Cell Longev 2012,2012:472932.
118. Fujita K, Yamafuji M, Nakabeppu Y, Noda M:Therapeutic approach to neurodegenerative diseases by medical gases:focusing on redox signaling and related antioxidant enzymes. Oxid Med Cell Longev 2012,2012:324256.
119. Sutachan JJ, Casas Z, Albarracin SL, Stab BR,2nd, Samudio I, Gonzalez J, Morales L, Barreto GE:Cellular and molecular mechanisms of antioxidants in Parkinson's disease. Nutr Neurosci 2012,15(3):120-126.
120. Aoyama K, Watabe M, Nakaki T:Regulation of neuronal glutathione synthesis. J Pharmacol Sci 2008,108(3):227-238.
121. Dringen R, Hirrlinger J:Glutathione pathways in the brain. Biol Chem 2003, 384(4):505-516.
122. Currais A, Maher P:Functional Consequences of Age-Dependent Changes in Glutathione Status in the Brain. Antioxid Redox Signal 2013.
123. Aschner M:Neuron-astrocyte interactions:implications for cellular energetics and antioxidant levels. Neurotoxicology 2000,21(6):1101-1107.
124. Raps SP, Lai JC, Hertz L, Cooper AJ:Glutathione is present in high concentrations in cultured astrocytes but not in cultured neurons. Brain Res 1989,493(2):398-401.
125. Langeveld CH, Schepens E, Jongenelen CA, Stoof JC, Hjelle OP, Ottersen OP, Drukarch B: Presence of glutathione immunoreactivity in cultured neurones and astrocytes. Neuroreport 1996,7(11):1833-1836.
126. Shih AY, Johnson DA, Wong G, Kraft AD, Jiang L, Erb H, Johnson JA, Murphy TH: Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci 2003,23(8):3394-3406.
127. Brown-Borg HM, Rakoczy SG:Glutathione metabolism in long-living Ames dwarf mice. Exp Gerontol 2005,40(1-2):115-120.
128. Sasaki T, Unno K, Tahara S, Kaneko T:Age-related increase of reactive oxygen generation in the brains of mammals and birds:is reactive oxygen a signaling molecule to determine the aging process and life span? Geriatr Gerontol Int 2010,10 Suppl 1:S10-24.
129. Sozmen EY, Kanit L, Kutay FZ, Hariri NI:Possible supportive effects of co-dergocrine mesylate on antioxidant enzyme systems in aged rat brain. Eur Neuropsychopharmacol 1998,8(1):13-16.
130. Ozturk G, Akbulut KG, Guney S, Acuna-Castroviejo D:Age-related changes in the rat brain mitochondrial antioxidative enzyme ratios:modulation by melatonin. Exp Gerontol 2012,47(9):706-711.
131. Cerbai F, Lana D, Nosi D, Petkova-Kirova P, Zecchi S, Brothers HM, Wenk GL, Giovannini MG:The neuron-astrocyte-microglia triad in normal brain ageing and in a model of neuroinflammation in the rat hippocampus. PLoS One 2012,7(9):e45250.
132. Berciano MT, Andres MA, Calle E, Lafarga M:Age-induced hypertrophy of astrocytes in rat supraoptic nucleus:a cytological, morphometric, and immunocytochemical study. Anat Rec 1995,243(1):129-144.
133. Itoh Y, Yamada M, Suematsu N, Matsushita M, Otomo E:An immunohistochemical study of centenarian brains:a comparison. J Neurol Sci 1998,157(1):73-81.
134. Zhang R, Kadar T, Sirimanne E, MacGibbon A, Guan J:Age-related memory decline is associated with vascular and microglial degeneration in aged rats. Behav Brain Res 2012,235(2):210-217.
135. Lively S, Schlichter LC:Age-Related Comparisons of Evolution of the Inflammatory Response After Intracerebral Hemorrhage in Rats. Transl Stroke Res 2012,3(Suppl 1):132-146.
