الفهرس 
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Abstract
Stress-induced depression is a common consequence of the stressful life events man experiencing every day. By 2030, it was expected to be the most prevalent mental disorder that has a negative impact on both individuals and society. Now, nearly 15% are diagnosed as depressed persons and this number is increasing drastically. chronic or persistent stress upregulates the HPA axis. This needs more energy production from mitochondria and as a result, large amount of reactive oxygen and nitrogen reactive species are produced. The antioxidant enzymes that scavenge these radicals fail to compensate for their overproduction resulting in stress-induced oxidative stress. Also, the upregulation of the HPA axis increases the neuroinflammation. The neuroinflammation along with the oxidative stress prompts neurotransmitters depletion, behavioral alteration, and eventually the onset of depression. Therefore, the inflammatory hypothesis or cytokine hypothesis for the pathophysiology of depression was postulated.
Chronic mild stress is a paradigm that mimics the way of developing stress-induced depression in humans. This model has proved its validity for testing, and screening new compounds with antidepressant activities, and elucidating their mechanism of action. A group of behavioral tests was designed to assess the anxiety-like behavior and depressive-like behavior and the effectiveness of the newly tested compounds in alleviating the behavioral alterations in comparison to a standard available antidepressant (venlafaxine). Moreover, the
monitoring of the bodyweight changes and anhedonic behavior gives more indication about the depressive/non-depressive status.
Enhancement of dietary diet with trace elements especially zinc is of crucial importance for mental health, emotional and cognitive functions. Currently available antidepressant drugs show delayed response, relapse, and adverse side effects on the subject health and pose environmental risks. Drug discovery should target multi mechanisms that lead to depression, especially neuroinflammation as it has a key role in modulating those mechanisms. Pumpkin seed oil was proved to have an anti-inflammatory impact in previous studies and despite the antidepressant effect of the whole seed consumption, there are no studies till now on the effect of pumpkin seed oil on depression. Therefore, this study aims to elucidate the impact of the treatment of chronic mild stress-induced depression in rats with pumpkin seed oil and zinc, shed a light on the neuroinflammatory role in the depression pathophysiology, and investigate the antidepressant activities of both pumpkin seed oil and zinc.
Eighty male rats (weighing " ~ "160 g) were assigned into eight groups in the present study. The 1st group was the control group. In the 2nd group (Venla), rats were treated orally and daily with venlafaxine (20 mg/kg) for 4 weeks. In the 3rd group (Zn), rats were treated with ZnSO4 (4 mg/kg) dissolved in water orally and daily for 4 weeks. The 4th group (PSO), rats were treated with 40 mg/kg pumpkin seed oil dissolved in 1% DMSO orally and daily for 4 weeks. The 5th group (CMS), rats were subjected to various stressors for 6 weeks. The 6th
group (CMS+Venla), rats were subjected to various stressors for 6 weeks, and they were treated orally and daily with Venlafaxine (20 mg/kg) from the 3rd week to the 6th week. The 7th group (CMS+Zn), rats were subjected to various stressors for 6 weeks, and they were treated with ZnSO4 orally and daily from the 3rd week to the 6th week. The 8th group (CMS+PSO), rats were subjected to various stressors for 6 weeks, and they were treated with PSO from the 3rd week to the 6th week.
The stressed rats were subjected to one/two stressor(s) daily as following: Sunday: swimming 45 °C for 5 min; Monday: cage tilting and wet bedding for 24h; Tuesday: shaking for 10 min; Wednesday: nip tail for one min and change pair housing; Thursday: swimming 4°C for 5 min; Friday: deprivation of food; Saturday: deprivation of water and light overnight.
During the experiment, the animals were monitored for body weight change, sucrose preference, and coat state score weekly. By the end of the experiment, the animals were assessed behaviorally by performing forced swimming test, tail suspension test, open field test, and novel cage test. Then the animals were decapitated, and the samples were collected (blood serum, brain cortex and hippocampus) and stored at -80°C for biochemical and molecular assessments.
In the CMS group, the experimental animals manifested depressive and anxiety-like behavior as the number of rearing was markedly diminished in both the novel cage test and the open field test (OPT). The immobility time was elevated drastically in the tail
The current study concluded that the administration of nutraceuticals such as zinc or pumpkin seed oil exerted their antidepressant activities through ameliorating the oxidative stress and neuroinflammation and providing the body with the essential substances which were deficient due to chronic mild stress condition. Current antidepressants develop pharmacodynamic tolerance, serotonin toxicity and high prevalence of relapse cases. Venlafaxine and the other available antidepressants have several side effects such as bipolar disorder, cirrhosis, kidney disease, heart disease, high blood pressure, high cholesterol, diabetes, narrow-angle glaucoma, thyroid disorder, seizures, bleeding, and low levels of sodium in the blood. Therefore, the nutraceutical and micronutrients which work on the inflammatory pathways provide new hope for developing more effective antidepressants. Further research is needed to elucidate the precise mechanisms implicated in ameliorating oxidative stress and neuroinflammation in depression treatment with pumpkin seed oil and zinc.