Antidepressant Like Effect of Endogenous SO 2 on Depression Caused by Chronic Unpredictable Mild Stress

doi:10.21203/rs.3.rs-2009721/v1

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Antidepressant Like Effect of Endogenous SO 2 on Depression Caused by Chronic Unpredictable Mild Stress

https://doi.org/10.21203/rs.3.rs-2009721/v1

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published 02 Feb, 2023

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Sulfur Dioxide (SO₂) is a toxic gas with harmful effects on various organs but recent studies, have confirmed the protective effect of SO₂ on ischemic heart disease, atherosclerosis, and lung infections. The present study was designed to investigate the effect of endogenous SO₂ on depression. Chronic Unpredictable Mild Stress (CUMS) model was performed to cause depression. Depression-Like Behaviors in animals were determined using open-field test, forced swimming test and sucrose consumption. Animal spatial learning and memory was assessed using the Morris water maze. The oxidative status of the hippocampus and serum corticosterone level assessed. A reduction in the tendency to consume sucrose, mobility, and curiosity, as well as learning and memory disorders were observed in CUMS animals. Depressed animals treated with SO₂ showed a significant improvement in behavioral and cognitive functions. SO₂ also reduced neuronal damage and lipid peroxidation of the hippocampus and serum corticosterone level in the CUMS group. Various evidences supports a mutual relationship between inflammation and depression, also growing studies shows the role of oxidative stress in the pathogenesis of mood-related disorders such as depression. In this study, increased hippocampal malondialdehyde (MDA) and serum corticosterone levels can be reasons for the existence of oxidative stress and possible activation of inflammatory processes. SO₂ donors reduced MDA and corticosterone levels in depressed animals. According to these results, SO₂ may have been able to reduce tissue damage and eventually behavioral disorders caused by depression by reducing oxidative stress and inflammation.

Chronic Unpredictable Mild Stress

Depression

Sulfur dioxide

oxidative stress

Depression is a complex, multifactorial, and often chronic mental disorder and is one of the most widespread psychiatric disorders in the world. The World Health Organization (WHO) has reported an 11% prevalence of this disorder worldwide (Kendler and Gardner 2010). This disease disrupts the patient's life by causing behavioral and physical problems. Despite the fact that numerous studies explain how depression develops, there is still no clear concept to explain the causes and mechanisms of the onset and progression of depressive disorders (Sullivan, et al. 2000). One of the main findings of depression is the reduction of monoamine and acetylcholine neurotransmitters in the Central nervous system (CNS). A wide range of antidepressants aims to increase the level of these transmitters (Aricioglu, et al. 2019), But monoamine hypothesis is not enough to explain the pathogenesis of depression, and the direction of studies is needed to investigate other possible mechanisms involved in depression.

Growing studies have shown a mutual relationship between inflammation and depression. Clinical studies have shown increased levels of proinflammatory cytokines in the blood of depressed individuals, which can be a reason for their resistance to antidepressant drugs (Aricioglu, et al. 2019; Strawbridge, et al. 2015). Today's life is full of unpredictable stress. Studies have shown that exposure to chronic stress leads to psychological disorders such as anxiety and depression, which are associated with increased hypothalamic-pituitary-adrenal responses and systemic inflammation (Shahidpour, et al. 2021; Strawbridge, et al. 2015). As well as the influence of inflammatory factors in the pathogenesis of psycho-neurological disorders, the role of oxidative stress has been investigated and confirmed in many studies (Hassan, et al. 2014). The presence and activity of oxidative stress in the central nervous system is predominant compared to other organs due to its high oxygen consumption and relatively limited antioxidant reserves. CNS also contains rich sources of unsaturated fatty acids that are a favorite target for oxidative stress (Andersen 2004). Also, reduction of enzymatic and non-enzymatic components of antioxidants which leads to imbalance of oxidants have been observed in various neurological disorders such as depression, Alzheimer's, autism and Parkinson (Hassan, et al. 2014). A direct association has been established between increased oxidative stress in peripheral leukocytes, cerebellum, hippocampus, and cortex with the occurrence of anxiety-like behaviors (Bouayed, et al. 2007; Rammal, et al. 2008). According to the content, the use of agents with antioxidant and anti-inflammatory properties can be effective in improving the prognosis of depression.

