Naringin Mediates Adult Hippocampal Neurogenesis for Antidepression via Activating CREB Signaling

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.

Implication of Wnt/GSK-3β/β-Catenin Signaling in the Pathogenesis of Mood Disturbances Associated with Hyperthyroidism in Rats: Potential Therapeutic Effect of Naringin

“…19 On the contrary, several studies have pointed out the promising antidepressant and anxiolytic properties of naringin. 10,11 Treatment low-and high-dose naringin restored the level of T4 and significantly boosted the TSH level, which corroborated with the work of Panda and Kar. 20 Inhibition of thyroid peroxidase and deiodinase enzymes by naringin explained their results.…”

“…Naringin (4′,5,7-trihydrocyflavanone-7- O -rhamnoglucoside) is a natural bioflavonoid found in many fruits including citrus fruits, and it gives them their bitter taste and sour flavor. Naringin has been reported to possess a broad spectrum of pharmacological properties including anti-inflammatory, antioxidative, and antiapoptotic properties, as well as advantageous neuroprotective effects and memory-enhancing properties. , Furthermore, it showed promising results in treating many diseases including Alzheimer’s, metabolic syndrome, and diabetes . Additionally, previous studies have pointed to the neuroactivity of naringin, which demonstrated beneficial neurobehavioral effects including anxiolytic, antidepressant, and memory-enhancing properties through modulation of 5-HT content and alleviation of oxidative stress in the hippocampus region. , Recently, the modulation of Wnt/β-catenin signaling has been reported to be involved in the therapeutic effects of naringin in different disorders. , However, the potential protective effects of naringin against the psychological changes induced by hyperthyroidism have not been investigated.…”

“…Naringin has been reported to possess a broad spectrum of pharmacological properties including anti-inflammatory, antioxidative, and antiapoptotic properties, as well as advantageous neuroprotective effects and memory-enhancing properties. 10,11 Furthermore, it showed promising results in treating many diseases including Alzheimer's, metabolic syndrome, and diabetes. 12 Additionally, previous studies have pointed to the neuroactivity of naringin, which demonstrated beneficial neurobehavioral effects including anxiolytic, antidepressant, and memory-enhancing properties through modulation of 5-HT content and alleviation of oxidative stress in the hippocampus region.…”

Therapeutic and Prophylactic Effects of Amphotericin B Liposomes on Chronic Social Defeat Stress-Induced Behavioral Abnormalities in Mice

“…Thus, the prophylactic effect of amphotericin B liposome on chronic stress-induced behavioral abnormalities in mice could also be mediated by its preventive effect on the disrupted CREB-BDNF signaling pathway in the brain. Because CSDS exposure and disruption of CREB-BDNF signaling are closely related to the impairment of neurogenesis in the brain (Maitra et al, 2020;Jiang et al, 2021;Gao et al, 2022) and stimulation of the innate immune system can promote neurogenesis (Reshef et al, 2017;Al-Onaizi et al, 2020;Seong et al, 2022), the prophylactic effect of amphotericin B liposomes on chronic stress-induced behavioral abnormalities might also be mediated by enhancing neurogenesis through improving CREB-BDNF signaling function. These uncertainties should be explored in future studies.…”

Late pregnancy maternal naringin supplementation affects the mitochondria in the cerebellum of Wistar rat offspring via sirtuin 3 and AKT

“…Data from experimental models have shown that naringin modulates key biological pathways related to cellular stress response, mitochondrial function, and metabolism (Biala et al, 2010; de Oliveira et al, 2017; Li et al, 2016; Liu et al, 2014; Petry et al, 2021; Syed et al, 2020). Particularly in the context of neurodegenerative diseases, naringin has been shown to increase neurogenesis and improve antioxidant defenses, ATP production, and the turnover of damaged mitochondria by regulating mitochondrial dynamics and biogenesis through sirtuins (SIRT), adenosine monophosphate‐activated protein kinase (AMPK), and the serine/threonine kinase (AKT) pathway activation (Gao et al, 2022; Okuyama et al, 2018; Wang et al, 2015).…”