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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 35  |  Issue : 4  |  Page : 1655-1661

The antidepressant effect of simvastatin in hydrocortisone-induced depression in rats


1 Department of Clinical Pharmacology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Biochemistry, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission03-Aug-2022
Date of Decision31-Aug-2022
Date of Acceptance05-Sep-2022
Date of Web Publication04-Mar-2023

Correspondence Address:
Ahlam E. A. Elwany
Menoufia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_265_22

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  Abstract 


Objective
This study aimed to investigate the antidepressant effect of simvastatin in the hydrocortisone model of depression.
Background
Depression is considered the most common psychiatric disorder that causes disability in our life. It puts a heavy burden on both human and society. Simvastatin therapy alone or with selective serotonin reuptake inhibitors has shown desirable effects in the treatment of depression.
Material and methods
Rats were divided into five groups treated for 3 weeks as follows: control group, hydrocortisone group received intraperitoneal injection of hydrocortisone 40 mg/kg/day to induce depression, fluoxetine group received fluoxetine 10 mg/kg/day orally in addition to hydrocortisone, simvastatin group received simvastatin 10 mg/kg/day orally in addition to hydrocortisone, and combination group received fluoxetine 10 mg/kg/day and simvastatin 10 mg/kg/day in addition to hydrocortisone. During the experiment, behavioral tests were done in addition to biochemical assessment in the hippocampal tissue.
Results
Hydrocortisone administration caused significant increase in immobility time in forced swim test, significant decrease in sucrose preference percentage in sucrose preference test, significant decrease in hippocampal brain-derived neurotrophic factor and serotonin, significant increase in hippocampal malondialdehyde, and significant decrease in hippocampal reduced glutathione. Treatment with fluoxetine and simvastatin showed a significant decrease in immobility time in forced swim test, significant increase in sucrose preference percentage in sucrose preference test, significant increase in hippocampal brain-derived neurotrophic factor and serotonin, significant decrease in hippocampal malondialdehyde, and significant increase in hippocampal glutathione.
Conclusion
Simvastatin alone or with fluoxetine could be a promising drug in the treatment of depression.

Keywords: antidepressant, depression, fluoxetine, hydrocortisone, simvastatin


How to cite this article:
Elwany AE, Elfiky SR, Hegazy GA, El-Hefnawy SM, Elbatsh MM. The antidepressant effect of simvastatin in hydrocortisone-induced depression in rats. Menoufia Med J 2022;35:1655-61

How to cite this URL:
Elwany AE, Elfiky SR, Hegazy GA, El-Hefnawy SM, Elbatsh MM. The antidepressant effect of simvastatin in hydrocortisone-induced depression in rats. Menoufia Med J [serial online] 2022 [cited 2024 Mar 28];35:1655-61. Available from: http://www.mmj.eg.net/text.asp?2022/35/4/1655/371002




  Introduction Top


Depression is one of the most severe and common psychiatric disorders in the world where there is low mood, low interest, and even suicidal tendencies. Many theories have been suggested about the pathogenesis of depression, such as monoamine, neurotrophic, neuroendocrine, and neuroinflammatory hypotheses [1].

Hydrocortisone model of depression is one of the common and suitable models that causes disturbance in the hypothalamic pituitary adrenal axis (HPA), downregulation of brain-derived neurotrophic factor (BDNF), neuroinflammation, and oxidative damage [2]. Fluoxetine is a selective serotonin reuptake inhibitor, and it is still one of the most widely used drugs in the treatment of depression [3]. Simvastatin is a member of statins used in the treatment of hyperlipidemia, and studies suggest that statins may have antidepressant effects [4].

The aim of this study was to evaluate the antidepressant effect of simvastatin alone or in combination with fluoxetine in the hydrocortisone model of depression.


  Materials and methods Top


A total of 40 male Sprague-Dawley rats weighing between 150 and 200 g were used in this study. Rats were put in fully ventilated cages (four rats in each cage). Free access to water and balanced diet was available for animals. The rats were acclimatized to the laboratory conditions 7 days before the experiment. All the experiments were carried out in accordance with protocols approved by the local ethical committee, Faculty of Medicine, Menoufia University. This was in compliance with the Guide for the Care and Use of Laboratory Animals [5].

