1. Introduction
In contemporary society, the use of nutritional supplements to enhance quality of life is gaining popularity. These supplements are often associated with significant health benefits [1,2,3,4,5,6]. For instance, research involving mice suggests that prebiotics can bolster resistance to depression and mitigate the effects of chronic stress [7]. Historically, polyunsaturated fatty acids obtained from sources such as fish and sesame oils have been used for alleviating pain and addressing cardiovascular issues [2,3,5,8]. Furthermore, combinations of shark and sesame oils have shown promise in reducing depression in animal studies, indicating their potential as effective supplements [8]. Notably, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) derived from salmon oil are well-regarded for their roles in stress and anxiety management [1,2,9].
Recently, diacyl glyceryl ethers (DAGE) extracted from deep-sea shark liver oil have been recognized for improving sleep quality and stress responses in humans. DAGE play a crucial role in the body’s antioxidant defenses by serving as a precursor to plasmalogens [10]. These compounds help combat oxidative stress in the brain, thereby safeguarding the nervous system [11]. Studies indicate that sleep deprivation can reduce plasmalogen levels, negatively affecting cognitive and emotional health [12]. Thus, increasing DAGE intake could enhance the brain’s resilience to oxidative stress and support mental well-being by maintaining cognitive function and mood stability [13]. Human perception of stress can be influenced by numerous factors, making it a complex phenomenon to study. This variability underscores the importance of using animal models, such as those involving mice, in research. Mice provide a controlled, consistent environment for examining the mechanisms through which DAGE influence anxiety-related behaviors and contribute to stress management. This study aimed to deepen our understanding of the psychological benefits of DAGE, with the goal of potentially guiding future dietary recommendations for mental health optimization [14].
We conducted three behavioral experiments, including the elevated plus maze (EPM) test [15,16], open-field test (OFT) [17,18], and forced swimming test (FST) [19,20,21], to evaluate the potential effects of DAGE on anxiety-related behavior in two mouse strains, BALB/cCrSIc and C57BL/6NCrSIc, which are known for their differing stress response strategies. The EPM test examined the ameliorative effects of DAGE on the exploratory behavior of mice in novel environments and their anxiety stemming from conflict behaviors due to the elevated open arms. The OFT was designed to measure whether DAGE ameliorate general anxiety behavior in mice. The FST was designed to investigate the antidepressant effects of DAGE in mice. Additionally, our research sought to explore behavioral differences between two testing sessions across these experiments [16,22,23,24,25,26,27,28,29]. By using the BALB/c and C57BL/6 strains, both of which are commonly used in anxiety behavior studies [30], our goal was to deepen our understanding of the capacity of DAGE to mitigate various stress forms. Our objective was not only to advance the studies using animal models but also to uncover evidence with significant implications for enhancing human mental health.
4. Discussion
In this study, we assessed the effects of DAGE treatment on anxiety- and depression-related behaviors in BALB/c and C57BL/6 mice using behavioral tests including the EPM, OFT, and FST. Our findings demonstrated that DAGE exerted pronounced anxiolytic effects in both strains, as shown by enhanced exploratory behaviors in the EPM and increased activity in the central areas of the OFT. Additionally, DAGE treatment resulted in reduced post-stress inhibited ingestion in BALB/c mice and decreased binge eating in C57BL/6 mice.
However, findings regarding the antidepressant effects of DAGE were less conclusive. Initial reductions in immobility time during the FST suggested possible antidepressant properties, but these were not consistently observed in the second test. This inconsistency implies that while DAGE treatment is effective in reducing anxiety, its effects on depressive behaviors are more variable and may depend on factors such as the mouse strain and specific stressors applied [38,39]. Consequently, while DAGE holds promise as an anxiolytic agent, further studies are needed to fully understand its potential in treating depressive symptoms.
The literature suggests that DAGE not only inhibit the reduction of leukocytes during radiotherapy but also enhance the production of immunoglobulins in saliva [10,40,41,42]. As a precursor to plasmalogens [10], DAGE facilitate the scavenging of reactive oxygen species through their vinyl ether bond, functioning as endogenous antioxidants [11]. Studies have shown that oxidative stress, particularly in sleep-deprived individuals, leads to decreased plasmalogen levels [12]. By consuming DAGE, the precursor to plasmalogens, one can increase plasmalogen levels, thereby mitigating brain oxidative stress. This reduction in stress is believed to enhance sleep quality and reduce anxiety [13]. Our findings align with this perspective, which demonstrate that DAGE supplementation not only increases activity levels but also the desire to explore in the Elevated Plus Maze and Open Field Tests. These increases in activity and exploration consequently lead to improvements in anxiety-related behaviors. Although previous research has pointed to antioxidant mechanisms as the basis for the anxiety-reducing properties of DAGE [11,13], this study did not directly measure oxidative stress markers. Future research should measure plasmalogen levels to validate the impact of DAGE on anxiety- and depression-related behaviors. Additionally, incorporating biochemical assays and brain imaging could provide deeper insights into the underlying biological mechanisms.