In this study, Sulfur Dioxide (SO₂) donor salts, which increase endogenous SO₂, were used to treat depression according to previous studies (Lu, et al. 2012). SO₂ is a toxic gas and is known as one of the most important air pollutants that can have destructive effects on body tissues, especially the respiratory, cardiovascular and nervous systems (Rall 1974). The damaging role of SO2 is well known, but new studies have looked at the lesser-known beneficial effects of SO2 (Zare Mehrjerdi, et al. 2018). SO₂ is produced endogenously in the body by the metabolism of the amino acids cysteine and homocysteine in the presence of the enzyme aspartate aminotransferase, also SO₂ is produced from oxidation of H2S (Yang, et al. 2018; Zhang, et al. 2018). It is involved as a gas transmitter in the body's physiological processes. Several studies have shown the anti-inflammatory and antioxidant role of SO₂ in reducing ischemic heart and brain damage, atherosclerosis, hypertension, and pulmonary inflammation (Li, et al. 2018; Lu, et al. 2012; Yang, et al. 2018; Zare Mehrjerdi, et al. 2018).

Considering the antioxidant and anti-inflammatory effects of sulfur dioxide, the aim of this study was to investigate the possible role of sulfur dioxide in reducing injuries following unpredictable chronic mild stress.

Animals and experimental procedures

Adult male wistar rats (n=40) randomly divided into four groups. Sham group, CUMS group, CUMS + first dose of SO₂ (9 mg NaHSO₃ + 34 mg Na₂SO₃) group, CUMS + second dose of SO₂ (18 mg NaHSO₃ + 68 mg Na₂SO₃) group. (Na₂SO₃ and NaHSO₃ were used in 3: 1 molar ratio, PH 7.4). SO₂ donors were dissolved in 1CC saline and injected intraperitoneally to five animals daily. The animals were maintained during the experimental period, except stress days, in standard conditions of 12h / 12h circadian rhythm, temperature of 22-25 ° C and free access to water and food.

This study was approved by the Ethics Committee of Yazd Shahid Sadoughi University of Medical Sciences which is accordance with the Guide for the Care and Use of Laboratory Animals from the USA National Institutes of Health with ethical code: IR.SSU.MEDICINE.REC.1399.008

To induce the CUMS model, the animals randomly exposed to one of the following stressors for 35 days: Food or water deprivation for 24 hours, continuous lighting, placing the animal on a 45-degree slope for 2 hours, placing the animal on the shaker for 20 minutes so that one shake given per second, keep the animal in a wet cage for 24 hours. Swim in cold water 25º C for 5 minutes, enclose the animal in the restrainer for 1 hour (Gáll, et al. 2020; Koprdova, et al. 2016).

Depressive-like behaviors in animals was measured during the experiment. The animals anesthetized deeply with ketamine and xylocaine at the end of the experiment. Blood sample was taken from the heart of animals to determine blood corticosterone level. After deep anesthesia and cardiac perfusion, the brains of four animals from each group were completely isolated and placed in a fixative solution for histological examination. In other animals, after complete anesthesia, the hippocampus were carefully isolated from the surrounding tissues to evaluate the activity of antioxidants and the amount of MDA.

Sucrose preference test

The sucrose preference test is based on the natural preference of rodents for sweets and is one of the standard tests to assess depression in rats. After a period of water deprivation for 24 hours, each rat had free access to two bottles for 1 hour, one containing 1% sucrose solution and the other containing pure water. Each bottle was weighed before and after the animal had access to water. The ratio of sucrose preference was calculated as the percentage of sucrose consumption to pure water + sucrose consumption (Gáll, et al. 2020; Koprdova, et al. 2016).

Forced Swimming Test (FST)

This test is one of the most common tests to evaluate depressive-like behaviors. The animal was placed in a cylindrical swimming tank made of Plexiglas, 50 cm high and 25 cm thick, filled to 30 cm depth with 25º C water. This test was performed on two consecutive days. On the first day which was pretest, the animal was left in the swimming pool for 15 minutes. Twenty-four hours later, after leaving the animal in the tank, the animal's behavior was observed for six minutes by a camera on the roof of the room. The duration of immobility in the last 4 minutes of the test was assessed. The immobility of the animal's limbs and its floating was considered as immobility behavior and this time was considered as immobility time (Koprdova, et al. 2016).

Open field test (OFT)

OFT is used for behavioral studies, motor deficits, anxiety, and depression in laboratory research. The open environment is a glass compartment with dimensions of 60 x 80 x 80 cm, divided into 25 equal squares and placed in the middle of a quiet room. The animal was placed in the experimental room one hour before the experiment. On the first day of the test, in order to acquaint the animals with the device, they were placed separately in the open field device for 10 minutes. Twenty-four hours later, each rat was placed in the square in the center of the open field, and the camera monitored the animal's behavior for 10 minutes. The number of crossing lines was considered an indicator of spontaneous movement, and the number of standing on two legs was considered an indicator of exploratory movements (Gáll, et al. 2020; Koprdova, et al. 2016).