Rats were divided into five groups, with eight rats each. Control group received the vehicle. Hydrocortisone group received intraperitoneal injection of hydrocortisone (Sigma Pharmaceutical Company, Cairo, Egypt ) 40 mg/kg/day for 21 consecutive days [6]. Fluoxetine group received hydrocortisone 40 mg/kg/day for 21 days and fluoxetine (JEDCO International Pharmaceutical, Nasr City, Cairo Governorate, Egypt) 10 mg/kg/day orally for 2 weeks starting from day 8 [7]. Simvastatin group received hydrocortisone 40 mg/kg/day for 21 days and simvastatin (T3A Pharma, Giza, Egypt) 10 mg/kg/day orally for 2 weeks starting from day 8 [8]. Combination group received hydrocortisone (intraperitoneal for 21 days) with fluoxetine and simvastatin (orally for 2 weeks) starting from day 8 at the same previous doses with 1-h interval between each dose.

The body weight of animals was measured weekly in the morning for all groups. Then, we evaluated the change in body weight of rats during the experiment.

Behavioral assessment was done through many behavioral tests. Open field test (OFT) was done 1 h after last drug administration for each group (day 21). The apparatus of this test was formed of wooden square (100 cm × 100 cm × 50 cm), and its floor was dark. The dark floor was divided by white lines into 25 squares [9]. A single rat was put in the center and allowed to explore freely for 5 min with a video camera on the top of the field. We used 70% alcohol to clean the floor between each rat to avoid giving any clue to the other rat. Horizontal locomotion (number of crossed squares), rearing frequency, and rearing total duration were counted manually. Forced swim test was done 24 h after last drug administration (day 22). Each rat was put in a glass cylinder (about 20 cm in diameter and 40 cm in height) filled to the depth of 20 cm with water (25 ± 1°C). The behavior of the rat was assessed by a video camera with an observer in the same room. We measured the immobility time (time during which each rat remained floating with all limbs motionless except for movement needed to keep head above water) for 4 min. Water was replaced between each rat [10]. Moreover, sucrose preference test (SPT) was done 24 h after last drug administration (day 22) but habituation and preparation for this test started 72 h before this (day 19). All rats were habituated to the presence of two bottles of sucrose 1% in each cage, and these two bottles were left for 24 h. Then, 24 h later, rats were deprived of water and food. During the last 24 h before test day, each rat was put in a separate cage with two bottles: one contained water and the other contained sucrose 1%. Then, on the test day, we measured the consumption of water and sucrose during the last 24 h.

The sucrose preference was calculated as follows: sucrose preference (%)=(sucrose solution consumption)/(sucrose solution consumption + tap water consumption)×100% [11].

Twenty-four hours after last drug administration (day 22), rats were killed, and we dissected the brain and got bilateral tissue hippocampus. Hippocampus was stored at −80, weighted, and crushed in tissue lyzer equipment for 2 min. Hippocampal tissue was homogenized in 20% phosphate-buffered saline and put again in a tissue lyzer for 30 s for proper mixing. The sample was put in a cooling centrifuge after that for 15 min at rate of 4000 rpm at 4°C. After the centrifugation, the supernatant was collected in a clean tube for estimation of the level of serotonin, BDNF, malondialdehyde (MDA), and glutathione (GSH).

Statistical analysis

Results were collected, tabulated, and statistically analyzed by Statistical Package for the Social Sciences (SPSS), version 22 (SPSS Inc., Chicago, Illinois, USA). Results were expressed as mean ± SEM and percentage (%). The statistical significance between the means of different groups was analyzed using one-way analysis of variance test (parametric method), Kruskal–Wallis test (nonparametric method), followed by post-hoc test. Level of statistical significance was set at P value less than or equal to 0.05.


  Results Top


Weight of rats was measured weekly during the experiment. At the beginning of the experiment in the first week, there was no significant difference in weight between groups (P = 0.5). In the second week, the hydrocortisone group showed significant decrease in body weight when was compared with the control group (187.3 ± 6.2 vs. 213.6 ± 9.1; P ≤ 0.05). In the third week, the hydrocortisone group showed significant decrease in body weight when compared with the control group (170.6 ± 6.7 vs. 216.8 ± 9.4; P ≤ 0.05). Fluoxetine-treated group showed significant increase in body weight when compared with the hydrocortisone group in the third week (189.2 ± 4.3 vs. 170.6 ± 6.7; P ≤ 0.05). Simvastatin-treated group showed a significant increase in body weight when compared with the hydrocortisone group in the third week (198.5 ± 6.1 vs. 170.6 ± 6.7; P ≤ 0.05). Moreover, the fluoxetine and simvastatin group (combination group) showed significant increase in body weight when compared with the hydrocortisone group in the third week (206.3 ± 5.6 vs. 170.6 ± 6.7; P ≤ 0.05) [Table 1].
Table 1: Effect of simvastatin, fluoxetine, and their combination on body weight

