Depression and anxiety are common mental disorders that affecting people worldwide and co-occur in approximately half of clinical subjects. A variety of genetic, endocrine and environmental factors have been reported to influence the susceptibility and occurrence of depression and anxiety . Susceptible individuals exposed to early life stress or traumatic life events may develop psychiatric disorders. Chronic stress could induce the activation of hypothalamic-pituitary-adrenal (HPA) axis, promote the production and release of inflammatory cytokines and alter the synapse number and function in the medial prefrontal cortex and hippocampus, thus contribute to the pathophysiology of depressive- and anxiety-like behaviors [1,2]. Additionally, cognitive impairment is also a core symptom in patients with depression and may persist even when depressive symptoms have improved in clinic . Approaches that ameliorate both depressive and anxious symptoms and cognitive deficits may be potential and promising for the treatment of depression in the future.
Eriodictyol is a flavonoid abundantly produced by numerous medicinal plants, such as Eupatorium arnottianum , Bauhinia ungulata , Arcytophyllum thymifolium , Elsholtzia bodinieri , Clinopodium chinense , Thymus pulegioides , and Cotoneaster integerrimus . Eriodictyol has been reported to alleviate lipopolysaccharide (LPS)-induced oxidative stress and inflammation [11,12] and protect against myocardial ischemia or infarction , lung injury , liver injury , kidney injury , traumatic brain injury  and LPS-induced cognitive impairments . Eriodictyol also attenuated β-amyloid peptide-induced oxidative cell death and inhibited amyloidogenesis, thus may be a potential treatment for Alzheimer’s disease [12,18]. Additionally, chronic eriodictyol treatment suppressed the LPS-induced expression of proinflammatory cytokines including tumor necrosis factor (TNF)-α and interleukin (IL)-1β in both serum and the brain, and prevented LPS-induced neuron damage in both cortex and hippocampus in mice . A previous study also showed the antidepressant effect of Erythrina variegata bark extract in mice, and liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry analysis identified its active components including eriodictyol, phenylethylamine and daidzein . These studies suggest that chronic eriodictyol administration may exert neuroprotective effects and produce antidepressant activity.
In the present study, we investigated the behavioral actions of chronic eriodictyol administration in the forced swim test (FST) and in the rat depression models induced by LPS and chronic unpredictable mild stress (CUMS). We also evaluated the effects of eriodictyol treatment on memory function in CUMS-exposed rats.
Materials and methods
Adult male Sprague–Dawley rats weighting 240–260 g were purchased from the Laboratory Animal Center, University of South China. The rats were housed in groups of four or five per cage and maintained in ambient temperature at 23 ± 2°C and relative humidity at 50 ± 5%. The rats were under a normal 12:12 h light/dark cycle with lights on at 08:00 a.m. Water was provided ad libitum, and a standard laboratory diet was provided throughout the experiments. All experimental procedures were approved by the University of South China and carried out in accordance with the corresponding guidelines.
Drugs and reagents
Eriodictyol (purity > 98%, confirmed by HPLC analysis, CAS: 552-58-9) was purchased from Chengdu Pufeide Biological Technology Co., Ltd. (Chengdu, China). The chemical structure of eriodictyol has been reported previously [13,20,21] and can also be found on the purchase website http://www.sc-victory.com/ProductView-3698.html. Eriodictyol (10, 30 and 100 mg/kg/day in sterilized saline) or vehicle (equivalent volume of sterilized saline) was administered by oral gavage once daily for 14 or 28 days. The doses of eriodictyol were based on previous studies [11,12]. Capsazepine was purchased from Tocris Bioscience (Ellisville, Missouri, USA). Capsazepine was dissolved in Tween 80:DMSO:saline in 1:2:7 ratios, and was administered intraperitoneally (i.p.) at doses of 1.5 or 5 mg/kg based on previous studies [22,23]. LPS (L2630) was purchased from Sigma (St. Louis, Missouri, USA). LPS was dissolved in sterile saline (0.9% NaCl solution) and administered intraperitoneally at a dose of 1 mg/kg based on previous studies [24,25]. Fluoxetine was purchased from Tokyo Chemical Industry Co., Ltd. (Shanghai, China). Fluoxetine was dissolved in sterile saline (0.9% NaCl solution) and administered by oral gavage at a dose of 10 mg/kg once daily for 14 days.
Open field test
The open field test (OFT) was used to measure spontaneous locomotor activity. The apparatus consisted of a 75 cm length × 75 cm width × 40 cm height square arena, and it was divided into 25 equal squares on the floor of the arena. The rat was placed in the center of the cage, and the number of crossings was counted and recorded for 5 mins.