Morris water maze Test

In this study, the Morris water maze was used to assess the spatial learning and memory of the animals. The maze includes a circular metal pool with a diameter of 150 cm and a height of 60 cm which is divided into four hypothetical quarters and was filled with water up to a height of 40 cm. A circular platform made of colorless plastic (10 cm in diameter and 27 cm high) was placed between the center and the wall in the southeast quarter (target quarter). The maze was placed in a quiet room and geometrical extra cues were installed in all four directions of the maze to identify the spatial position of the place by the animals. Animals in the first four days of the test were randomly released into the maze from four directions separately after a 5-minutes break between each trial. Time elapsed, and the distance traveled to reach the platform in each trial was tracked by a camera at the top of the maze and recorded by video tracking software.

After 24 hours, the platform came out of the maze and again, four trials were performed for each animal, and the elapsed time and distance traveled in the target quarter were tracked and recorded by video tracking software (Zare Mehrjerdi, et al. 2020).

Biochemical factors of the hippocampus

After deep anesthesia, the brains of six animals from each group carefully removed and the hippocampus was separated from the surrounding tissues and immediately exposed to -80° C, at the right time, 1cc of PBS solution added to 100 mg of hippocampal tissue and the sample was homogenized and then centrifuged at 6000 rpm for 10 minutes. The supernatant was separated from suspension and the activity of enzymes and the amount of MDA was measured based on the kits protocols.

Malondialdehyde (MDA) of the hippocampus

MDA is an indicator of lipid peroxidation. The basis of MDA testing is the binding of thiobarbituric acid (TBA) to it and the formation of a pigment. This study prepared eight standard solutions with a certain concentration to evaluate the MDA following the kit protocol (Zelbio, Como, Italy). After adding 50 μl of thiobarbituric acid solution to the standard vials and samples, 1 ml of chromogen solution was added. All vials were placed at boiling temperature for one hour, after which, the samples were incubated at 0 ° C for 30 minutes, then, the samples were centrifuged at 0 ° C at 4000 rpm for 10 minutes. Finally, the samples' optical density (OD) was read at 535 nm and the concentration of MDA was calculated according to the standard diagram (Zare Mehrjerdi, et al. 2020).

Glutathione peroxidase (GPX) and Catalase (CAT) enzymes Activity

Glutathione peroxidase (GPX) activity assessment was performed following Zelbio's kit. Three series of microtubules were prepared to measure GPX. The first series consisted of tissue serum samples with reagents according to the kit's protocol, and the second series consisted of blanks containing odd-water with reagents, and the third series, control samples containing only reagents. All microtubules were heated at 37 ° C for 5 minutes. Then, by adding reagent 6 to the microtubules, the samples were centrifuged and poured into microplate wells. Finally, after adding reagent 7th, the OD of the samples at 412 wavelengths was read by an ELISA reader.

To measure Catalase (CAT) activity, hippocampus homogenized samples were first added to the microplate wells. According to the kit protocol, normal saline was considered blank. 100 μl of assay buffer and 10 μl of H2O2 reagent were added to the wells and incubated at 37 ° C for one minute. Finally, after adding chromogen and diluent solution, the OD of the samples at 405 nm was read by an ELISA reader. The following formula was used to measure catalase activity (Zare Mehrjerdi, et al. 2020).

Catalase activity (U/ml ) = ( ODblank - ODsample ) * 271 * ( 1.6 *sample volume )

Serum corticosterone

Corticosterone level was measured by an ELISA kit (Zelbio, Com, Italy), in which two monoclonal antibodies were used against two separate antigen sites on the corticosterone molecule. The procedure was that 20 μl of each standard serum sample (7 concentrations of l-240 nmol) was poured into separate wells, and 200 μl of the conjugated enzyme was added to all of them incubated at room temperature for 60 minutes. The wells were rinsed three times with buffer solution, and 100 μl of substrate solvent was added to all wells. Then 50 μl of stop solution was added to all plate wells, and finally, the OD of the samples was read at 450 nm, and the amount of corticosterone was calculated according to the standard diagram.

