Future Antidepressant Targets: Neurotrophic Factors and Related Signaling Cascades

Abstract

Preclinical and clinical studies demonstrate that neurotrophic factors play critical roles in the etiology and treatment of depression. While the mechanisms underlying the therapeutic efficacy of antidepressants remain unknown, increasing evidence supports a role for increased trophic support in the treatment of depression. Furthermore, antidepressants block or reverse stress-induced down regulation of neurotrophic factor expression in limbic and cortical nuclei involved in the underlying pathophysiology of depression. Thus, components of neurotrophic factor-mediated signaling cascades or the signal transduction pathways that regulate neurotrophic factor expression may provide additional targets for the development of novel, more efficacious antidepressant drugs.

Figure 1. Neurotrophic/growth factor expression, neurogenesis and depressive-like behaviors are differentially regulated by antidepressants and exposure to stress

Exposure to chronic stress decreases expression of trophic factors including BDNF, VEGF and NGF in the dentate gyrus, increases expression of the inflammatory cytokine IL-1β, and decreases neurogenesis in the dentate gyrus. In contrast, chronic antidepressant administration increases expression of trophic factors including BDFN, VEGF, NGF, IGF-1 and FGF-2 in the dentate gyrus and increases neurogenesis. Furthermore, chronic antidepressant administration reverses or blocks stress-induced downregulation of trophic factor expression and neurogenesis. Neurotrophic/growth factors may have differential effects on stages of adult hippocampal neurogenesis. Increased expression of VEGF, IGF-1 and FGF-2 in the dentate gyrus result in increased rates of proliferation of neural progenitor cells in the subganular zone. Moreover, increased expression of BDNF and NGF in the dentate gyrus result in increased survival and maturation of newborn neurons. Chronic antidepressant administration produces neurogenesis-dependent and neurogenesis-independent behavioral responses that coincide with increased expression of trophic factors. ADT, antidepressant; BDNF, brain-derived neurotrophic factor; FGF-2, fibroblast growth factor 2; GCL, granule cell layer; IGF-1; insulin-like growth factor 1; IL-1β, interleukin-1β; NGF, nerve growth factor; SGZ, subgranular zone; VEGF, vascular endothelial growth factor;