Forced swim test
The FST was used to measure depressive-like behavior. The rats were placed in a plastic cylinder (25 cm diameter × 50 cm height) that was filled with 23–25°C water to a depth of 45 cm. On the first day, each rat was adapted and placed in the cylinder for 15 mins. Then, they were removed, dried, and returned to their home cage. On the next day, the rat was placed in the cylinder for 5 mins and videotaped, and immobility time was measured. The definition of immobility was the absence of all movements with the exception of motions required to maintain the animal’s head above the water. Observers were blind to the group condition of the rats.
Lipopolysaccharide-induced depression model
LPS was diluted in 0.9% saline at a constant dose of 1 mg/kg and administered i.p. based on previous studies [24,25]. Twenty-four hours after LPS or saline injection, behavioral tests were conducted.
Chronic unpredictable mild stress
The CUMS protocol was designed as previously described [26,27]. The rats were exposed to a variable sequence and random pattern of mild and unpredictable stressors over a period of 28 consecutive days (two stressors per day). The stressors included water or food deprivation for 24 h, soiled bedding for 24 h, empty cage exposure for 24 h, 45° cage tilt for 24 h, crowding for 24 h, day-night reversal (12/12 h), tail clamp (1 min), forced cold swim (4°C, 5 mins), vibration (1 h), white noise (120 db, 1 h) and restraint (in a 25 cm × 7 cm plastic box for 1 h). During a period of 28 days, two of the stressors were chosen randomly and were given to the rats at a random time every day so that the stress was unpredictable in terms of time and manner. The control rats were housed in a separate room and received handling for 5 mins each day.
Sucrose preference test
The sucrose preference test (SPT) was used to measure depressive-like behavior. Before the test, the rats were individual housed and adapted to sucrose solution (1%, w/v) by placing two bottles of sucrose solution in each cage for 48 h. After adaptation, the rats were deprived of water for 6 h. During the test, the rats had free access to two bottles that contained 1% sucrose or tap water respectively for 1 h. The volumes of the consumed sucrose solution and water were measured and recorded. Then, sucrose preference was calculated as sucrose consumption/(sucrose consumption + water consumption) × 100%.
Novelty-suppressed feeding test
The novelty-suppressed feeding test (NSFT) was used to measure anxiety-like behavior. Before the test, the rats were food-deprived for 24 h. During the test, the rats were individually placed in a corner of an open field apparatus (75 cm × 75 cm × 40 cm) with several small pellets of food placed on a piece of white paper (10 cm × 10 cm) in the center. The latency(s) to approach and eat the first bite of food was recorded for the maximum of 10 mins. As control, the amount of food intake in home cage was measured during the first 5 mins after rats being taken back to their home cage.
Novel object recognition
The novel object recognition (NOR) paradigm was performed according to previous studies with minor modifications . Before NOR training, each rat was habituated to the apparatus (60 cm × 40 cm × 50 cm, Plexiglas cage) for two daily 5-min sessions without objects. During training, two identical objects were fixed to the floor by double-sided tape, and the rats were allowed to freely explore the arena for 5 mins, followed by a 5-min test session 24 h later. During the test session, the rats were returned to the arena that contained one familiar object and one different novel object for 5 mins. The texture, shape and color patterning of the novel object were different from the familiar object. The object assignments (familiar or novel) and locations (left or right side of the arena) were counterbalanced. All objects and the apparatus were wiped down with 70% ethanol between sessions. The time that each individual rat spent exploring both familiar and novel objects was recorded. The exploration index was calculated as the difference in time spent exploring the novel and familiar objects divided by the total exploration time for both objects.
All of the statistical analyses were performed using SPSS 16.0 software (SPSS, Chicago, Illinois, USA). The data are expressed as mean ± SEM. The data were analyzed using one- or two-way analysis of variance with appropriate between- and within-group factors, followed by least significant difference post-hoc tests. A value of P <0.05 was considered to be statistically significant for analysis.
Chronic eriodictyol treatment dose-dependently produced antidepressant effect in the forced swim test
We first investigated the antidepressant effect of chronic eriodictyol treatment in the FST. Different doses of eriodictyol (10, 30 and 100 mg/kg), positive control fluoxetine (10 mg/kg) or vehicle were administered by oral gavage once daily for 14 consecutive days. On day 14, 55 mins after the last administration, a number of crossings in the OFT were recorded for 5 mins. Immediately after the OFT, the rats were subjected to the FST for 5 mins.
