Escitalopram Can Ameliorate Cognitive Dysfunction In Rats Caused By Chronic Unpredicted Stress

Background and Objective:Alzheimer's disease is the most common type of dementia, characterized by cognitive dysfunction and psychiatric symptom. Pathological markers are the deposition of amyloid P-protein and neurofibrillary tangles (NFTs). Clinical data show that the stress of lifestyle or mental illness (depression) is a risk factor for AD. Escitalopram is selective serotonin reuptake inhibitors (SSRI), which can enhance the serotonin function in central nervous system. The purpose of this paper is to study the effect of stress on the cognitive function of rats and whether escitalopram can ameliorate cognitive dysfunction in rats, and investigate the mechanism of cognitive improvement induced by escitalopram.Methods:Experimental groups:normal Control+saline group (Control), depression +saline group (CUSA), depression+drug group (CUSA+E) and non-depression+ saline group (CUSR) and non-depression+drug group (CUSR+E). Two-month-old male SD rats were receivied chronic unpredictable stress (CUS:including 1 min clip tail, ice water swim 5 min, constraint 1 h, night lighting, ban drink bound fast 24 h, oblique cage 12 h, wet cage 18 h). After a month of CUS, Sucrose intake test and Forced swimming test were evaluated. The rats showed anhedonia were assigned to stress susceptibility (CUSA), the rest of the stressed animals were considered to be non-anhedonic or resistant to stress (CUSR). Escitalopram or saline was administered daily during the next month of CUS. On the last week of CUS, five groups of rats were evaluated the Sucrose intake test?Forced swimming test and Morris water maze. Then the rats were killed between 08:00min and 10:00min. Brains, blood and adrenal were removed and frozen until stress, cognitive related indicators determined by Western blot and Elisa experimental technology.Results:Firs, after a month of CUS,59% rats showed significant decrease of Sucrose intake and increased immobility time of forced swimming, assigning to CUS A group; the remaining 41% rats had no difference with the Control, assigning to CUSR group. Second, after two month of CUS, compared with Control group, only CUSA rats displayed a significant decrease of Sucrose intake and increase in the immobility time in the forced swimming test, consistent with increased depression-like behavior. This effect was reversed by Escitalopram. There was no significant difference between Control and CUSR group. Third, Compared with the Control, CUSA and CUSR rats showed spatial learning and memory impairment, as determined by the significant increase in the time of escape latency and reduced time in the platform quadrant. Compared with the Control group, CUSA and CUSR rats had significantly higher plasma corticosterone (CORT) and the hippocampus levels of total Tau and p-Tau; Notably, Escitalopram reduced stress levels in rats and ameliorated the spatial learning and memory impairment in MWM and Tau protein pathological changes in the hippocampus. Finally, compared with the Control, CUSA and CUSR rats had significantly lower level of p-GSK3?, which could be almost reversed by escitalopram.Conclusion:Our results demonstrated that escitalopram depressed the level of CORT which negatively regulated GSK3? and ameliorated Tau hyperphosphorylation and spatial learning and memory dysfunction induced by CUS.