136. Enongene EN, Sun PN, Mehta CS: Sodium thiosulfate protects against acrylonitrile-induced elevation of glial fibrillary acidic protein levels by replenishing glutathione. Environ Toxicol Pharmacol 2000,8(2):153-161.
137. Javed H, Khan MM, Ahmad A, Vaibhav K, Ahmad ME, Khan A, Ashafaq M, Islam F, Siddiqui MS, Safhi MM:Rutin prevents cognitive impairments by ameliorating oxidative stress and neuroinflammation in rat model of sporadic dementia of Alzheimer type. Neuroscience 2012,210:340-352.
138. Ghoddoussi F, Galloway MP, Jambekar A, Bame M, Needleman R, Brusilow WS: Methionine sulfoximine, an inhibitor of glutamine synthetase, lowers brain glutamine and glutamate in a mouse model of ALS. J Neurol Sci 2010,290(1-2):41-47.
139. Castegna A, Palmieri L, Spera I, Porcelli V, Palmieri F, Fabis-Pedrini MJ, Kean RB, Barkhouse DA, Curtis MT, Hooper DC:Oxidative stress and reduced glutamine synthetase activity in the absence of inflammation in the cortex of mice with experimental allergic encephalomyelitis. Neuroscience 2011,185:97-105.
140. Smith CD, Carney JM, Starke-Reed PE, Oliver CN, Stadtman ER, Floyd RA, Markesbery WR: Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci U S A 1991,88(23):10540-10543.
141. Head E, Liu J, Hagen TM, Muggenburg BA, Milgram NW, Ames BN, Cotman CW: Oxidative damage increases with age in a canine model of human brain aging. J Neurochem 2002,82(2):375-381.
142. Poon HF, Vaishnav RA, Getchell TV, Getchell ML, Butterfield DA:Quantitative proteomics analysis of differential protein expression and oxidative modification of specific proteins in the brains of old mice. Neurobiol Aging 2006,27(7):1010-1019.
143. Nichols NR, Day JR, Laping NJ, Johnson SA, Finch CE:GFAP mRNA increases with age in rat and human brain. Neurobiol Aging 1993,14(5):421-429.
144. Wu Y, Zhang AQ, Yew DT:Age related changes of various markers of astrocytes in senescence-accelerated mice hippocampus. Neurochem Int 2005,46(7):565-574.
145. Carrette O, Burkhard PR, Hochstrasser DF, Sanchez JC:Age-related proteome analysis of the mouse brain:a 2-DE study. Proteomics 2006,6(18):4940-4949.
146. Chen Y, Ai Y, Slevin JR, Maley BE, Gash DM:Progenitor proliferation in the adult hippocampus and substantia nigra induced by glial cell line-derived neurotrophic factor. Exp Neurol 2005,196(1):87-95.
147. Islam O, Loo TX, Heese K: Brain-derived neurotrophic factor (BDNF) has proliferative effects on neural stem cells through the truncated TRK-B receptor, MAP kinase, AKT, and STAT-3 signaling pathways. Curr Neurovasc Res 2009,6(1):42-53.
148. Perez-Martin M, Cifuentes M, Grondona JM, Lopez-Avalos MD, Gomez-Pinedo U, Garcia-Verdugo JM, Fernandez-Llebrez P:IGF-I stimulates neurogenesis in the hypothalamus of adult rats. Eur J Neurosci 2010,31(9):1533-1548.
149. Vallieres L, Campbell IL, Gage FH, Sawchenko PE:Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci 2002,22(2):486-492.
150. Wu MD, Hein AM, Moravan MJ, Shaftel SS, Olschowka JA, O'Banion MK:Adult murine hippocampal neurogenesis is inhibited by sustained IL-lbeta and not rescued by voluntary running. Brain Behav Immun 2012,26(2):292-300.
151. Godbout JP, Johnson RW:Interleukin-6 in the aging brain. J Neuroimmunol 2004, 147(1-2):141-144.
152. Liu X, Wu Z, Hayashi Y, Nakanishi H:Age-dependent neuroinflammatory responses and deficits in long-term potentiation in the hippocampus during systemic inflammation. Neuroscience 2012,216:133-142.
