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Neurogénesis regulada por dieta
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  Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue:  Nutrition and Physical Activity in Aging, Obesity, and Cancer  Neurogenic contributions made by dietary regulationto hippocampal neurogenesis Hee Ra Park and Jaewon Lee Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Longevity Life Science andTechnology Institutes, Pusan National University, Geumjeong-gu, Busan, Republic of KoreaAddress for correspondence: Jaewon Lee, Department of Pharmacy, College of Pharmacy and Research Institute for DrugDevelopment, Longevity Life Science and Technology Institutes, Pusan National University, Geumjeong-gu, Busan 609-735,Republic of Korea. neuron@pusan.ac.kr Adult neural stem cells in the dentate gyrus of the hippocampus are negatively and positively regulated by a broad range of environmental stimuli that include aging, stress, social interaction, physical activity, and dietary modulation. Interestingly, dietary regulation has a distinct outcome, such that reduced dietary intake enhancesneurogenesis, whereas excess calorie intake by a high-fat diet has a negative effect. As a type of metabolic stress,dietary restriction (DR) is also known to extend life span and increase resistance to age-related neurodegenerativediseases. However, the potential application of DR as a “neurogenic enhancer” in humans remains problematic because of the severity of restriction and the protracted duration of the treatment required. Therefore, the authorsconsider that an understanding of the neurogenic mechanisms of DR would provide a basis for the identification of the pharmacological and nutraceutical interventions that mimic the beneficial effects of DR without limiting caloricintake.ThecurrentreviewdescribestheregulatoryeffectofDRonhippocampalneurogenesisandpresentsapossibleneurogenic mechanism.Keywords:  BDNF; curcumin; dietary restriction; hippocampal neurogenesis; neural stem cell Introduction Dietary restriction (DR) can increase life span ina wide variety of species, reduce neuronal damage,and improve behavioral outcome in experimentalanimal models relevant to the pathogenesis of sev-eral age-related neurological disorders. 1 , 2 Severalstudies have described the molecular mechanismresponsible for the beneficial effects of DR on agingand age-related neurodegenerative diseases. In par-ticular,ithasbeenshownthatDRchangesmetabolicprocesses under lower glucose conditions, and thusproduces mild stress in cells to adapt to the stressedcondition by orchestrating cellular and molecularchanges—within physiological limits. 3 , 4 It has beenreported that altered gene expressions by DR arerelated to energy metabolism, stress, inflammation,and neural plasticity. 5 , 6 Subsequent studies demon-strated that DR enhances neurogenesis, indicatingthat the metabolic environment can modulate animportant brain function. 7 Our current research isaimed at developing neurogenic modulators basedon the molecular mechanisms of DR and stem cellregulation. In this review, we present an overview of the regulation of adult hippocampal neuroge-nesis by DR and the developments of neurogenicphytochemicals. Environmental stimuli can enhancehippocampal neurogenesis in the adultbrain Findings over the past two decades that demon-strated persistent neurogenesis in the adult brainhave overturned the long-held dogma that neuronsareformedexclusivelybeforebirth.Theexistenceof neural stem cells (NSCs) in the adult brain has pro-voked a reevaluation of cellular plasticity in the ma-ture brain and raised hopes that novel approachesto brain repair can be devised. The generation of  doi: 10.1111/j.1749-6632.2011.06089.x Ann. N.Y. Acad. Sci. 1229 (2011) 23–28  c  2011 New York Academy of Sciences.  23  Dietary regulation on hippocampal neurogenesis Park & Lee newborn cells is maintained throughout adulthoodin the mammalian brain via the proliferation anddifferentiation of adult NSCs. 8 Proliferating, differ-entiating, and migrating NSCs are eventually in-tegrated into neural networks. 8 Adult NSCs ex-ist in the dentate gyrus of the hippocampus andin the subventricular zone of the lateral ventri-cle, in which NSCs differentiate into new granu-lar neurons and olfactory neurons, respectively. 8 Since the hippocampus is important for the stor-age and formation of memory, newly generatingneurons in the hippocampus are considered to con-tribute the new memories and maintain the sta-bility of old memories by connecting with exist-ing neurons. 9 Adult hippocampal neurogenesis canbe altered by the neuronal network activity mod-ulating effects of neurotransmitters, growth fac-tors, and neurotrophic factors. 10 In addition, var-ious environmental stimuli, such as environmentalenrichment and exercise, increase hippocampalneurogenesis. Interestingly, studies performed atour laboratory and those of others have reportedthat DR, as a metabolic stress, enhances adulthippocampal neurogenesis. 11 Voluntary running isknown to enhance hippocampal neurogenesis by increasing the numbers of newly generated cells inthe dentate gyrus. 12 However, DR significantly pro-motesthesurvivalofnewlygeneratedneuronswith-out affecting numbers of proliferating cells in thehippocampus. Similarly, enriched environments,such as social activity, also promote the survival of cells generated by hippocampal neurogenesis ratherthan elevating proliferation. 