DAGE have demonstrated potential for alleviating symptoms related to anxiety and depression, with the most notable effects observed on the first test day. In our study, the mice receiving DAGE treatment exhibited significantly greater behavioral improvements in stressful and despairing environments than those given standard control food. Moreover, DAGE treatment enhanced overall activity levels, as evidenced by increased total distance traveled, and boosted exploratory behavior, as indicated by reduced latency to exploring. These findings position DAGE as a promising supplement for the prevention and mitigation of anxiety and depression [13]. However, while the initial data are encouraging, verifying these effects through clinical trials is crucial to confirm the efficacy of DAGE supplementation in a clinical setting.
Despite ongoing debates regarding the inherent anxiety levels of BALB/c and C57BL/6 mice [9,33,43,44,45], our study demonstrated that both strains, when treated with DAGE supplementation, showed significant reductions in anxiety and depressive behaviors on the initial test day compared to the controls. Notably, DAGE-treated BALB/c mice displayed variability in their OFT performance across the first and second days, suggesting that genetic factors may influence the effectiveness of DAGE treatment. This variability was also observed in the EPM in the C57BL/6 group, indicating potential genetic interactions that affect treatment outcomes [46]. Additionally, the control groups of both BALB/c and C57BL/6 mice exhibited distinct feeding responses to stress. While BALB/c mice reduced their food intake in response to stressors, including the EPM and OFT, C57BL/6 mice exhibited binge eating patterns under similar conditions. Following the FST, however, both strains increased their food intake, which is consistent with the findings of previous research [35,36]. These observations emphasize that different mouse strains may adopt varying adaptive strategies to cope with stress [38,39]. Future research should focus on identifying genetic determinants that influence responses to DAGE treatment, which could elucidate the mechanisms driving stress-related behaviors in diverse strains.
Behavioral differences observed across the two test days are typically attributed to various emotional responses. For instance, in the EPM, behaviors on the first test day are predominantly influenced by anxiety, whereas on the second test day, they are more driven by fear [16,22,47]. Similarly, in the FST, immobile behavior on the first day is often linked to depression-like emotions, while on the second day, it tends to be associated with unpleasant memories [48]. Given these findings, the less pronounced effects of DAGE treatment on the second test day may be partially due to shifts in emotional states; that is, while DAGE treatment is effective in alleviating anxiety and depression, its impact may diminish when these conditions transition to fear or unpleasant memories. However, limitations of our study, such as budget constraints that restricted access to necessary equipment, prevented us from confirming whether DAGE can cross the blood-brain barrier to directly influence brain states and functions, unlike fatty acids, such as DHA [49,50]. Further research is needed to determine the in vivo effects of DAGE and their interactions to fully understand the neural mechanisms underlying their effects on behavior.
In human studies, nutritional supplements containing a combination of DHA, EPA, and DAGE have been shown to enhance sleep quality [13], particularly by increasing the proportion of non-rapid eye movement (REM) sleep stage N3 and REM sleep stage R. These supplements also reduced daytime dysfunction and improved mood states, with participants reporting lower depression and tension scores and overall reduced mood disturbance. These benefits were particularly notable in individuals with low vigor and high stress levels, suggesting that the supplement offers significant anti-stress advantages [13]. However, it is important to note that these supplements also contained DHA and EPA, both of which have been previously documented to positively impact stress management [1,2]. Therefore, the specific contributions of DAGE to the observed improvements in sleep and anxiety cannot be conclusively isolated. While our results do support the potential effectiveness of DAGE supplementation in reducing anxiety and depression [13], our initial exploratory study did not include direct comparisons with traditional anxiolytic medications, such as benzodiazepines or SSRIs. Future research should aim to compare these supplements with conventional medications to more accurately delineate their mechanisms of action and relative efficacy.
The present study revealed a potential alleviating effect of DAGE on anxiety-related behaviors in mice. However, it is crucial to acknowledge certain limitations that highlight areas for further research. Firstly, the duration of the study was limited to a few weeks, which restricted our understanding of the long-term effects and sustainability of DAGE’s benefits. To address this, future studies should consider extended observation periods to more thoroughly investigate potential long-term side effects and changes in efficacy. Secondly, environmental factors such as housing conditions, which were not varied in this study, could significantly influence behavioral outcomes. Subsequent research should include these environmental variables (such as multi-cage environment and enriched environment) to determine their impact on the efficacy of DAGE and ensure that the results are robust across different settings. Finally, our study employed only male mice, which may limit the generalizability of the findings across genders. Including female mice in future research will not only help explore potential gender-related behavioral differences but also shed light on hormonal influences that could affect the efficacy of DAGE.
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Rong Jiang www.mdpi.com
