Desipramine improves depression-like behavior and working memory by up-regulating p-CREB in Alzheimer's disease associated mice

Aggregation of amyloid beta protein (A beta) and progressive loss of memory are the main characteristics of Alzheimer's disease (AD). It is noteworthy that approximately 40% of AD patients have depressive symptom. The close correlation between cognitive deficits and mental depression suggests a possibility that antidepression treatment might be beneficial to cognitive improvement in AD. The present study, by using tail-suspension test (TST), forced swimming, alternative electro-stimulus Y maze test and immunohistochemistry, examined the neuro-protective effects of desipramine, a newer generation tricyclic antidepressants (TCA), and investigated its possible molecular mechanism. The results showed that: (1) intra-hippocampal injection of A beta(1-42) induced depression-like behavior and associative learning deficits in mice, with an increased mean immobility time in tail-suspension and forced swimming test and an increased mean error times in Y maze test; (2) after treatment with desipramine (10 mg/kg, i.p.), the average immobility time significantly decreased, from 101.60 +/- 8.37 s in A beta(1-42) group to 57.7 +/- 9.31 s in A beta(1-42) plus desipramine group (n = 10; p < 0.05) in TST and from 184.70 +/- 6.52 s to 144.13 +/- 8.63 s (n = 8 or 9, p < 0.05) in forced swimming test, respectively; the mean error times of mice in Y maze test also significantly decreased, from 6.50 +/- 2.95 in A beta(1-4) group to 4.90 +/- 3.11 in A beta(1-4) plus desipramine group (n = 10, p < 0.05); (3) desipramine administration significantly prevented against A beta(1-4)-induced down-regulation of phosphorylated cAMP response element binding protein (p-CREB) in the hippocampus. These results indicate that A beta(1-4) could concurrently mimic the depression-like behavior and working memory disorder in mice, while desipramine could effectively reverse both the deficits induced by A beta(1-4). The neuroprotection of desipramine may be involved in the up-regulation of p-CREB level in the hippocampus of mice.