Brain-derived neurotrophic factor enhances the therapeutic effect of oleuropein in the lipopolysaccharide-induced models of depression

Major depressive disorder (MDD) is a heterogeneous disease, involving multiple mechanisms and factors, which commonly result in injury to the psychosocial function of the central nervous system, and even suicidality of patients. However, effective treatment for MDD is still lacking. Oleuropein is a newly discovered natural compound extracted from olive leaves, which has a strong antioxidative effect by reducing the production of reactive oxygen species (ROS). Oleuropein also reduces blood pressure in humans and experimental animals, and protects blood vessels. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, which supports the function of the central nervous system. BDNF plays an important role in the development of the nervous system via the regulation of cellular differentiation, survival neurogenesis and synaptic plasticity; therefore, we hypothesized that overexpression of BDNF might contribute to the therapeutic effect of oleuropein. Here, we first demonstrated that oleuropein reverses depressive-like behaviour and restores the inflammatory response in a mouse lipopolysaccharide (LPS) model of MDD. We further established a cell model of BDNF overexpression and inhibition in SH-SY5Y cells, and found that the concentration of intercellular calcium was increased after treatment with oleuropein combined with BDNF overexpression, which may be mediated by the BDNF-TrkB-CaMKII signalling pathway. In addition, we observed that the expression of neurotrophic factors, including epidermal growth factor (EGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), was increased, which may be mediated by inhibition of the RhoA-ROCK signalling pathway.