Antidepressant effect of ketamine : Regulation of MMP9 in corticosterone mouse model

Abstract

ABSTRACT : Over the past years, development of antidepressants targeting the monoamine system has been the approach to treat major depressive disorder (MDD). However, approximately 10-30% of patients do not respond adequately to conventional treatments, while others become treatment resistant. Thus, ongoing research on novel fast-acting antidepressants is a key area to understand the complex neurobiology of this disorder. Recent studies have indicated that ketamine, a methyl-D-aspartate receptor (NMDA) antagonist, is a promising fast-acting drug with sustained antidepressant effects. Moreover, human brain imaging and post-mortem studies of patients with depression have reported structural changes in the prefrontal cortex and hippocampus and increased plasma matrix metalloproteinases (MMPs) levels. Antidepressants are known to induce remodeling of these regions and this process occurs in the extracellular matrix (ECM) regulated by MMPs. Previous studies in the mouse corticosterone model of depression show increased matrix metallopeptidase-9 (MMP-9) protein levels in prefrontal cortex and hippocampus. Thus, we hypothesize that acute ketamine treatment may downregulate MMP-9 expression and function, as well as its endogenous substrates in the corticosterone model, in parallel to its antidepressant-like effect. In addition, experiments in primary hippocampal cell cultures would also contribute to unravel its effect. Current research suggests that a better understanding on the mechanisms that underlie the antidepressant effect of ketamine on the glutamatergic system and other signaling cascades, is essential to develop more efficient treatments. These results could help to find a novel brain biomarker that may be linked to the development of mood disorders and/or the antidepressant effect.