Histological studies

From each group, four animal were perfused transcardially with 10% Formalin solution after deep anesthesia. The animals' brains were carefully removed and placed in a fixative solution for 48 hours. Paraffin embedding was performed with a tissue processor according to the following steps: dehydration with ascending alcohols, clarification with Xylen, and impregnation with paraffin. Following the molding of samples, the coronal 5-μ sections were obtained by microtome in sections at a distance of 2.7 mm from the Bregma. The sections were in three cross-sections at a distance of 25 μm (Zare Mehrjerdi, et al. 2020). The sections were transferred onto an albumin-coated glass slide to explore the cell density and necrosis in the CA1 region of the hippocampus after H&E staining. To evaluate cell density, the number of healthy cells in the CA1 region of the hippocampus was counted using image J software. Small, scalloped and swollen neurons with small nuclei are considered as necrotic cells .

Statistical data analysis

The data obtained from this study were analyzed using GraphPad Prism version 8. Data on animal weight, sucrose consumption and spatial learning were analyzed by two-way analysis of variance followed by Bonferroni post hoc test, and the rest of the data were analyzed by one-way analysis of variance followed by Tukey post hoc test. Differences with p≤0.05 were considered as a significant levels.

Animal weight

The weight of the animals was measured every week. On days 21 and 35, a significant decrease in the weight of depressed animals was observed (Fig. 1, P≤ 0.05). SO₂ donors did not affect the weight of depressed animals

Depression-Like Behaviors:

Sucrose preference test

Sucrose preference was similar between groups at the first day of this test (day 26), but the CUMS group appeared a marked reduction in the sucrose preference on days 27, 28, 29 compared with the sham group (Fig. 2A, P≤ 0.05). A significant increase in the average consumption of sucrose observed in the CUMS groups treated with the both dose of SO₂ on days 27, 29 (P≤ 0.05 and P≤ 0.01).

Forced swimming test

In the forced swimming test, the duration of immobility in the CUMS group was significantly increased compared to the sham group (Fig. 2B, P≤ 0.01). In both stress groups treated with the first and second dose of SO₂, a significant decrease in the mean duration of immobility was observed (Fig. 2B, P≤ 0.05 ).

Open field test

The results showed that CUMS has affected the movement indices so that during the six minutes of this test, the number of crossings from the center to the environment and vice versa (Fig. 2C) and the number of times standing on the legs (rearing) (Fig. 2D) in the CUMS group was significantly decreased compared to the sham group (P≤0.01). The normal levels of these open-field parameters were retrieved in the CUMS groups treated with SO₂. (Fig. 2C and 2D, P≤0.05 and P≤0.01).

Morris Water Waze Test

To determine the effect of SO₂ on spatial learning and memory, rats were subjected to the morris water maze task. The CUMS group exhibited a decrease in learning progress as latency in reaching the platform on day 4 (Fig. 3A, P≤0.05) and increase in distatance to reach the platform on days 3 and 4 (Fig. 3B, P≤0.01 and P≤0.01).

The time and distance in reaching the platform decreased in the In CUMS groups treated with sulf SO₂ donors (Fig. 3A and 3B, P≤0.05, P≤0.01 and P≤0.001).

Distance and time spent in the target quarter on the last day of the water maze examination were compared to evaluate spatial memory. In the study of time spent and traveling distance in the target quadrant, A significant decrease was seen in the CUMS group in comparision to the sham group (Fig. 3C and 3D, P≤0.05) which increased in the depressed SO2-treated groups (Fig. 3C and 3D, P≤0.05).

MDA and CAT and GPX activity in hippocampal tissue

The level of hippocampal MDA in CUMS group increased significantly compared to the sham group (Fig. 4A, P≤0.01). In both CUMS groups receiving SO₂ donors, MDA levels was significantly decreased (Fig. 4A, P≤0.05). As shown in Fig. 4B and 4C, No significant changes were observed in glutathione and catalase activity among groups.

Serum corticosterone levels

The results of serum corticosterone measurement in CUMS rats indicate a significant increase in serum corticosterone compared to sham group (Fig. 5, P≤0.05). A significant decrease in corticosterone levels was observed in the treatment group with the first dose of SO₂ compared to the CUMS group (Fig. 5, P≤0.05). The second dose of SO₂ donors had no significant effect on serum corticosterone.

Histological studies

As shown in Fig 6A, The density of healthy cells in the CA1 subregion of the hippocampus of CUMS rats was significantly decreased (Fig. 6A, P≤0.05). The number of healthy cells in the CUMS groups treated with SO₂ did not show a significant change compared to the CUMS group. Also, the number of necrotic cells in the CA1 region of the CUMS group was significantly higher than in the sham group (Fig. 6B, P≤0.01). It was revealed that CUMS rats receiving the first dose of SO₂ exhibited a significant reduction in the number of necrotic cells (Fig. 6B, P≤0.05).