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Moreover, weight change was evaluated as the difference between final weight and the initial weight. The hydrocortisone group showed a significant decrease in weight when compared with the control group, with a mean value of final body weight change of −42.1 ± 1.1 versus 4.3 ± 0.70 (P ≤ 0.05). Fluoxetine treatment significantly attenuated body weight loss compared with hydrocortisone group by ~62% (−15.7 ± 3.1 vs. −42.1 ± 1.1; P ≤ 0.05). Simvastatin treatment significantly attenuated body weight loss compared with the hydrocortisone group by ~61% (−16 ± 2.5 vs. 42.1 ± 1.1; P ≤ 0.05). Fluoxetine and simvastatin treatment in the combination group significantly attenuated body weight loss when compared with the hydrocortisone group by ~60% (−17.1 ± 2.6 vs. 42.1 ± 1.1; P ≤ 0.05) [Table 2].
Table 2: Effect of simvastatin, fluoxetine, and their combination on body weight change

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The effect of therapy on behavioral assessment parameters was evaluated [Table 3]. In forced swim test, hydrocortisone showed a significant increase in immobility time when compared with the control group (129.1 ± 7.6 vs. 85.1 ± 4.1; P ≤ 0.05). Fluoxetine showed a significant decrease in immobility time when compared with the hydrocortisone group (89 ± 5.5 vs. 129.1 ± 7.6; P ≤ 0.05). Moreover, simvastatin significantly decreased immobility time in comparison with the hydrocortisone group (90.5 ± 5.3 vs. 129.1 ± 7.6; P ≤ 0.05). The combination group showed significant decrease in immobility time when compared with the hydrocortisone group (88.1 ± 6.7 vs. 129.1 ± 7.6; P ≤ 0.05).
Table 3: Effect of simvastatin, fluoxetine, and their combination on behavioral assessment parameters in hydrocortisone-induced depression rats

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In SPT, hydrocortisone showed a significant decrease in sucrose preference percentage when compared with the control group (46.8 ± 11.6 vs. 81.1 ± 6.6; P ≤ 0.05). Fluoxetine showed significant increase in sucrose preference percentage when compared with the hydrocortisone group (74.7 ± 6.3 vs. 46.8 ± 11.6; P ≤ 0.05). Moreover, simvastatin showed a significant increase in sucrose preference percentage when compared with the hydrocortisone group (70.8 ± 8.1 vs. 46.8 ± 11.6; P ≤ 0.05). Combination group showed a nonsignificant change when compared with the hydrocortisone group or the fluoxetine or simvastatin group.

In OFT, hydrocortisone showed a significant decrease in the mean number of crossed squares when compared with the control group (53.1 ± 3.6 vs. 73.6 ± 1.8; P ≤ 0.05). Hydrocortisone showed a significant decrease in rearing frequency when compared with the control group (11.5 ± 1.1 vs. 21.2 ± 1.5; P ≤ 0.05). Moreover, hydrocortisone showed a significant decrease in rearing total duration when compared with the control group (14.7 ± 1.1 vs. 26.3 ± 2.04; P ≤ 0.05). Simvastatin, fluoxetine, and their combination showed a nonsignificant change in mean number of crossed squares, rearing frequency, and rearing total duration when compared with the hydrocortisone group except for the combination group, which showed a significant increase in rearing total duration when compared with the hydrocortisone group (21.8 ± 2.4 vs. 14.7 ± 1.1; P ≤ 0.05).

