SEARCH

SEARCH BY CITATION

Keywords:

  • BDNF;
  • curcumin;
  • dietary restriction;
  • hippocampal neurogenesis;
  • neural stem cell

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Environmental stimuli can enhance hippocampal neurogenesis in the adult brain
  5. Neurogenic mechanisms of DR
  6. Effects of DR mimetics on neurogenesis
  7. Potent neurogenic phytochemicals that enhance hippocampal neurogenesis
  8. Conclusion
  9. Acknowledgments
  10. Conflicts of interest
  11. References

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 enhances neurogenesis, 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 neurodegenerative diseases. 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 authors consider 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 caloric intake. The current review describes the regulatory effect of DR on hippocampal neurogenesis and presents a possible neurogenic mechanism.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Environmental stimuli can enhance hippocampal neurogenesis in the adult brain
  5. Neurogenic mechanisms of DR
  6. Effects of DR mimetics on neurogenesis
  7. Potent neurogenic phytochemicals that enhance hippocampal neurogenesis
  8. Conclusion
  9. Acknowledgments
  10. Conflicts of interest
  11. References

Dietary restriction (DR) can increase life span in a wide variety of species, reduce neuronal damage, and improve behavioral outcome in experimental animal models relevant to the pathogenesis of several age-related neurological disorders.1,2 Several studies have described the molecular mechanism responsible for the beneficial effects of DR on aging and age-related neurodegenerative diseases. In particular, it has been shown that DR changes metabolic processes under lower glucose conditions, and thus produces mild stress in cells to adapt to the stressed condition by orchestrating cellular and molecular changes—within physiological limits.3,4 It has been reported that altered gene expressions by DR are related to energy metabolism, stress, inflammation, and neural plasticity.5,6 Subsequent studies demonstrated that DR enhances neurogenesis, indicating that the metabolic environment can modulate an important brain function.7 Our current research is aimed at developing neurogenic modulators based on the molecular mechanisms of DR and stem cell regulation. In this review, we present an overview of the regulation of adult hippocampal neurogenesis by DR and the developments of neurogenic phytochemicals.

Environmental stimuli can enhance hippocampal neurogenesis in the adult brain

  1. Top of page
  2. Abstract
  3. Introduction
  4. Environmental stimuli can enhance hippocampal neurogenesis in the adult brain
  5. Neurogenic mechanisms of DR
  6. Effects of DR mimetics on neurogenesis
  7. Potent neurogenic phytochemicals that enhance hippocampal neurogenesis
  8. Conclusion
  9. Acknowledgments
  10. Conflicts of interest
  11. References

Findings over the past two decades that demonstrated persistent neurogenesis in the adult brain have overturned the long-held dogma that neurons are formed exclusively before birth. The existence of neural stem cells (NSCs) in the adult brain has provoked a reevaluation of cellular plasticity in the mature brain and raised hopes that novel approaches to brain repair can be devised. The generation of newborn cells is maintained throughout adulthood in the mammalian brain via the proliferation and differentiation of adult NSCs.8 Proliferating, differentiating, and migrating NSCs are eventually integrated into neural networks.8 Adult NSCs exist in the dentate gyrus of the hippocampus and in the subventricular zone of the lateral ventricle, in which NSCs differentiate into new granular neurons and olfactory neurons, respectively.8 Since the hippocampus is important for the storage and formation of memory, newly generating neurons in the hippocampus are considered to contribute the new memories and maintain the stability of old memories by connecting with existing neurons.9 Adult hippocampal neurogenesis can be altered by the neuronal network activity modulating effects of neurotransmitters, growth factors, and neurotrophic factors.10 In addition, various environmental stimuli, such as environmental enrichment and exercise, increase hippocampal neurogenesis. Interestingly, studies performed at our laboratory and those of others have reported that DR, as a metabolic stress, enhances adult hippocampal neurogenesis.11 Voluntary running is known to enhance hippocampal neurogenesis by increasing the numbers of newly generated cells in the dentate gyrus.12 However, DR significantly promotes the survival of newly generated neurons without affecting numbers of proliferating cells in the hippocampus. Similarly, enriched environments, such as social activity, also promote the survival of cells generated by hippocampal neurogenesis rather than elevating proliferation.13 These findings indicate that mild stressors derived from physical, social, or metabolic alterations are beneficial in terms of the activation of NSCs and the formation of new neural circuits in the adult hippocampus.

