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

ABSTRACT

Aggregation of amyloid [Formula see text] protein (A[Formula see text] 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 neuroprotective 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[Formula see text] 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[Formula see text]mg/kg, i.p.), the average immobility time significantly decreased, from [Formula see text][Formula see text]s in A[Formula see text] group to [Formula see text][Formula see text]s in A[Formula see text] plus desipramine group ([Formula see text]) in TST and from [Formula see text][Formula see text]s to [Formula see text][Formula see text]s ([Formula see text] or 9, [Formula see text]) in forced swimming test, respectively;the mean error times of mice in Y maze test also significantly decreased, from [Formula see text] in A[Formula see text] group to [Formula see text] in A[Formula see text] plus desipramine group ([Formula see text], [Formula see text]); (3) desipramine administration significantly prevented against A[Formula see text]-induced down-regulation of phosphorylated cAMP response element binding protein (p-CREB) in the hippocampus. These results indicate that A[Formula see text] could concurrently mimic the depression-like behavior and working memory disorder in mice, while desipramine could effectively reverse both the deficits induced by A[Formula see text]. The neuroprotection of desipramine may be involved in the up-regulation of p-CREB level in the hippocampus of mice.