Moreover, the effect of therapy on biochemical parameters was evaluated [Table 4].
Table 4: Effect of simvastatin, fluoxetine, and their combination on biochemical assessment parameters in hydrocortisone-induced depression rats

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Hydrocortisone significantly decreased BDNF when compared with the control group (2.21 ± 0.67 vs. 4.27 ± 1.1; P ≤ 0.05). Hydrocortisone significantly decreased serotonin when compared with the control group (42.3 ± 2.8 vs. 98.5 ± 19.3; P ≤ 0.05). Hydrocortisone significantly increased MDA when compared with the control group (76.3 ± 1.1 vs. 24.1 ± 0.33; P ≤ 0.05). Hydrocortisone significantly decreased GSH when compared with the control group (12.2 ± 0.54 vs. 17.4 ± 0.20; P ≤ 0.05). Fluoxetine significantly increased BDNF when compared with the hydrocortisone group (3.48 ± 0.93 vs. 2.21 ± 0.67; P ≤ 0.05). Fluoxetine significantly increased serotonin when compared with the hydrocortisone group (76.1 ± 14.5 vs. 42.3 ± 2.8; P ≤ 0.05). Fluoxetine significantly decreased MDA when compared with the hydrocortisone (32.1 ± 1.6 vs. 76.3 ± 1.1; P ≤ 0.05). Fluoxetine significantly increased GSH when compared with the hydrocortisone group (15.6 ± 0.47 vs. 12.2 ± 0.54; P ≤ 0.05). Simvastatin significantly increased BDNF when compared with the hydrocortisone group (3.47 ± 1.2 vs. 2.21 ± 0.67; P ≤ 0.05). Simvastatin significantly increased serotonin when compared with the hydrocortisone group (79.6 ± 5.7 vs. 42.3 ± 2.8; P ≤ 0.05). Simvastatin significantly decreased MDA when compared with hydrocortisone (32.5 ± 1.01 vs. 76.3 ± 1.1; P ≤ 0.05). Simvastatin significantly increased GSH when compared with the hydrocortisone group (15.5 ± 0.95 vs. 12.2 ± 0.54; P ≤ 0.05). The combination group showed significant increase in BDNF when compared with the hydrocortisone group (4.05 ± 1.3 vs. 2.21 ± 0.67; P ≤ 0.05). The combination group showed a significant increase in serotonin when compared with hydrocortisone (89.4 ± 7.7 vs. 42.3 ± 2.8; P ≤ 0.05). The combination group showed a significant decrease in MDA when compared with the hydrocortisone group (24.6 ± 0.55 vs. 76.3 ± 1.1; P ≤ 0.05). The combination group showed a significant increase in GSH when compared with the hydrocortisone group (17.2 ± 0.30 vs. 12.2 ± 0.54; P ≤ 0.05). The combination group when compared with either fluoxetine or simvastatin group showed a nonsignificant change in BDNF and serotonin. The combination group compared with fluoxetine group showed a significant decrease in MDA (24.6 ± 0.55 vs. 32.1 ± 1.6; P ≤ 0.05). The combination group compared with the fluoxetine group showed a significant increase in GSH (17.2 ± 0.30 vs. 15.6 ± 0.47; P ≤ 0.05). The combination group compared with the simvastatin group significantly decreased MDA (24.6 ± 0.55 vs. 32.5 ± 1.01; P ≤ 0.05). The combination group compared with the simvastatin group significantly increased GSH (17.2 ± 0.30 vs. 15.5 ± 0.95; P ≤ 0.05).


  Discussion Top


Depression is one of the most common psychiatric disorders. Despite the increase in the drug categories as a treatment of depression, the prevalence of the disease is still steady. This means that antidepressants used in practice have limited effect in addition to their multiple adverse effects compared with psychotherapy [12]. So, we are still in need of developing new drugs in the treatment of depression.

Various animal models have demonstrated good face validity to human depression. Several behavioral tests are usually used to evaluate diverse components of depression and assess the antidepressant effect of novel drugs.

Hydrocortisone model of depression simulates depression caused by exposure to stress in humans. Hydrocortisone induces depression by different mechanisms: decrease in BDNF level, disturbances in HPA axis, and creation of a state of neuroinflammation causing oxidative damage [2].

In this study, depression was induced by intraperitoneal injection of hydrocortisone 40 mg/kg once daily for 21 consecutive days before doing behavioral tests [6].

Fluoxetine, which is a selective serotonin reuptake inhibitor, increases level of BDNF and causes enhancement in HPA axis dysfunction [13]. Simvastatin, one of the lipid-lowering drugs, was suggested to have antidepressant effect through increasing BDNF, its anti-inflammatory effect, and increasing level of serotonin [4].

Therefore, this study was performed to investigate the antidepressant effect of simvastatin alone or in combination with fluoxetine in the hydrocortisone model of depression.