Neurogenic mechanisms of DR

  1. Top of page
  2. Abstract
  3. Introduction
  4. Environmental stimuli can enhance hippocampal neurogenesis in the adult brain
  5. Neurogenic mechanisms of DR
  6. Effects of DR mimetics on neurogenesis
  7. Potent neurogenic phytochemicals that enhance hippocampal neurogenesis
  8. Conclusion
  9. Acknowledgments
  10. Conflicts of interest
  11. References

The neurotrophic factor, brain-derived neurotrophic factor (BDNF), binds to TrkB plasma membrane receptors, which leads to the autophosphorylation of its tyrosine residues in the intracellular kinase domain.14 Tyrosine phosphorylation activates various signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K)/Akt, MAPK, and PLC-γ pathways. The BDNF signaling pathway involving TrkB has been implicated in the control of cell proliferation and survival in the adult hippocampus.15 Furthermore, hippocampal BDNF levels were increased by both DR and an enriched environment, and it was concluded that BDNF is required for the enhancement of hippocampal neurogenesis by DR and environment enrichment in heterozygous BDNF knockout (BDNF+/−) mice.16 In addition, DR upregulates another neurotrophic factor, neurotrophin-3 (NT-3), in the hippocampus, and this facilitates hippocampal plasticity and neurogenesis by neuronal differentiation rather than proliferation.17 Hippocampal NT-3 is often downregulated in response to brain damage caused by seizures, while other neurotrophic factors are dramatically upregulated in brain injury;18 thus, DR-mediated stress response is a novel stimulus paradigm distinct from that of brain injury. Several cytokines are elevated in brain cells in response to stress, and it has been reported that interferon-gamma (IFN-γ) is upregulated in the hippocampus of rats fed on a DR regimen.19 Interestingly, IFN-γ is known to promote neuronal differentiation and the neurite outgrowth of murine adult stem cells, and we have found that IFN-γ promotes the differentiation of NSCs via the JNK pathway.20,21 Taken together, these results suggest that altered gene regulation by DR could explain the neurogenic mechanism underlying DR via the promotion of the differentiation of NSCs in the adult hippocampus.

Effects of DR mimetics on neurogenesis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Environmental stimuli can enhance hippocampal neurogenesis in the adult brain
  5. Neurogenic mechanisms of DR
  6. Effects of DR mimetics on neurogenesis
  7. Potent neurogenic phytochemicals that enhance hippocampal neurogenesis
  8. Conclusion
  9. Acknowledgments
  10. Conflicts of interest
  11. References

Although it seems clear that reducing dietary intakes beneficially enhances hippocampal neurogenesis and cognitive function, practicing DR in humans is problematic for social and practical reasons in this food-rich society. In fact, previous studies have reported that a high-fat diet disrupts cognition, exacerbates neurodegenerative diseases, and impairs hippocampal synaptic plasticity and cognitive abilities, such as learning and memory.22 In addition, elevated fasting glucose levels and hyperlipidemia induced by a high-sugar diet decrease hippocampal neurogenesis and cognitive function.23 Therefore, efforts to search for DR mimetics are expanding in the hope of finding some treatment that does not require DR. Several DR mimetics, including 2-deoxy-d-glucose (2DG), metformin, and resveratrol, have been shown to have beneficial effects in neurodegenerative disease models by mimicking the DR-based mechanism.24–26 2DG is a nonmetabolizable analog of glucose that inhibits glycolysis. Furthermore, 2DG efficiently blocks neuronal loss in neurodegenerative diseases models, such as in model of Alzheimer's disease, Parkinson's disease, and stroke.2,25,27 However, the neurogenic property of 2DG has not been tested, although we have reported that 2DG can protect NSCs against oxidative stress. In fact, 2DG appears to both have a toxic effect and reduce NSC proliferation by limiting available energy, thus activating AMP-activated protein kinase (AMPK).28 Interestingly, AICAR, an adenosine analog used to activate AMPK, induces the astroglial differentiation of NSCs independently of AMPK. However, metformin, a DR mimetic, failed to show astrogenic activity, although it activated AMPK.29 Resveratrol is another potent DR mimetic that stimulates Sir2, extending lifespan in yeast and nematodes.30,31 Furthermore, the beneficial effects of resveratrol in diabetes and in age-related neurodegenerative diseases have been well documented,32,33 and it has been recently reported that resveratrol improves cognitive function in mice by increasing hippocampal IGF-I and hippocampal neurogenesis.34 Although only a few studies have been conducted on the neurogenic potencies of DR mimetics, novel neurogenic supplements are likely to be discovered by simulating the neurogenic molecular mechanism of DR.

Potent neurogenic phytochemicals that enhance hippocampal neurogenesis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Environmental stimuli can enhance hippocampal neurogenesis in the adult brain
  5. Neurogenic mechanisms of DR
  6. Effects of DR mimetics on neurogenesis
  7. Potent neurogenic phytochemicals that enhance hippocampal neurogenesis
  8. Conclusion
  9. Acknowledgments
  10. Conflicts of interest
  11. References