As shown in Fig. 1a, oral treatment with eriodictyol at a dose of 100 mg/kg for 14 days significantly reduced immobility time (P = 0.014), but eriodictyol treatment at the doses of 10 mg/kg (P = 0.359) and 30 mg/kg (P = 0.142) had no significant effects on the immobility time in the FST, compared with vehicle-treated rats. The positive control fluoxetine (10 mg/kg) significantly reduced immobility time in the FST (P = 0.009; Fig. 1a) compared with vehicle-treated rats. Eriodictyol (10, 30 and 100 mg/kg) and the positive control fluoxetine (10 mg/kg) treatment had no significant effects on the number of crossings in the OFT (all P > 0.05; Fig. 1b) compared with the vehicle-treated rats, indicating that the antidepressant-like effects of chronic eriodictyol treatment may not be attributable to a stimulatory effect on locomotor activity.
Chronic administration of eriodictyol prevented lipopolysaccharide-induced depressive- and anxiety-like behaviors
We next evaluated the behavioral actions of eriodictyol in an inflammation model of depression induced by repetitive LPS administrations . The rats were randomly divided into four groups: the Veh+Veh group (n = 10), the Veh+LPS group (n = 10), the 30 mg/kg eriodictyol+LPS group (n = 9) and the 100 mg/kg eriodictyol+LPS group (n = 10). Briefly, the rats received vehicle or eriodictyol (30 and 100 mg/kg) orally once daily for 28 consecutive days. At the last two days of eriodictyol administration, the rats received two injections with LPS (1 mg/kg, i.p.) or vehicle (sterile saline, i.p.) once daily. Then, the behavioral tests including SPT, FST and NSFT were performed to evaluate depressive- and anxiety-like behaviors.
As shown in Fig. 2a, LPS injections significantly decreased sucrose preference in the SPT (P = 0.001), which was reversed by 100 mg/kg eriodictyol (P = 0.005) but not 30 mg/kg eriodictyol (P = 0.238) administration. LPS or eriodictyol treatment had no significant effect on total fluid consumption in the SPT (all P > 0.05; Fig. 2a). As shown in Fig. 2b, LPS injections significantly increased the immobility time in the FST (P = 0.024), which was reversed by 100 mg/kg eriodictyol (P = 0.049) but not 30 mg/kg eriodictyol (P = 0.275) administration. As shown in Fig. 2c, LPS injections significantly increased the latency to feeding in the NSFT (P = 0.004), which was reversed by 100 mg/kg eriodictyol (P = 0.003) but not 30 mg/kg eriodictyol (P = 0.262) administration. LPS or eriodictyol treatment did not significantly affect total food intake in home cage in the NSFT (all P > 0.05; Fig. 2c). These data indicate that oral administration of eriodictyol for 28 days attenuated the depressive-like and anxiety-like behaviors induced by LPS.
Co-administration of subthreshold doses of eriodictyol and capsazepine prevented depressive- and anxiety-like behaviors induced by lipopolysaccharide
Previous studies showed that eriodictyol may act as an antagonist of the transient potential vanilloid 1 receptor (TRPV1) . Moreover, TRPV1 can modulate stress-related behaviors and its antagonists such as capsazepine produced antidepressant effects in the FST [30–32]. Then, we investigated the specific receptor pharmacology of eriodictyol and evaluated whether its behavioral actions could be potentiated by capsazepine.
The rats were randomly divided into six groups: the Veh+Veh+Veh group (n = 9), the Veh+Veh+LPS group (n = 9), the Veh+1.5 mg/kg capsazepine+LPS group (n = 9), the Veh+5 mg/kg capsazepine+LPS group (n = 9), the 10 mg/kg eriodictyol+1.5 mg/kg capsazepine+LPS group (n = 9) and the 30 mg/kg eriodictyol+1.5 mg/kg capsazepine +LPS group (n = 9). Briefly, the rats received vehicle or eriodictyol (10 and 30 mg/kg) orally once daily for 28 consecutive days. At the last 2 days of eriodictyol administration, the rats received two injections with vehicle or capsazepine (1.5 and 5 mg/kg, i.p.) once daily, followed by LPS (1 mg/kg, i.p.) or vehicle 30 mins later. Then, the behavioral tests including SPT, FST and NSFT were performed to evaluate depressive- and anxiety-like behaviors.