13 These findings indi-catethatmildstressorsderivedfromphysical,social,ormetabolicalterationsarebeneficialintermsoftheactivationofNSCs and theformationofnew neuralcircuits in the adult hippocampus. Neurogenic mechanisms of DR The neurotrophic factor, brain-derived neu-rotrophic factor (BDNF), binds to TrkB plasmamembrane receptors, which leads to the autophos-phorylation of its tyrosine residues in the intracel-lular kinase domain. 14 Tyrosine phosphorylationactivates various signaling pathways, such as thephosphatidylinositol 3-kinase (PI3K)/Akt, MAPK,and PLC-   pathways. The BDNF signaling path-way involving TrkB has been implicated in the con-trol of cell proliferation and survival in the adulthippocampus. 15 Furthermore, hippocampal BDNFlevels were increased by both DR and an enrichedenvironment, and it was concluded that BDNFis required for the enhancement of hippocam-pal neurogenesis by DR and environment enrich-ment in heterozygous BDNF knockout (BDNF + / − )mice. 16 In addition, DR upregulates another neu-rotrophicfactor,neurotrophin-3(NT-3),inthehip-pocampus, and this facilitates hippocampal plas-ticity and neurogenesis by neuronal differentiationrather than proliferation. 17 Hippocampal NT-3 isoften downregulated in response to brain damagecaused by seizures, while other neurotrophic fac-tors are dramatically upregulated in brain injury; 18 thus, DR-mediated stress response is a novel stimu-lusparadigmdistinct fromthatofbraininjury.Sev-eral cytokines are elevated in brain cells in responseto stress, and it has been reported that interferon-gamma(IFN-  )isupregulatedinthehippocampusofratsfedonaDRregimen. 19 Interestingly,IFN-   isknown to promote neuronal differentiation and theneuriteoutgrowthofmurineadultstemcells,andwehavefoundthatIFN-   promotesthedifferentiationof NSCs via the JNK pathway. 20 , 21 Taken together,these results suggest that altered gene regulation by DRcouldexplaintheneurogenicmechanismunder-lying DR via the promotion of the differentiation of NSCs in the adult hippocampus. Effects of DR mimetics on neurogenesis Although it seems clear that reducing dietary in-takes beneficially enhances hippocampal neuroge-nesis and cognitive function, practicing DR in hu-mans is problematic for social and practical reasonsin this food-rich society. In fact, previous studieshave reported that a high-fat diet disrupts cogni-tion, exacerbates neurodegenerative diseases, andimpairs hippocampal synaptic plasticity and cog-nitive abilities, such as learning and memory. 22 Inaddition, elevated fasting glucose levels and hyper-lipidemiainducedbyahigh-sugardietdecreasehip-pocampal neurogenesis and cognitive function. 23 Therefore, efforts to search for DR mimetics areexpanding in the hope of finding some treatmentthat does not require DR. Several DR mimetics, in-cluding 2-deoxy- d -glucose (2DG), metformin, andresveratrol, have been shown to have beneficial ef-fects in neurodegenerative disease models by mim-icking the DR-based mechanism. 24–26 2DG is anonmetabolizable analog of glucose that inhibitsglycolysis. Furthermore, 2DG efficiently blocks 24  Ann. N.Y. Acad. Sci. 1229 (2011) 23–28  c  2011 New York Academy of Sciences.  Park & Lee Dietary regulation on hippocampal neurogenesis neuronal loss in neurodegenerative diseases mod-els, such as in model of Alzheimer’s disease, Parkin-son’s disease, and stroke. 2 , 25 , 27 However, the neu-rogenic property of 2DG has not been tested,although we have reported that 2DG can protectNSCs against oxidative stress. In fact, 2DG appearsto both have a toxic effect and reduce NSC pro-liferation by limiting available energy, thus activat-ing AMP-activated protein kinase (AMPK). 28 In-terestingly, AICAR, an adenosine analog used toactivate AMPK, induces the astroglial differentia-tion of NSCs independently of AMPK. However,metformin,aDRmimetic,failedtoshowastrogenicactivity, although it activated AMPK. 29 Resveratrolis another potent DR mimetic that stimulates Sir2,extendinglifespaninyeastandnematodes. 30 , 31 Fur-thermore, the beneficial effects of resveratrol in dia-betes and in age-related neurodegenerative diseaseshave been well documented, 32 , 33 and it has beenrecently reported that resveratrol improves cogni-tive function in mice by increasing hippocampalIGF-I and hippocampal neurogenesis. 34 Althoughonly a few studies have been conducted on theneurogenic potencies of DR mimetics, novel neu-rogenic supplements are likely to be discovered by simulating the neurogenic molecular mechanism of DR. Potent neurogenic phytochemicals thatenhance hippocampal neurogenesis DietarymodulationbyDR,dietcontent,anddietary sources are important for the control of hippocam-pal neurogenesis and subsequent hippocampus-mediated cognitive ability. Several dietary phytochemicals, or flavonoids, are known tohave beneficial effects in the central nervous systemby protecting neurons against injury or diseases,although they are not classified as DR mimetics.For example, curcumin is the natural phenoliccomponent of yellow curry spice, and it has beentraditionally used in India to treat diseases asso-ciated with oxidative stress and inflammation. 35 Although curcumin research has focused primarily on cancer chemoprevention, it has been suggestedthat its neuroprotective properties may be usefulfor the treatment of neurodegenerative diseases andage-associated cognitive deficit. 