Dietary modulation by DR, diet content, and dietary sources are important for the control of hippocampal neurogenesis and subsequent hippocampus-mediated cognitive ability. Several dietary phytochemicals, or flavonoids, are known to have beneficial effects in the central nervous system by protecting neurons against injury or diseases, although they are not classified as DR mimetics. For example, curcumin is the natural phenolic component of yellow curry spice, and it has been traditionally used in India to treat diseases associated with oxidative stress and inflammation.35 Although curcumin research has focused primarily on cancer chemoprevention, it has been suggested that its neuroprotective properties may be useful for the treatment of neurodegenerative diseases and age-associated cognitive deficit.36,37 Recently, it was reported that curcumin has neurogenic properties and that it stimulates embryonic NSC proliferation and adult hippocampal neurogenesis.38 Interestingly, curcumin has biphasic effects on cultured NSCs, whereby low concentrations stimulate cell proliferation and high concentrations are cytotoxic. This is consistent with the finding that high concentrations of curcumin induce oxidative stress and trigger apoptosis in cancer cells.39 Our previous data suggest that the NSC-specific mitogenic action of low-concentration curcumin is mediated by the activation of extracellular signal-regulated kinases (ERK) and p38 MAP kinases.38 Taken together, the concentration-dependent neurogenic property of curcumin resembles the hormesis hypothesis of DR, which is dependent on available energy. In one study, the administration of curcumin significantly increased the numbers of newly generated cells in the dentate gyrus of the hippocampus by stimulating their proliferation rather than their survival rate.40 Enhanced neurogenesis by promoting NSC proliferation is typically observed in exercise paradigms.12 Physical activity often elevates reactive oxygen species (ROS) production, and polyphenols including curcumin can activate the Nrf2-antioxidant response element pathway.47 Therefore, altered redox balance in the hippocampus is supposed to trigger NSC proliferation. In addition, elevated hippocampal BDNF levels are considered to be important for enhancing neurogenesis by physical exercise or curcumin.40,42 Hippocampal BDNF also seems to be correlated with spatial learning and memory, since flavonoid-enriched foods have been reported to increase hippocampal neurogenesis under chronically stressed condition by maintaining hippocampal BDNF levels and pCREB expression.43 However, other dietary interventions have been found to have adverse effects on hippocampal neurogenesis. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is the major pungent ingredient in red pepper, and it stimulates pain and primary afferent nerves through transient receptor vanilloid channels.44 Capsaicin has also been reported to reduce the number of newly generated cells in the dentate gyrus of the hippocampus by attenuating the ERK signaling pathway.45 These findings suggest that the ERK signaling pathway and BDNF signaling could constitute a neurogenic molecular mechanism that will both facilitate the discovery and development of novel drugs that induce adult hippocampal neurogenesis and be useful for the treatment of neurodegenerative diseases and disorders.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Environmental stimuli can enhance hippocampal neurogenesis in the adult brain
  5. Neurogenic mechanisms of DR
  6. Effects of DR mimetics on neurogenesis
  7. Potent neurogenic phytochemicals that enhance hippocampal neurogenesis
  8. Conclusion
  9. Acknowledgments
  10. Conflicts of interest
  11. References

All mammals possess stem cells in many organs, notably in blood, skin, and gut, and these stem cells are considered to contribute to rapid cell replacement throughout life. The existence of NSCs in the adult mammalian brain that are capable of dividing and forming new nerve cells continues to drive the developments of novel approaches to brain repair. In particular, the enhancement of hippocampal neurogenesis is associated with the amelioration of the cognitive deficits associated with aging and Alzheimer's disease.46 Therefore, much recent focus has been placed on the discovery and development of novel compounds that are capable of specifically promoting adult NSCs.47–49 The factors that control the formation of new nerve cells in the human brain are largely unknown, and identifying such factors is likely to lead to new ways of preventing or treating brain disorders. This review introduces the neurogenic properties and molecular mechanisms of DR and provides a basis for a possible preventative strategy whereby endogenous NSCs are recruited by dietary and/or pharmaceutical modulation to address neuronal loss and damage. DR and an enriched environment increase the survival rates of newly generated cells and enhance neurogenesis by upregulating neurotrophic factors. However, exercise and curcumin activate the mitogenic property of NSCs and promote NPC proliferation by BDNF and MAP kinase activation. The action mechanism of DR mimetics is primarily due to energy limitation and the activation of AMPK, and probably the stimulation of astrogliogenesis rather than neurogenesis (Fig. 1). Collectively, understanding the neurogenic mechanisms of DR, DR mimetics, and other small molecules could provide a neurorestorative strategy that stimulates endogenous NSCs and thereby prevents age-related cognitive deficits in aging and age-related neurodegenerative diseases.

image

Figure 1. Neurogenic actions of environmental stimuli and dietary modulation including those of DR and its mimetics. DR and an enriched environment increase the survival rate of newly generated cells by upregulating neurotrophic factors or IFN-γ, which can promote neuronal differentiation. However, exercise and curcumin trigger the mitogenic property of NSCs by elevating BDNF levels 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 promote the 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 or stimulating NPC proliferation can expand the hippocampal capacity of endogenous NSCs and probably improve neurocognitive function in neurodegenerative disorders and during aging.

Download figure to PowerPoint

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Environmental stimuli can enhance hippocampal neurogenesis in the adult brain
  5. Neurogenic mechanisms of DR
  6. Effects of DR mimetics on neurogenesis
  7. Potent neurogenic phytochemicals that enhance hippocampal neurogenesis
  8. Conclusion
  9. Acknowledgments
  10. Conflicts of interest
  11. References