Depression is one of the most common diseases in the world, which has led many experts to study it in order to identify the main symptoms, effective factors, and ways to treat depression. Multiple studies have shown that there is a close relationship between depression and stress and anxiety, and those who have a background of stress and anxiety are more susceptible to depression, and sometimes stress is a factor that facilitates the occurrence of depression (Antoniuk, et al. 2019). One of the most common models of depression to study the behavioral and molecular effects of this disorder is the application of chronic unpredictable mild stress (CUMS) model. In this model, rodents are chronically exposed to multiple stressors which are unpredictable and pose no threat to their survival. This method is compatible with the causes of depressive in humans.

The chronic stress model was used to induce depression in the present study. The effect of SO2 on depression was also considered. During and after the stress induction, the animals underwent weight measurement, behavioral tests of sucrose preference, forced swimming, open field, Morris water maze, and oxidative changes in the hippocampus and serum corticosterone levels.

The effect of CUMS on behavioral studies and oxidative changes in the hippocampus

This study showed that CUMS reduces the consumption of sucrose, increases immobility, decreases movement in open field testing, and impairs the learning and spatial memory of animals. Necrotic hippocampal damage was also observed in stressed animals. Examination of the hippocampal oxidative factors in stressed mice also showed an increase in MDA as an indicator of lipid peroxidation, but did not alter the activity of the CAT and GPX enzymes in the hippocampus in the CUMS group. Serum corticosterone levels also increased in the CUMS group.

During chronic stress, a variety of damaging factors, including oxidative stress, can cause irreversible damage to the nervous system.Previous studies have shown that during chronic stress, the amount of free radicals such as superoxide (O₂^-), hydroxyl (OH^-), and hydrogen peroxide (H₂O₂) increases in several regions of the brain especially the hippocampus which leads to peroxidation of cellular components, especially membrane lipids and proteins, as well as reducing the level of antioxidant enzymes. Lipid peroxidation reduces the lifespan of neurons, affects the release of neurotransmitters and it is recognized as one of the main factors in the loss of cellular function in depression. The hippocampus, which plays an important role in controlling cognitive activity and behavior, is the main target of the escalating effects of oxidative stress.Hippocampus is a brain region that may be related to the pathogenesis of depression-like symptoms. Even mild CUMS intensities lead to increased depressive and anxiety-like behaviors and decreased hippocampal neurogenesis. CUMS reduces the proliferation of neuronal stem cells (NSCs) in the hippocampus as well as the survival of newly formed neurons in the hippocampus, which is likely to contribute to hippocampal atrophy (Bajpai, et al. 2014; Şahin and Gümüşlü 2004; Vaváková, et al. 2015). In addition to the prominent role of oxidative stress in the pathology of depression, during severe depressive disorders, the activity of the hypothalamic, pituitary, adrenal axis increases, resulting in increased corticosterone levels in rodents and increased cortisol levels in humans (Huang, et al. 2011; Lee, et al. 2015). Due to the high density of glucocorticoid receptors in the hippocampus, this area is one of the areas sensitive to increased glucocorticoids. Glucocorticoids increase the chance of dendritic atrophy and reduces synaptic connections. In the long term, even the amount of neurotransmitters and the density and activity of their receptors will be affected. Finally, dysfunction of the hippocampus can cause changes in cognitive activity (Huang, et al. 2011; Lee, et al. 2015). These findings are consistent with the findings of the present study that elevated serum corticosterone may play an important role in cognitive and emotional changes following chronic stress.

In addition to the pathogenesis factors of depression that have been investigated in this study and mentioned above, many inflammatory mediators, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), are present in depressed animal models, the same as in depressed patients (Fan, et al. 2017). Administration of inflammatory mediators such as IL-1β, IL-6, TNF-α, and lipopolysaccharide can cause depressive-like behaviors in animal models (Sulakhiya, et al. 2016).

Nerve growth factors, especially BDNF and NGF, are also important in the pathophysiology of depression (Jesse, et al. 2015). BDNF expression, an important neurological factor is regulated by neural activity. In depressed animal models, a decrease in BDNF has been observed in the neocortex and hippocampus, which may be related to the several neurological dysfunction including dysregulation of synaptic plasticity and neurogenesis (Grønli, et al. 2006; Jesse, et al. 2015).