36 , 37 Recently, it wasreported that curcumin has neurogenic propertiesand that it stimulates embryonic NSC proliferationand adult hippocampal neurogenesis. 38 Interest-ingly, curcumin has biphasic effects on culturedNSCs, whereby low concentrations stimulate cellproliferation and high concentrations are cytotoxic.This is consistent with the finding that highconcentrations of curcumin induce oxidative stressandtriggerapoptosisincancercells. 39 Ourpreviousdata suggest that the NSC-specific mitogenic actionof low-concentration curcumin is mediated by theactivation of extracellular signal-regulated kinases(ERK) and p38 MAP kinases. 38 Taken together,the concentration-dependent neurogenic property of curcumin resembles the hormesis hypothesisof DR, which is dependent on available energy. Inone study, the administration of curcumin signifi-cantly increased the numbers of newly generatedcells in the dentate gyrus of the hippocampusby stimulating their proliferation rather thantheir survival rate. 40 Enhanced neurogenesis by promoting NSC proliferation is typically observedin exercise paradigms. 12 Physical activity oftenelevates reactive oxygen species (ROS) production,and polyphenols including curcumin can activatethe Nrf2-antioxidant response element pathway. 47 Therefore, altered redox balance in the hippocam-pus is supposed to trigger NSC proliferation.In addition, elevated hippocampal BDNF levelsare considered to be important for enhancingneurogenesis by physical exercise or curcumin. 40 , 42 Hippocampal BDNF also seems to be correlatedwith spatial learning and memory, since flavonoid-enriched foods have been reported to increasehippocampal neurogenesis under chronically stressed condition by maintaining hippocampalBDNF levels and pCREB expression. 43 However,other dietary interventions have been found to haveadverse effects on hippocampal neurogenesis. Cap-saicin ( trans  -8-methyl- N  -vanillyl-6-nonenamide)is the major pungent ingredient in red pepper,and it stimulates pain and primary afferent nervesthrough transient receptor vanilloid channels. 44 Capsaicin has also been reported to reduce thenumber of newly generated cells in the dentategyrus of the hippocampus by attenuating the ERKsignaling pathway. 45 These findings suggest that theERK signaling pathway and BDNF signaling couldconstitute a neurogenic molecular mechanism thatwill both facilitate the discovery and developmentof novel drugs that induce adult hippocampalneurogenesis and be useful for the treatment of neurodegenerative diseases and disorders. Ann. N.Y. Acad. Sci. 1229 (2011) 23–28  c  2011 New York Academy of Sciences.  25  Dietary regulation on hippocampal neurogenesis Park & Lee Figure 1.  Neurogenic actions of environmental stimuli and dietary modulation including those of DR and its mimetics. DR andan enriched environment increase the survival rate of newly generated cells by upregulating neurotrophic factors or IFN-  , whichcan promote neuronal differentiation. However, exercise and curcumin trigger the mitogenic property of NSCs by elevating BDNFlevels and activating the MAP kinase signaling pathway. Inhibitions of neurogenic factors by a high-fat diet (HFD) or capsaicin(CPS) impair hippocampal neurogenesis. DR mimetics that putatively limit available energy are unlikely to be able to promotethe ATP-consuming process of NPCs proliferation. Note that astrogliogenesis promoted by AICAR is independent of metformin-induced AMPK activation. Enhanced neurogenesis achieved by either increasing the survival rate and neuronal differentiation orstimulating NPC proliferation can expand the hippocampal capacity of endogenous NSCs and probably improve neurocognitivefunction in neurodegenerative disorders and during aging. Conclusion All mammals possess stem cells in many organs,notably in blood, skin, and gut, and these stem cellsare considered to contribute to rapid cell replace-ment throughout life. The existence of NSCs in theadult mammalian brain that are capable of divid-ing and forming new nerve cells continues to drivethe developments of novel approaches to brain re-pair. In particular, the enhancement of hippocam-palneurogenesisisassociatedwiththeameliorationof the cognitive deficits associated with aging andAlzheimer’sdisease. 46 Therefore,muchrecentfocushas been placed on the discovery and developmentof novel compounds that are capable of specifically promoting adult NSCs. 47–49 The factors that con-trol the formation of new nerve cells in the humanbrainarelargelyunknown,andidentifyingsuchfac-tors is likely to lead to new ways of preventing ortreating brain disorders. This review introduces theneurogenic properties and molecular mechanismsof DR and provides a basis for a possible preven-tative strategy whereby endogenous NSCs are re-cruited by dietary and/or pharmaceutical modula-tion to address neuronal loss and damage. DR andan enriched environment increase the survival ratesof newly generated cells and enhance neurogenesisby upregulating neurotrophic factors. However, ex-erciseandcurcuminactivatethemitogenicproperty of NSCs and promote NPC proliferation by BDNF 26  Ann. N.Y. Acad. Sci. 1229 (2011) 23–28  c  2011 New York Academy of Sciences.
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