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2008 SURI Intern Year: Junior Research Project Oxidative stress is due to an imbalance in the formation of free radicals and the consumption of these free radicals by antioxidants. Several neuropsychiatric disorders including Alzheimer's Disease and depression have been experimentally linked to oxidative stress. One of the consequences of the presence of oxidative stress is apoptosis in the brain. In regards to depression, previous research (Sarandol et al., 2007) has shown that major depressive disorder is accompanied with both oxidative stress as well as apoptosis. However, current use of short-term (6 weeks) antidepressant treatment with generic drugs such as, Effexor XR, Edronax and Serta did not significantly alter the oxidative-antioxidative system. Additionally, a previous study (Masood et al., 2008) has shown that oxidative stress can induce anxiety-like behavior in mice, which could be reversed by using a PDE-2 inhibitor. This reversal is most likely achieved through an increase in cGMP signaling. For the purpose of this study, a PDE2 inhibitor will be used to evaluate the effects of oxidative stress and oxidative stress induced apoptosis, which could present a novel pharmacological approach to treat depression. This study will be looking at both animal behavior models using mice and cell cultures from rat pups. Mice will be separated into different treatment groups. For control groups saline or PDE2 inhibitor Bay 60-7550 at 3mg/kg, i.p. will be administered to mice. For the other treatment groups, mice will be subjected to 10 days of unpredictable stress. Two different stressors will be used each day which include, restraint (1h), forced swim (4 min), food/water deprivation (overnight), cold environment (15min), cage tilt (2h) and lastly light/dark cycle manipulation. The types of stressors used each day have to be different from the stressors used the day before. 24 hours after the completion of the stress procedures mice will be tested on different models of depression and anxiety which include Tail suspension test, elevated plus maze test, and the hole-board test. Following behavioral testing, the hippocampus and amygdala will be dissected and stored at -80°C until biochemical and molecular analyses will be carried out. For an additional perspective on the treatments, cell cultures will be prepared using the cortices of newborn rat pups. Once the cell cultures have been prepared they will be evenly distributed into different treatment groups and a control group. The drug treatments for the cell cultures include Staurosporine, an inducer of apoptotic cell death, Bay 60-7550, KT-5823, a PKG inhibitor, H-89, a PKA inhibitor and KT-5720, a PKA inhibitor. The treatment groups will all have staurosporine present and will be treated with one of the inhibitor drugs in combination with Bay 60-7550. In addition, one group will have only staurosporine applied and another group will contain Bay 60-7550 with staurosporine and no inhibitor in order to see how each of these drugs individually affects the cells. These cell cultures will provide us with an opportunity to evaluate the effects of different drug treatments on different biochemical parameters. Using the cell cultures it will be possible to obtain results by using assays such as protein assays, LDH assay, cGMP assay and caspase-3/9 activity assay.
Masood A, Nadeem A, Mustafa SJ, O'Donnell JM. Reversal of oxidative stress-induced anxiety by inhibition of phosphodiesterase-2 in mice. Journal of Pharmacology and Experimental Therapeutics (2008, in press). Sarandol A, Sarandol E, Eker SS, Erdinc S, Vatansever E, Kirli S. Major depressive disorder is accompanied with oxidative stress: short-term antidepressant treatment does not alter oxidative-antioxidative systems. Human Psychopharmacology (2007) 22(2):67-73.
Click here to review the summary report of this project. |
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