Behavioral Effects of Eritoran, a Toll-like receptor-4 antagonist, in an Experimental Model of Depression: Role of Prefrontal Cortex and Hippocampus Neurogenesis and GABA/Glutamate Balance

Abstract

Depression is one of the major psychiatric diseases. It is estimated to affect 13–17% of the population at some point during the lifetime of an individual. All antidepressants have been developed based on the monoaminergic deficit hypothesis of depression. These antidepressants immediately increase synaptic concentrations of norepinephrine and/or serotonin. However, in general, a latency period of several weeks elapses before the therapeutic effects of antidepressants are observed. Importantly, fewer than 50% of all patients with depression show full remission with optimized treatment, including trials on numerous medications with and without concurrent psychotherapy. Therefore, there remains a great need for the development of faster-acting, safer, and more effective compounds for depression treatment (Saitoh and Yamada, 2012). There is a pressing need to identify novel pathophysiological pathways relevant to depression that can help to reveal targets for the development of new medications.Recent years has shown that both depression and chronic stressors have been associated with activation of innate inflammatory/immune response (Garcia-Bueno et al., 2008; Miller et al., 2009). The brain monitors peripheral immune responses by several means acting in parallel (Dantzer et al., 2008): some involve locally produced cytokines or pro-inflammatory cytokine transporters at the BBB and cells surrounding the perivascular space; in another humoral pathway, Toll-like receptors (TLRs) on macrophage-like cells residing in the CNS respond to circulating pathogen components by producing pro-inflammatory cytokines and other pro-inflammatory mediators. Recently, several studies have focused on TLRs and their potential roles in neuropathology (Crack et al., 2007). The discovery that not only immune cells, but also neurons, astrocytes and resident microglia express a large majority of the already discovered ten TLRs has challenged the way neuroscience explains the role of the immune system in the brain and, as a result, the view of the brain as an immune privileged organ has been re-evaluated. TLRs are pattern recognition receptors. Recent experimental study demonstrated the TLR-4 signaling pathway becomes activated in brain cortex of rats exposed to an animal model of depression. This activation occurs with increased levels of inflammatory nuclear factor κB activation, upregulation of the pro-inflammatory cytokines e.g TNF-α, IL-6, IL-1β and of one of the main enzymatic sources of inflammatory and oxidative mediators, COX-2 and its product PGE2 thus causing a superinduction of neuro-inflammatory responses (Garate et al., 2011).