As shown in Fig. 3a, LPS injections significantly decreased sucrose preference in the SPT (P < 0.001), which was reversed by 5 mg/kg capsazepine (P = 0.001) but not 1.5 mg/kg capsazepine (P = 0.275) administration. Co-administration of subthreshold doses of eriodictyol (30 mg/kg) and capsazepine (1.5 mg/kg) significantly increased sucrose preference in the SPT (P < 0.001). There were no differences in total fluid consumption in the SPT among these groups (all P > 0.05; Fig. 3a). As shown in Fig. 3b, LPS injections significantly increased the immobility time in the FST (P = 0.001), which was reversed by 5 mg/kg capsazepine (P = 0.002) but not 1.5 mg/kg capsazepine (P = 0.055) administration. As shown in Fig. 3c, LPS injections significantly increased the latency to feeding in the NSFT (P = 0.005), which was reversed by 5 mg/kg capsazepine (P = 0.024) but not 1.5 mg/kg capsazepine (P = 0.125) administration. Co-administration of subthreshold doses of eriodictyol (30 mg/kg) and capsazepine (1.5 mg/kg) significantly decreased the immobility time in the FST (P < 0.001; Fig. 3b) and decreased the latency to feeding in the NSFT (P = 0.003; Fig. 3c). There were no differences in total food intake in home cage in the NSFT (all P > 0.05; Fig. 3c).
These data indicate that co-administration of subthreshold doses of eriodictyol and capsazepine produced a synergistic effect in an inflammation model of depression induced by LPS, and eriodictyol may act as a TRPV1 antagonist to exert antidepressant-like effects.
Chronic administration of eriodictyol produced antidepressant- and anxiolytic-like effects in rat model of chronic unpredictable mild stress
Then, we tested the behavioral effects of eriodictyol in the CUMS model. The rats were randomly divided into four groups: the Control+vehicle group (n = 10), the CUMS+vehicle groups (n = 9), the Control+ eriodictyol group (n = 9) and the CUMS+ eriodictyol group (n = 10). The CUMS rats were subjected to different types of stressors for 28 consecutive days. At the same time, the rats received vehicle or 100 mg/kg eriodictyol orally once daily for 28 days. Then, the behavioral test including SPT, FST and NSFT were performed to evaluate depressive- and anxiety-like behaviors.
CUMS significantly decreased the sucrose preference in the SPT (P = 0.002), which was reversed by oral administration of eriodictyol (100 mg/kg) for 4 weeks (P = 0.020; Fig. 4a). Additionally, eriodictyol administration did not significantly alter the sucrose preference in the control group (P = 0.638). There were no differences in total fluid consumption in the SPT among four groups (all P > 0.05; Fig. 4a). CUMS significantly increased the immobility time in the FST (P = 0.010), which was reversed by chronic eriodictyol administration with eriodictyol (P = 0.019; Fig. 4b). CUMS significantly increased the latency to feeding in the NSFT (P = 0.004), which was reversed by oral administration of eriodictyol (100 mg/kg) for 28 days (P = 0.020; Fig. 4c). Additionally, CUMS or eriodictyol treatment did not significantly alter the total food intake in home cage in the NSFT among four groups (all P > 0.05; Fig. 4c). These data indicate that oral administration of eriodictyol for 28 days attenuated the CUMS-induced depressive- and anxiety-like behaviors in rats.
Chronic administration of eriodictyol rescued the memory impairment induced by chronic unpredictable mild stress
Previous studies showed that chronic unpredictable stress, as a classical animal model of depression, could recapitulate several symptoms of clinical depression including anhedonia, hopelessness, anxiety and cognitive impairment [26,27]. Thus, we want to investigate whether eriodictyol treatment rescues cognitive impairment that is induced by CUMS. The rats were randomly divided into four groups: the Control+vehicle group (n = 9), the CUMS+vehicle groups (n = 9), the Control+ eriodictyol group (n = 9) and the CUMS+ eriodictyol group (n = 9). The CUMS or Control-treated rats received vehicle or 100 mg/kg eriodictyol orally once daily for 28 consecutive days. Then, the NOR paradigm was performed to evaluate memory function.
As shown in Fig. 5a, CUMS significantly decreased the time spent exploring the novel object in the NOR test (P = 0.042), which was reversed by oral administration of eriodictyol (100 mg/kg) for 4 weeks (P = 0.040). There were no differences in the time spent exploring the familiar object in the NOR test among four groups (all P > 0.05; Fig. 5b). CUMS also significantly decreased the exploration index in the NOR test (P < 0.001), which was reversed by chronic eriodictyol treatment (P < 0.001; Fig. 5c). These data indicate that oral administration of eriodictyol for 28 days significantly rescued the cognitive impairment induced by CUMS.
