Melatonin attenuates dexamethasone-induced spatial memory impairment and dexamethasone-induced reduction of synaptic protein expressions in the mouse brain

Chronic stress or prolonged exposure to high levels of glucocorticoid induces neuropathological alterations, such as dendritic atrophy of hippocampal or cortical neurons. The chronic administration of high doses of dexamethasone (DEX), a synthetic glucocorticoid receptor agonist, impairs long-term memory and motor coordination, reduces body weight and induces mortality in mice. DEX is typically administered clinically for a prolonged period. Therefore, we are interested in studying the mechanism by which chronic DEX administration affects cognitive function. In this study, we attempted to explore whether chronic DEX administration alters the process of memory formation and to determine the mechanism underlying the detrimental effect of DEX. The results showed that mice treated with DEX for 21 consecutive days had significantly impaired spatial memory in the Morris Water Maze task. Mice treated with DEX had prolonged water maze performance latencies and spent less time in the target quadrant compared to the control group. Furthermore, DEX reduced brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartate (NMDA) receptor subunit (NR2A/B), calcium/calmodulin-dependent protein kinase II (CaMKII) in both the prefrontal cortex and hippocampus and synaptophysin in the prefrontal cortex. We also investigated whether melatonin, a hormone synthesized in the pineal gland, could protect against DEX-induced changes in spatial memory and synaptic plasticity. The results showed that mice pretreated with melatonin prior to the DEX treatment had shorter escape latencies and remained in the target quadrant longer compared to the group only treated with DEX. Melatonin significantly prevented a DEX-induced reduction in the expression of NR2A/B, BDNF, CaMKII and synaptophysin. The results from the present study demonstrate that melatonin pretreatment prevents cognitive impairment caused by DEX. However, the precise mechanism by which melatonin affects cognitive function requires further investigation. (C) 2013 Elsevier Ltd. All rights reserved.