153. Muto Y, Hayashi T, Higashi Y, Endo T, Yamamoto T, Sato K:Age-related decrease in brain-derived neurotrophic factor gene expression in the brain of the zitter rat with genetic spongiform encephalopathy. Neurosci Lett 1999,271(2):69-72.
154. Miyazaki H, Okuma Y, Nomura J, Nagashima K, Nomura Y:Age-related alterations in the expression of glial cell line-derived neurotrophic factor in the senescence-accelerated mouse brain. J Pharmacol Sci 2003,92(1):28-34.
155. Tiwari V, Chopra K: Attenuation of oxidative stress, neuroinflammation, and apoptosis by curcumin prevents cognitive deficits in rats postnatally exposed to ethanol. Psychopharmacology (Berl) 2012,224(4):519-535.
156. King MD, McCracken DJ, Wade FM, Meiler SE, Alleyne CH, Jr., Dhandapani KM: Attenuation of hematoma size and neurological injury with curcumin following intracerebral hemorrhage in mice. J Neurosurg 2011,115(1):116-123.
157. Hurley LL, Akinfiresoye L, Nwulia E, Kamiya A, Kulkarni AA, Tizabi Y:Antidepressant-like effects of curcumin in WKY rat model of depression is associated with an increase in hippocampal BDNF. Behav Brain Res 2013,239:27-30.
158. Zhang L, Xu T, Wang S, Yu L, Liu D, Zhan R, Yu SY:Curcumin produces antidepressant effects via activating MAPK/ERK-dependent brain-derived neurotrophic factor expression in the amygdala of mice. Behav Brain Res 2012,235(1):67-72.
159.Steele ML, Fuller S, Maczurek AE, Kersaitis C, Ooi L, Munch G:Chronic inflammation alters production and release of glutathione and related thiols in human U373 astroglial cells. Cell Mol Neurobiol 2013,33(1):19-30.
160. Schell MJ:The N-methyl D-aspartate receptor glycine site and D-serine metabolism:an evolutionary perspective. Philos Trans R Soc Lond B Biol Sci 2004,359(1446):943-964.
161. Billard JM:D-serine signalling as a prominent determinant of neuronal-glial dialogue in the healthy and diseased brain. J Cell Mol Med 2008,12(5B):1872-1884.
162. Nagai T, Yu J, Kitahara Y, Nabeshima T, Yamada K:D-Serine ameliorates neonatal Polyl:C treatment-induced emotional and cognitive impairments in adult mice. J Pharmacol Sci 2012,120(3):213-227.
163. Fossat P, Turpin FR, Sacchi S, Dulong J, Shi T, Rivet JM, Sweedler JV, Pollegioni L, Millan MJ, Oliet SH et al:Glial D-serine gates NMDA receptors at excitatory synapses in prefrontal cortex. Cereb Cortex 2012,22(3):595-606.
164. Turpin FR, Potier B, Dulong JR, Sinet PM, Alliot J, Oliet SH, Dutar P, Epelbaum J, Mothet JP, Billard JM:Reduced serine racemase expression contributes to age-related deficits in hippocampal cognitive function. Neurobiol Aging 2011,32(8):1495-1504.
165. Haxaire C, Turpin FR, Potier B, Kervern M, Sinet PM, Barbanel G, Mothet JP, Dutar P, Billard JM:Reversal of age-related oxidative stress prevents hippocampal synaptic plasticity deficits by protecting D-serine-dependent NMDA receptor activation. Aging Cell 2012, 11(2):336-344.
166. Ullian EM, Sapperstein SK, Christopherson KS, Barres BA:Control of synapse number by glia. Science 2001,291(5504):657-661.
167. Tanaka M, Shih PY, Gomi H, Yoshida T, Nakai J, Ando R, Furuichi T, Mikoshiba K, Semyanov A, Itohara S:Astrocytic Ca2+ signals are required for the functional integrity of tripartite synapses. Mol Brain 2013,6:6.