In the present study, behavioral changes include significant increase in immobility time in forced swim test and significant decrease in sucrose preference percentage in SPT, with biochemical changes include significant decrease in hippocampal level of serotonin and BDNF in the hydrocortisone group compared with the control group, which judged the occurrence of depression. This was in accordance with Bai et al.[14].

Regarding clinical assessment, in the present study, hydrocortisone group showed a significant decrease in body weight over 21 days when compared with the control group, and this was in accordance with Gregus et al.[15], who reported that repeated hydrocortisone administration produces changes in emotional behavior that corresponds to symptoms of clinical depression like decrease in body weight. It is worthy to mention that simvastatin treatment, fluoxetine treatment, and their combination attenuated body weight loss compared with the hydrocortisone group, indicating their antidepressant effect.

Regarding behavioral assessment, in the present study, forced swim test was done, and the hydrocortisone group showed a significant increase in immobility time when compared with the control group. This finding is in agreement with Bai et al.[14]. Simvastatin group, fluoxetine group, and combination group showed a significant decrease in immobility time when compared with the hydrocortisone group. This finding is in agreement with Naserzadeh et al.[16].

In the present study, SPT was done. This test is used as a measure of anhedonia, which is decreased ability to experience pleasure and represents one of the main symptoms of depression. Rodents have an inherent preference for sweet food. Reduced preference for sweet solution in the SPT is indicative of anhedonia, which can be corrected by antidepressant drugs [11].

In SPT, the hydrocortisone group showed a significant decrease in sucrose preference when compared with the control group. This finding is in agreement with Bai et al.[14]. The simvastatin group showed a significant increase in sucrose preference when compared with the hydrocortisone group, and this finding is in agreement with Lin et al.[17]. Moreover, fluoxetine treatment showed a significant increase in sucrose preference when compared with the hydrocortisone group. This finding is in agreement with Hu et al.[18].

In the present study, OFT was done, and the hydrocortisone group showed a significant decrease in the number of crossed squares when compared with the control group, and this was in accordance with Badr et al.[19]. It is worthy to mention that the hydrocortisone group showed a significant decrease in rearing frequency and rearing total duration when compared to control group. These changes can be explained as depressed rats showed changes in exploratory and emotional behavior resulting in decrease in the number of crossings, rearing frequency, and rearing total duration [20]. The combination group showed a significant increase in rearing total duration when compared with the hydrocortisone group, and this was in accordance with Santos et al.[21].

Regarding biochemical assessment, in the present study, hippocampal BDNF level was assessed. The hydrocortisone group showed a significant decrease in the level of BDNF when compared with the control group, and this was in accordance with Bai et al.[14]. Simvastatin treatment significantly increased the level of BDNF compared with the hydrocortisone group, and this was in accordance with Nasef et al.[22], who reported that simvastatin has a neuroprotective effect and increases the level of BDNF.

The fluoxetine group also showed a significant increase in BDNF level compared with the hydrocortisone group, and this was in accordance with Sakhaie et al.[23], who reported that fluoxetine increases expression of BDNF, and the level of BDNF is affected by manipulation of the serotonergic system. It is worthy to mention that the combination group showed a significant increase in the level of BDNF compared with the hydrocortisone group.

In the present study, hippocampal serotonin level was assessed. Hydrocortisone group showed a significant decrease in the level of serotonin when compared with the control group, and this was in accordance with Bai et al.[14] Simvastatin group, fluoxetine group, and combination group showed significant increases in the level of serotonin when compared with the hydrocortisone group, and this was in accordance with Al-Asmari et al.[24].

In the present study, hippocampal level of MDA was assessed. The hydrocortisone group showed a significant increase in the level of MDA when compared with the control group, and this was in accordance with Oliveira et al.[25], who reported that repeated hydrocortisone administration increases oxidant markers, suggesting that it has a causal role in oxidative processes inducing local damage that can be correlated with depressive-like behavior. Simvastatin treatment significantly decreased the level of MDA compared with the hydrocortisone group, and this was in accordance with Houshmand et al.[26], who reported that simvastatin decreases the level of MDA, indicating its antioxidant effect. The fluoxetine group also showed a significant decrease in MDA level compared with the hydrocortisone group, and this was in accordance with Athira et al.[27] It is worthy to mention that the combination group showed a significant decrease in the level of MDA when compared with the hydrocortisone group or fluoxetine group or simvastatin group.

