Naringin Mediates Adult Hippocampal Neurogenesis for Antidepression Via Activating CREB Signaling

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2022 Apr 28

PMID 35478969

Authors

Chong Gao

Meiling Wu

Qiaohui Du

Jiagang Deng

Jiangang Shen

Affiliations

Soon will be listed here.

Abstract

The brain-derived neurotrophic factor/tropomyosin receptor kinase B/cAMP response element-binding protein (BDNF/TrkB/CREB) signaling pathway is a critical therapeutic target for inducing adult hippocampal neurogenesis and antidepressant therapy. In this study, we tested the hypothesis that naringin, a natural medicinal compound, could promote adult hippocampal neurogenesis and improve depression-like behaviors via regulating the BDNF/TrkB/CREB signaling pathway. We first investigated the effects of naringin on promoting adult hippocampal neurogenesis in both normal and chronic corticosterone (CORT)-induced depressive mice. Under physiological condition, naringin treatment enhanced the proliferation of neural stem/progenitor cells (NSPCs) and accelerated neuronal differentiation. In CORT-induced depression mouse model, naringin treatment promoted neuronal differentiation and maturation of NSPCs for hippocampal neurogenesis. Forced swim test, tail suspension test, and open field test confirmed the antidepressant and anxiolytic effects of naringin. Co-treatment of temozolomide (TMZ), a neurogenic inhibitor, abolished these antidepressant and anxiolytic effects. Meanwhile, naringin treatment increased phosphorylation of cAMP response element binding protein (CREB) but had no effect on the expression of brain-derived neurotrophic factor and phosphorylation of TrkB in the hippocampus of CORT-induced depressive mice. Co-treatment of CREB inhibitor 666-15, rather than TrkB inhibitor Cyc-B, abolished the neurogenesis-promoting and antidepressant effects of naringin. Taken together, naringin has antidepressant and anxiolytic effects, and the underlying mechanisms could be attributed to enhance hippocampal neurogenesis via activating CREB signaling.

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References

Shu X, Sun Y, Sun X, Zhou Y, Bian Y, Shu Z . The effect of fluoxetine on astrocyte autophagy flux and injured mitochondria clearance in a mouse model of depression. Cell Death Dis. 2019; 10(8):577. PMC: 6675792. DOI: 10.1038/s41419-019-1813-9. View

He Y, Chen S, Tsoi B, Qi S, Gu B, Wang Z . Miq. and Its Active Compound -Coumaric Acid Promote Brain-Derived Neurotrophic Factor Signaling for Inducing Hippocampal Neurogenesis and Improving Post-cerebral Ischemic Spatial Cognitive Functions. Front Cell Dev Biol. 2021; 8:577790. PMC: 7849625. DOI: 10.3389/fcell.2020.577790. View

Luo Y, Zhang C, Li P, Nie Y, Wu H, Shen J . Naringin attenuates enhanced cough, airway hyperresponsiveness and airway inflammation in a guinea pig model of chronic bronchitis induced by cigarette smoke. Int Immunopharmacol. 2012; 13(3):301-7. DOI: 10.1016/j.intimp.2012.04.019. View

Aggarwal A, Gaur V, Kumar A . Nitric oxide mechanism in the protective effect of naringin against post-stroke depression (PSD) in mice. Life Sci. 2010; 86(25-26):928-35. DOI: 10.1016/j.lfs.2010.04.011. View

Brezun J, Daszuta A . Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats. Neuroscience. 1999; 89(4):999-1002. DOI: 10.1016/s0306-4522(98)00693-9. View

Yau S, Lau B, Tong J, Wong R, Ching Y, Qiu G . Hippocampal neurogenesis and dendritic plasticity support running-improved spatial learning and depression-like behaviour in stressed rats. PLoS One. 2011; 6(9):e24263. PMC: 3174166. DOI: 10.1371/journal.pone.0024263. View

Xie F, Li B, Xiao X . Design, synthesis and biological evaluation of regioisomers of 666-15 as inhibitors of CREB-mediated gene transcription. Bioorg Med Chem Lett. 2017; 27(4):994-998. PMC: 5296214. DOI: 10.1016/j.bmcl.2016.12.078. View

