Evaluation of COX-2 as a new target for antidepressant treatment in mice

Abstract

Numerous studies have proposed a link between psychiatric disorders and inflammation. Cyclooxygenase-2 (COX-2) and its reaction products are important messengers in the central nervous system that participate in brain functions, such as inflammation, signal transduction, synaptic plasticity and memory consolidation. Furthermore, COX-2 has been found to be markedly upregulated in neuropsychiatric disorders, including depression. A functional hyperactivity of the COX-2 pathway is suggested to contribute to the pathogenesis of depressive disorders and beneficial effects of co-treatment with a selective COX-2 inhibitor have been demonstrated in a human study. The purpose of the present study was to evaluate COX-2 as a new target for antidepressant treatment. Therefore, the influence of acute and chronic oral treatment with a selective COX-2 inhibitor, rofecoxib, on behaviour of DBA/2JOla (DBA) mice was investigated in different test paradigms. Additionally, different biochemical parameters were investigated to enlighten a possible pathway of its antidepressant effects. In animal studies, the forced swimming test is the most frequently used test paradigm for antidepressant treatment effects. Oral administration of rofecoxib had antidepressant effects, as it decreased passive behaviour while active escape oriented behaviour was increased. The expression level of COX-2 in the hippocampus after chronic oral treatment with rofecoxib was significantly reduced. Furthermore, protein levels of brain-derived-neurotophin-factor (BDNF), a possible biomarker for antidepressant treatment effects were assessed. Neither acute nor chronic treatment with rofecoxib altered expression levels of BDNF, indicating that the mode of antidepressant action of COX-2 inhibitors might be different from existing antidepressant compounds. Major depression has been associated with hypothalamus-pituitary-adrenal (HPA) dysregulation, which might be a consequence of impaired functioning of the GR receptor. In the present study, it could be shown that acute and chronic oral treatment with the selective COX-2 inhibitor rofecoxib increased GR mRNA expression levels in the hippocampus of DBA mice. Taken together, the results of the present study point towards the potential use of COX-2 inhibitors as stand-alone therapy in depression. We could show antidepressant effects as well as positive effects on HPA regulatory elements. In combination with published findings, this allows to position COX-2 in a network considered to be of high importance in the understanding of neurobiological mechanisms underlying depression.