In the present study, hippocampal level of GSH was assessed. Hydrocortisone group showed a significant decrease in the level of GSH when compared with the control group, and this was in accordance with Oliveira et al.[25], who reported that hydrocortisone decreases the level of GSH as it causes decline in antioxidant mechanisms in the brain. Simvastatin treatment significantly increased the level of GSH compared with the hydrocortisone group, and this was in accordance with Houshmand et al.[26]. The fluoxetine group also showed a significant increase in GSH level compared with the hydrocortisone group, and this was in accordance with Athira et al.[27]. It is worthy to mention that the combination group showed a significant increase in the level of GSH when compared with the hydrocortisone group or fluoxetine group or simvastatin group.


  Conclusion Top


Simvastatin alone or in combination with fluoxetine was shown to possess antidepressant effects in the animal model of depression induced by hydrocortisone. This antidepressant effect may be attributed to increase in serotonin and BDNF or decrease in oxidative stress.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Li Z, Ruan M, Chen J, Fang Y Major depressive disorder: advances in neuroscience research and translational applications. Neurosci Bull 2021; 37:863–880.  Back to cited text no. 1
    
2.
Nandam LS, Brazel M, Zhou M, Jhaveri DJ. Cortisol and major depressive disorder—translating findings from humans to animal models and back. Front Psychiatry 2020; 10:974.  Back to cited text no. 2
    
3.
Deodhar M, Rihani SB, Darakjian L, Turgeon J, Michaud V. Assessing the mechanism of fluoxetine-mediated CYP2D6 inhibition. Pharmaceutics 2021, 13:148.  Back to cited text no. 3
    
4.
Wu H, Lv W, Pan Q, Kalavagunta PK, Liu Q, Qin G, et al. Simvastatin therapy in adolescent mice attenuates HFD-induced depression-like behavior by reducing hippocampal neuroinflammation. J Affect Disord 2019; 243:83–95.  Back to cited text no. 4
    
5.
MacArthur Clark JA, Sun D. Guidelines for the ethical review of laboratory animal welfare People's Republic of China National Standard GB/T 35892-2018 [Issued 6 February 2018 Effective from 1 September 2018]. Anim Models Exp Med 2020; 3:103–113.  Back to cited text no. 5
    
6.
Cheng D, Chang H, Ma S, Guo J, She G, Zhang F, et al. Tiansi liquid modulates gut microbiota composition and tryptophan–kynurenine metabolism in rats with hydrocortisone-induced depression. Molecules 2018; 23:2832.  Back to cited text no. 6
    
7.
Zeni AL, Camargo A, Dalmagro AP. Lutein prevents corticosterone-induced depressive-like behavior in mice with the involvement of antioxidant and neuroprotective activities. Pharmacol Biochem Behav 2019; 179:63–72.  Back to cited text no. 7
    
8.
ElBatsh MM. Antidepressant-like effect of simvastatin in diabetic rats. Can J Physiol Pharmacol 2015; 93:649–656.  Back to cited text no. 8
    
9.
Hazzaa SM, Ewida SF, Elbatsh MM. Influence of the phosphodiesterase type 5 inhibitor, sildenafil, on some behavioral and central biochemical changes on chronic restraint stress in rats. Cairo Univ Med J 2014; 82:483–493.  Back to cited text no. 9
    
10.
Yu XB, Zhang HN, Dai Y, Zhou ZY, Xu RA, Hu LF, et al. Simvastatin prevents and ameliorates depressive behaviors via neuroinflammatory regulation in mice. J Affect Disord 2019; 245:939–949.  Back to cited text no. 10
    
11.
Jia M, Li C, Zheng Y, Ding X, Chen M, Ding J, et al. Leonurine exerts antidepressant-like effects in the chronic mild stress-induced depression model in mice by inhibiting neuroinflammation. Int J Neuropsychopharmacol 2017; 20:886–895.  Back to cited text no. 11
    
12.
Ormel J, Kessler RC, Schoevers R. Depression: more treatment but no drop in prevalence: how effective is treatment? And can we do better?. Curr Opin Psychiatry 2019; 32:348–354.  Back to cited text no. 12
    
13.
Tian P, Zou R, Song L, Zhang X, Jiang B, Wang G, et al. Ingestion of Bifidobacterium longum subspecies infantis strain CCFM687 regulated emotional behavior and the central BDNF pathway in chronic stress-induced depressive mice through reshaping the gut microbiota. Food Funct 2019; 10:7588–7598.  Back to cited text no. 13
    