Growing evidence suggest that dysfunction of neuroimmune system plays a critical role in the pathogenesis of depression. Proinflammatory cytokine levels were significantly increased in the blood of patients with depression, and their alterations were associated with the response to antidepressant treatment . Preclinical studies also showed that activation of the immune system by administration of LPS or recombinant proinflammatory cytokines could resemble the sickness behavior . Animal inflammation-based models are often utilized to characterize the etiology and pathophysiology of depression and develop novel antidepressant therapy . Previous studies showed that eriodictyol had anti-inflammatory activity and suppressed LPS-induced microglia activation and the inflammatory mediator expression such as TNFα and IL-1β [12,14]. Heat-processed eriodictyol also significantly improved cytotoxic T lymphocyte and natural killer activities, and inhibited the phagocytic activity of activated macrophages in vitro . Consistent with these findings, in the present study, we found that LPS administration induced depressive- and anxiety-like behaviors in rats, as indicated by the decrease in sucrose preference in the SPT and the increases in immobility time in the FST and feeding latency in the NSFT. These behavioral effects could be reversed by chronic eriodictyol treatment. We also found that eriodictyol dose-dependently decreased the immobility time in the FST, as effective as the positive control fluoxetine. These results indicate that eriodictyol has antidepressant and anxiolytic activities in rats.
Eriodityol is a natural flavonoid that widely distributed in citrus fruits and protects against oxidative stress-induced cell death through multiple mechanisms, such as the transcription factor Nrf2 activation and Phase 2 gene expression . Eriodityol may act as a TRPV1 antagonist, and exerted an antinociceptive effect in the capsaicin test and antihyperalgesic and antiallodynic effects in the complete Freund’s adjuvant test . In the present study, we found that a combination of subthreshold doses of eriodictyol and capsazepine prevented LPS-induced depressive- and anxiety-like behaviors, suggesting that the behavioral actions of eriodictyol may be due to TRPV1 antagonism. However, much works still remain to be done to determine the specific receptor pharmacology of eriodictyol using in-vitro radio-ligand receptor binding assay or other methods.
Eriodictyol reduced infarct area, neurological and memory deficits induced by permanent middle cerebral artery occlusion in mouse experimental stroke model, and these therapeutic effects may be attributed to its inhibition of neuroinflammatory responses and neuronal death in the cortex and striatum [38,39]. In the present study, we utilized the chronic unpredictable mild stress, the most commonly used and acknowledged rodent model of depression , to recapitulate several symptoms of clinical depression including anhedonia, hopelessness, anxiety and cognitive impairment. We found that oral administration with eriodictyol (100 mg/kg) for 28 days reversed the depressive- and anxiety-like behaviors and memory impairments induced by CUMS. Eriodictyol is a flavonoid that consumed in the intestine and metabolized in the liver and kidney . The pharmacokinetic parameters and brain concentration after administering eriodictyol by oral gavage daily still remain unclear and need further investigation. Additionally, under normal condition, we found that eriodictyol treatment did not affect the sucrose preference in the SPT, which may be attributable to the ceiling effect. The FST is a behavioral test in rodents that has been widely used as a model for predicting the behavioral action of antidepressant drugs or pharmaceutical screening of potential antidepressants [41,42]. The present study revealed that chronic eriodictyol administration had a significant tendency to decrease the immobility time in both CUMS-exposed and nonstressed rats, indicating that eriodictyol may be a potential and promising component for the prevention and treatment of depression.
Eriodictyol has been reported to exert anti-inflammatory activity, antimonoamine oxidase activity, antioxidative activity and antiproliferative and neuroprotective effects [11,12,19], which may be related to its antidepressant and anxiolytic-like effects. Additionally, eriodictyol could act on the Nrf2/HO-1 axis to ameliorate oxidative stress in cellular and animal models . Protein levels of Nrf2 in the CA3 and dentate gyrus of hippocampus and prefrontal cortex of susceptible mice after repeated social defeat stress were significantly decreased . Moreover, Nrf2 knockout mice exhibited increased serum levels of proinflammatory cytokines and depression-like phenotypes, while Nrf2 activator sulforaphane produced antidepressant-like effects [43,44]. Inflammatory and oxidative processes have been well recognized as a major contributor to the pathophysiology of stress-related disorders. Chronic eriodictyol treatment may induce anti-inflammatory state in the hippocampus and prefrontal cortex via multiple mechanisms such as the activation of transcription factor Nrf2, thus contributing to its behavioral effects, which needs further investigations.
In conclusion, this study showed the neuroprotective effect of eriodictyol on behavioral deficits and memory impairment in depressed rats induced by LPS or CUMS. Eriodictyol, act as a TRPV1 antagonist, may be a potential and promising approach for therapeutic intervention of depression and anxiety. Further studies are needed to elucidate the molecular signaling pathways underlying the behavioral actions of eriodictyol.
This work was supported by the National Natural Science Foundation of China (no. 81801160).
Conflicts of interest
There are no conflicts of interest.
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