168. Nakayama T, Momoki-Soga T, Inoue N:Astrocyte-derived factors instruct differentiation of embryonic stem cells into neurons. Neurosci Res 2003,46(2):241-249.
169. Kuzumaki N, Ikegami D, Imai S, Narita M, Tamura R, Yajima M, Suzuki A, Miyashita K, Niikura K, Takeshima H et al:Enhanced IL-lbeta production in response to the activation of hippocampal glial cells impairs neurogenesis in aged mice. Synapse 2010, 64(9):721-728.
170. Ueki T, Tanaka M, Yamashita K, Mikawa S, Qiu Z, Maragakis NJ, Hevner RF, Miura N, Sugimura H, Sato K: A novel secretory factor, Neurogenesin-1, provides neurogenic environmental cues for neural stem cells in the adult hippocampus. J Neurosci 2003, 23(37):11732-11740.
171. Panatier A, Theodosis DT, Mothet JP, Touquet B, Pollegioni L, Poulain DA, Oliet SH: Glia-derived D-serine controls NMDA receptor activity and synaptic memory. Cell 2006, 125(4):775-784.
172. Yang S, Qiao H, Wen L, Zhou W, Zhang Y:D-serine enhances impaired long-term potentiation in CAl subfield of hippocampal slices from aged senescence-accelerated mouse prone/8. Neurosci Lett 2005,379(1):7-12.
173. Suzuki A, Stern SA, Bozdagi O, Huntley GW, Walker RH, Magistretti PJ, Alberini CM: Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 2011,144(5):810-823.
174. Toescu EC, Verkhratsky A:Neuronal ageing from an intraneuronal perspective:roles of endoplasmic reticulum and mitochondria. Cell Calcium 2003,34(4-5):311-323.
175. Dringen R, Gutterer JM, Hirrlinger J:Glutathione metabolism in brain metabolic interaction between astrocytes and neurons in the defense against reactive oxygen species. EurJ Biochem 2000,267(16):4912-4916.
176. Marosi K, Bori Z, Hart N, Sarga L, Koltai E, Radak Z, Nyakas C:Long-term exercise treatment reduces oxidative stress in the hippocampus of aging rats. Neuroscience 2012,226:21-28.
177. El-Sawalhi MM, Darwish HA, Mausouf MN, Shaheen AA:Modulation of age-related changes in oxidative stress markers and energy status in the rat heart and hippocampus:a significant role for ozone therapy. Cell Biochem Funct 2012.
178. Sakul A, Cumaoglu A, Aydin E, Ari N, Dilsiz N, Karasu C:Age- and diabetes-induced regulation of oxidative protein modification in rat brain and peripheral tissues: Consequences of treatment with antioxidant pyridoindole. Exp Gerontol 2013.
179. Siqueira IR, Fochesatto C, de Andrade A, Santos M, Hagen M, Bello-Klein A, Netto CA: Total antioxidant capacity is impaired in different structures from aged rat brain. Int J Dev Neurosci 2005,23(8):663-671.
180. Benzi G, Moretti A:Age- and peroxidative stress-related modifications of the cerebral enzymatic activities linked to mitochondria and the glutathione system. Free Radic Biol Med1995,19(1):77-101.
181. Leutner S, Eckert A, Muller WE:ROS generation, lipid peroxidation and antioxidant enzyme activities in the aging brain. J Neural Transm 2001,108(8-9):955-967.
182. Gottfried C, Tramontina F, Goncalves D, Goncalves CA, Moriguchi E, Dias RD, Wofchuk ST, Souza DO:Glutamate uptake in cultured astrocytes depends on age:a study about the effect of guanosine and the sensitivity to oxidative stress induced by H(2)O(2). Mech Ageing Dev 2002,123(10):1333-1340.