14.
Bai Y, Song L, Dai G, Xu M, Zhu L, Zhang W, et al. Antidepressant effects of magnolol in a mouse model of depression induced by chronic corticosterone injection. Steroids 2018; 135:73–78.  Back to cited text no. 14
    
15.
Gregus A, Wintink AJ, Davis AC, Kalynchuk LE. Effect of repeated corticosterone injections and restraint stress on anxiety and depression-like behavior in male rats. Behav Brain Res 2005; 156:105–114.  Back to cited text no. 15
    
16.
Naserzadeh R, Abad N, Ghorbanzadeh B, Dolatshahi M, Mansouri MT. Simvastatin exerts antidepressant-like activity in mouse forced swimming test: role of NO-cGMP-KATP channels pathway and PPAR-gamma receptors. Pharmacol Biochem Behav 2019; 180:92–100.  Back to cited text no. 16
    
17.
Lin PY, Chang AY, Lin TK. Simvastatin treatment exerts antidepressant-like effect in rats exposed to chronic mild stress. Pharmacol Biochem Behav 2014; 124:174–179.  Back to cited text no. 17
    
18.
Hu MZ, Wang AR, Zhao ZY, Chen XY, Li YB, Liu B. Antidepressant-like effects of paeoniflorin on post-stroke depression in a rat model. Neurol Res 2019; 41:446–455.  Back to cited text no. 18
    
19.
Badr AM, Attia HA, Al-Rasheed N. Oleuropein reverses repeated corticosterone-induced depressive-like behavior in mice: evidence of modulating effect on biogenic amines. Sci Rep 2020; 10:1–0.  Back to cited text no. 19
    
20.
Chkhartishvili E, Maglakelidze N, Babilodze M, Chijavadze E, Nachkebia N. Changes of open field behavior in animal model of depression. Georgian Med News 2011; 11:107–112.  Back to cited text no. 20
    
21.
Santos T, Baungratz MM, Haskel SP, de Lima DD, da Cruz JN, Dal Magro DD, et al. Behavioral interactions of simvastatin and fluoxetine in tests of anxiety and depression. Neuropsychiatr Dis Treat 2012; 8:413.  Back to cited text no. 21
    
22.
Nasef NA, Keshk WA, El-Meligy SM, Allah AA, Ibrahim WM. Modulatory effect of simvastatin on redox status, caspase-3 expression, p-protein kinase B (p-Akt), and brain-derived neurotrophic factor (BDNF) in an ethanol-induced neurodegeneration model. Can J Physiol Pharmacol 2021; 99:478–489.  Back to cited text no. 22
    
23.
Sakhaie N, Sadegzadeh F, Dehghany R, Adak O, Hakimeh S. Sex-dependent effects of chronic fluoxetine exposure during adolescence on passive avoidance memory, nociception, and prefrontal brain-derived neurotrophic factor mRNA expression. Brain Res Bull 2020; 162:231–236.  Back to cited text no. 23
    
24.
Al-Asmari AK, Ullah Z, Al Masoudi AS, Ahmad I. Simultaneous administration of fluoxetine and simvastatin ameliorates lipid profile, improves brain level of neurotransmitters, and increases bioavailability of simvastatin. J Exp Pharmacol 2017; 9:47.  Back to cited text no. 24
    
25.
Oliveira IC, Mallmann AS, de Paula Rodrigues FA, Vidal LM, Sales IS, Rodrigues GC, et al. Neuroprotective and antioxidant effects of riparin I in a model of depression induced by corticosterone in female mice. Neuropsychobiology 2022; 81:28–38.  Back to cited text no. 25
    
26.
Houshmand G, Pourasghar M, Shiran M, Firozjae AA, Goudarzi M, Manouchehr F, et al. Simvastatin prevents morphine antinociceptive tolerance and withdrawal symptoms through antioxidative effect and nitric oxide pathway in mice. Behav Brain Res 2021; 402:113104.  Back to cited text no. 26
    
27.
Athira KV, Madhana RM, Js IC, Lahkar M, Sinha S, Naidu VG. Antidepressant activity of vorinostat is associated with amelioration of oxidative stress and inflammation in a corticosterone-induced chronic stress model in mice. Behav Brain Res 2018; 344:73–84.  Back to cited text no. 27
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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