Antidepressant mechanisms of ketamine’s action: NF-κB in the spotlight

Ketamine recently approved for therapy of treatment-resistant depression shows a complex and not fully understood mechanism of action. Apart from its classical glutamatergic N-methyl-D-aspartate receptor antagonistic action, it is thought that anti-inflammatory properties of the drug are of clinical relevance due to the contribution of activated inflammatory mediators to the pathophysiology of depression and non-responsiveness of a group of patients to current antidepressant therapies. In a search of the mechanism underlying anti-inflammatory effects of ketamine, the nuclear factor kappa B transcription factor (NF-κB) has been proposed as a target for ketamine. The NF-κB forms precisely regulated protein signaling cascades enabling a rapid response to cellular stimuli. In the central nervous systems, NF-κB signaling appears to have pleiotropic but double-edged functions: on the one hand it participates in the regulation of processes that are crucial in the treatment of depression, such as neuroplasticity, neurogenesis or neuronal survival, on the other – in the activation of neuroinflammation and cell death. Ketamine has been found to reduce inflammation mediated by NF-κB, leading to decreased level of pro-inflammatory cytokines and other inflammatory or stress mediators. Therefore, this review presents recent data on the significance of the NF-κB cascade in the mechanism of ketamine’s action and its future perspectives in designing new strategies for the treatment of depression.