Sakata K, Mastin J, Duke S, Vail M, Overacre A, Dong B . Effects of antidepressant treatment on mice lacking brain-derived neurotrophic factor expression through promoter IV. Eur J Neurosci. 2013; 37(11):1863-74. DOI: 10.1111/ejn.12148. View

Feng J, Chen X, Lu S, Li W, Yang D, Su W . Naringin Attenuates Cerebral Ischemia-Reperfusion Injury Through Inhibiting Peroxynitrite-Mediated Mitophagy Activation. Mol Neurobiol. 2018; 55(12):9029-9042. DOI: 10.1007/s12035-018-1027-7. View

10.

Ben-Azu B, Nwoke E, Aderibigbe A, Omogbiya I, Ajayi A, Olonode E . Possible neuroprotective mechanisms of action involved in the neurobehavioral property of naringin in mice. Biomed Pharmacother. 2018; 109:536-546. DOI: 10.1016/j.biopha.2018.10.055. View

11.

Gao C, Chen X, Xu A, Cheng K, Shen J . Adaptor Protein APPL2 Affects Adult Antidepressant Behaviors and Hippocampal Neurogenesis via Regulating the Sensitivity of Glucocorticoid Receptor. Mol Neurobiol. 2017; 55(7):5537-5547. DOI: 10.1007/s12035-017-0785-y. View

12.

Sairanen M, Lucas G, Ernfors P, Castren M, Castren E . Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J Neurosci. 2005; 25(5):1089-94. PMC: 6725966. DOI: 10.1523/JNEUROSCI.3741-04.2005. View

13.

David D, Samuels B, Rainer Q, Wang J, Marsteller D, Mendez I . Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron. 2009; 62(4):479-93. PMC: 2759281. DOI: 10.1016/j.neuron.2009.04.017. View

14.

Encinas J, Enikolopov G . Identifying and quantitating neural stem and progenitor cells in the adult brain. Methods Cell Biol. 2007; 85:243-72. DOI: 10.1016/S0091-679X(08)85011-X. View

15.

Rehm J, Shield K . Global Burden of Disease and the Impact of Mental and Addictive Disorders. Curr Psychiatry Rep. 2019; 21(2):10. DOI: 10.1007/s11920-019-0997-0. View

16.

Kinlein S, Phillips D, Keller C, Karatsoreos I . Role of corticosterone in altered neurobehavioral responses to acute stress in a model of compromised hypothalamic-pituitary-adrenal axis function. Psychoneuroendocrinology. 2018; 102:248-255. PMC: 7649055. DOI: 10.1016/j.psyneuen.2018.12.010. View

17.

Brachman R, McGowan J, Perusini J, Lim S, Pham T, Faye C . Ketamine as a Prophylactic Against Stress-Induced Depressive-like Behavior. Biol Psychiatry. 2015; 79(9):776-786. PMC: 4633406. DOI: 10.1016/j.biopsych.2015.04.022. View

18.

Odaira T, Nakagawasai O, Takahashi K, Nemoto W, Sakuma W, Lin J . Mechanisms underpinning AMP-activated protein kinase-related effects on behavior and hippocampal neurogenesis in an animal model of depression. Neuropharmacology. 2019; 150:121-133. DOI: 10.1016/j.neuropharm.2019.03.026. View

19.

Luo Y, Kuang S, Li H, Ran D, Yang J . cAMP/PKA-CREB-BDNF signaling pathway in hippocampus mediates cyclooxygenase 2-induced learning/memory deficits of rats subjected to chronic unpredictable mild stress. Oncotarget. 2017; 8(22):35558-35572. PMC: 5482598. DOI: 10.18632/oncotarget.16009. View

20.

Sharma M, Akhtar N, Sambhav K, Shete G, Bansal A, Sharma S . Emerging potential of citrus flavanones as an antioxidant in diabetes and its complications. Curr Top Med Chem. 2014; 15(2):187-95. DOI: 10.2174/1568026615666141209163013. View