183. Klamt F, Gottfried C, Tramontina F, Dal-Pizzol F, Da Frota ML, Jr., Moreira JC, Dias RD, Moriguchi E, Wofchuk S, Souza DO:Time-related increase in mitochondrial superoxide production, biomolecule damage and antioxidant enzyme activities in cortical astrocyte cultures. Neuroreport 2002,13(12):1515-1518.
184. Tucker AM, Stern Y:Cognitive reserve in aging. Curr Alzheimer Res 2011,8(4):354-360.
185. Ding J, Strachan MW, Reynolds RM, Frier BM, Deary IJ, Fowkes FG, Lee AJ, McKnight J, Halpin P, Swa K et al Diabetic retinopathy and cognitive decline in older people with type 2 diabetes:the Edinburgh Type 2 Diabetes Study. Diabetes 2010, 59(11):2883-2889.
186. Kuo CK, Lin LY, Yu YH, Wu KH, Kuo HK:Inverse association between insulin resistance and gait speed in nondiabetic older men:results from the U.S. National Health and Nutrition Examination Survey (NHANES) 1999-2002. BMC Geriatr 2009,9:49.
187. Doucet J, Druesne L, Capet C, Greboval E, Landrin I, Moirot P, Micaud G:Risk factors and management of diabetes in elderly French patients. Diabetes Metab 2008,34(6 Pt 1):574-580.
188. Okereke OI, Kurth T, Pollak MN, Gaziano JM, Grodstein F:Fasting plasma insulin, C-peptide and cognitive change in older men without diabetes:results from the Physicians' Health Study II. Neuroepidemiology 2010,34(4):200-207.
189. Peila R, Rodriguez BL, White LR, Launer U:Fasting insulin and incident dementia in an elderly population of Japanese-American men. Neurology 2004,63(2):228-233.
190. van Elderen SG, de Roos A, de Craen AJ, Westendorp RG, Blauw GJ, Jukema JW, Bollen EL, Middelkoop HA, van Buchem MA, van der Grond J:Progression of brain atrophy and cognitive decline in diabetes mellitus: a 3-year follow-up. Neurology 2010, 75(11):997-1002.
191. Yaffe K, Falvey C, Hamilton N, Schwartz AV, Simonsick EM, Satterfield S, Cauley JA, Rosano C, Launer U, Strotmeyer ES et al: Diabetes, glucose control, and 9-year cognitive decline among older adults without dementia. Arch Neurol 2012, 69(9):1170-1175.
192. Bialecka M, Kurzawski M, Roszmann A, Robowski P, Sitek EJ, Honczarenko K, Gorzkowska A, Budrewicz S, Mak M, Jarosz M et al:Association of COMT, MTHFR, and SLC19A1(RFC-1) polymorphisms with homocysteine blood levels and cognitive impairment in Parkinson's disease. Pharmacogenet Genomics 2012,22(10):716-724.
193. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA:Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 2002,346(7):476-483.
194. Schafer JH, Glass TA, Bolla Kl, Mintz M, Jedlicka AE, Schwartz BS:Homocysteine and cognitive function in a population-based study of older adults. J Am Geriatr Soc 2005, 53(3):381-388.
195.胡晓舟,王少亭,刘章锁,刘东伟：郑州市社区老年人群血脂异常分布与慢性肾脏病 的相关性.中国老年学杂志2011,31(18)：3584-3586.
196. Hilal S, Ikram MK, Saini M, Tan CS, Catindig JA, Dong YH, Lim LB, Ting EY, Koo EH, Cheung CY et al: Prevalence of cognitive impairment in Chinese: Epidemiology of Dementia in Singapore study. J Neurol Neurosurg Psychiatry 2013.
197. Solomon A, Sippola R, Soininen H, Wolozin B, Tuomilehto J, Laatikainen T, Kivipelto M: Lipid-lowering treatment is related to decreased risk of dementia:a population-based study (FINRISK). Neurodegener Dis 2010,7(1-3):180-182.
198. Asha Devi S:Aging brain:prevention of oxidative stress by vitamin E and exercise. ScientificWorldJournal 2009,9:366-372.