Luteolin-7-O-Glucuronide Improves Depression-like and Stress Coping Behaviors in Sleep Deprivation Stress Model by Activation of the BDNF Signaling

Abstract

Stress exposure is a major risk factor for mental disorders such as depression. Because of the limitations of classical antidepressants such as side effects, low efficacy, and difficulty in long-term use, new natural medicines and bioactive molecules from plants with greater safety and efficacy have recently attracted attention. Luteolin-7-O-glucuronide (L7Gn), a bioactive molecule present in Perilla frutescens, is known to alleviate severe inflammatory responses and oxidative stress in macrophages. However, its antistress and antidepressant effects have not been elucidated. The present study aims to explore the antidepressant the effect of L7Gn on stress-induced behaviors and the underlying mechanism in a mouse sleep deprivation (SD) model. L7Gn treatment improved depression-like and stress coping behaviors induced by SD stress, as confirmed by the tail suspension test and forced swimming test. Furthermore, L7Gn treatment reduced the blood corticosterone and hippocampal proinflammatory cytokine levels which were increased by SD stress, and L7Gn also increased the mRNA and protein levels of hippocampal brain-derived neurotrophic factor (BDNF) which were reduced by SD stress. Additionally, treatment with L7Gn resulted in increases in the phosphorylation of tropomyosin-related kinase B (TrkB), extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB), which are downstream molecules of BDNF signaling. These findings suggest that L7Gn have therapeutic potential for SD-induced stress, via activating the BDNF signaling.

Antidepressive Effect of Natural Products and Their Derivatives Targeting BDNF-TrkB in Gut–Brain Axis

“…A recent study illustrated that L7Gn has therapeutic potential for sleep-deprivation-induced stress via the activation of BDNF signaling. Additionally, L7Gn increased BDNF mRNA and protein levels, which were reduced by SD stress, and an L7Gn intervention resulted in the upregulation of TrkB, ERK, and CREB, which are downstream molecules of BDNF signaling, reducing depression in rat and mouse models of inflammation [ 94 ].…”

“…Several studies included in this review focused on BDNF, targeting the gut–brain signaling pathway. However, the exact mechanism of action of BDNF in the gut remains unknown for most natural products [ 78 , 91 , 94 , 102 , 112 ]. Many animal and clinical studies have been conducted to determine the crucial effects of natural products on depression and neuroprotection; however, the constituents of these products remain mainly unknown [ 155 , 159 , 160 , 162 , 163 ].…”

“…However, the involvement of baicalein targeting BDNF in neuroprotein needs to be evaluated. Luteolin-7- O -glucuronide reduces depression via BDNF activation; however, further studies are needed on the gut–brain axis or the microbial community of the GIT [ 94 ]. By modifying the expression of NF-kB and BDNF, naringenin alleviates depression and anxiety-like behaviors in mice subjected to repeated hypoxic stress; however, using the gut–brain axis experimental parameters, there is a need to determine the involvement of naringenin in the gut–brain axis pathway to reduce depression [ 97 ].…”

Ocimum tenuiflorum extract (HOLIXERTM): Possible effects on hypothalamic–pituitary–adrenal (HPA) axis in modulating stress

“…Rosmarinic acid has also been reported to reduce maternal stress induced corticosterone increase [ 39 ], chronic unpredictable stress induced increase in corticosterone [ 40 ] and reverse stress induced changes of SUV39H1, Mkp-1, and BDNF expression in the mice hippocampus [ 41 ]. Luteolin-7-O-glucuronide, another constituent of OBC, has been found to reduce blood corticosterone in a mouse sleep deprivation model, wherein the compound improved depression-like and stress coping behaviours [ 42 ].…”

Use of machine learning to identify risk factors for insomnia

“…The visualizations completed for the top four continuous covariates were concordant with current literature: there is strong epidemiological evidence that sleep problems are heavily linked with depression. Multiple papers have found difficulty falling asleep and decreased hours of sleep with increased depression [41][42][43][44][45][46][47][48][49][50][51][52][53]. Additionally, depression has bene linked to lower quality sleep and increased day time exhaustion [31,34,46,54,55].…”