The brain cholinergic system is also significant in finding the cause of psychological disorders such as depression. The hippocampus has many cholinergic inputs that can affect cognitive functions related to this area. Many recent studies have suggested that increasing the function of the cholinergic system by inhibiting cholinesterase enzyme or the use of cholinergic agonists may be effective in increasing depressive-like behaviors (Dulawa and Janowsky 2019).

The effects of SO₂ donors on disorders caused by CUMS

The results of the present study showed that sulfur dioxide donors improve depressive-like behaviors and cognitive disorders in the CUMS animals. Biochemical and histological examination also showed that lipid peroxidation and tissue damage of the hippocampus and serum corticosterone levels of depressed animals can be reduced by prescribing of SO₂ donors.

SO₂ is widely known as an air pollutant that have destructive effects on various parts of the body especially, the lungs and cardiovascular system. SO₂ as an oxidative agent can cause lipid peroxidation and change the status of antioxidants in various organs, but in recent years, Extensive evidence has shown that sulfur dioxide has many physiological activities, especially in the cardiovascular system. So2 is mostly produced endogenously following the oxidation of sulfur-containing amino acids by the aspartate aminotransferase (AAT). Disruption of the SO₂ / AAT pathway in the cardiovascular system has been associated with hypertension, atherosclerosis, the proliferation of vascular smooth muscle cells, and increased extracellular collagen, leading to vascular dysfunction (Huang, et al. 2016; Wang and Wang 2018).

The results of several studies conducted in recent years show that SO₂ donors have protective effects on various disorders by reducing oxidative stress and inflammatory factors, which are consistent with the results of the present study. In 2011, LIANG et al found that SO₂ could protect the myocardium against isoproterenol-induced damage by increasing its antioxidant capacity (Liang, et al. 2011). In a model of acute lung injury caused by oleic acid, a decrease in the amount of SO₂ in lung tissue was observed, which led to an increase in inflammatory factors such as NF-κB p65, and SO₂ donors were able to reduce inflammatory factors. In the investigation of oxidative stress and apoptosis in the same model of lung damage, it was also observed that SO₂donors reduce O^- and OH^- radicals generated by oleic acid and increase lung tissue's antioxidant capacity (Chen, et al. 2017; Chen, et al. 2015). In a D-gal-induced aging model, SO₂ donors also reduced endothelial dysfunction by reducing oxidative stress and AT1R (Dai, et al. 2018). In two studies performed on temporary and chronic cerebral, SO₂ donors was able to increase the activity of antioxidants, which was accompanied by a decrease in lipid peroxidation. In tissue studies. In histological studies, sulfur dioxide donors reduced the death of hippocampal pyramidal neurons in the form of apoptosis and necrosis during ischemia, which ultimately led to improvement in the cognitive activities of animals (Ghasemi, et al. 2020; Zare Mehrjerdi, et al. 2018). Even in a clinical study performed on children with congenital heart failure, it was found that serum SO₂ levels were inversely related to the prevalence of pulmonary hypertension in these children. Serum SO₂ levels in children with pulmonary hypertension were half those of children who did not have pulmonary hypertension despite heart failure (Yang, et al. 2014).

In general, the results of the present study suggest that sulfur dioxide donors may have been effective in improving anxiety-like behaviors and cognitive impairment in depressed animals by reducing oxidative stress as well as lowering corticosterone, which is an indicator of stress in the blood.

Acknowledge

The information included in this article is extracted from the thesis of Mrs mahdieh salari, a master´s student in medical physiology.

Author Contribution statement

All authors have actively participated in this project. F.Z, and M.S. participated in designing, collecting and analyzing data and writing the article. Other authors contributed to the data collection and review of the article. All authors read and approved the final manuscript.

Funding Information This research was supported by the international campus of Shahid Sadoughi University of Medical Science and Health Services. The results presented in this article are the result of research project No. 7932

Consent for publication All the authors were aware of all stages of this project and the article has been prepared with the full consent and participation of all the authors.

Ethics approval All stages of work in this study were approved by Ethics Committee of Yazd University of Medical Sciences which is accordance with the US National Institutes of Health Publication guide for the care and use of laboratory animals with ethical code: IR.SSU.MEDICINE.REC.1399.008.

Conflict of Interest The authors declare that there are no conflicts of interest.

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No competing interests reported.

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Antidepressant Like Effect of Endogenous SO 2 on Depression Caused by Chronic Unpredictable Mild Stress

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