Abstract
Depression is one of the most common psychiatric disorders. Recently, studies demonstrate that antidepressants generating BDNF not only maintain synaptic signal transmission but also repress neuroinflammatory cytokines such as IL-6 and IL-1β. Therefore, promoting BDNF expression provides a strategy for the treatment of depression. Our recent research has indicated that programmed cell death 4 (Pdcd4) is a new target for antidepressant treatment by facilitating BDNF. Herein, we modified Pdcd4 specific small interfering RNA (siPdcd4) with the rabies virus glycoprotein peptide (RVG/siPdcd4) which enables it cross the blood-brain barrier (BBB). We found that RVG/siPdcd4 complex was selectively delivered to neurons and microglia and silenced the expression of Pdcd4, thereby up-regulating the level of BDNF and down-regulating IL-6 and IL-1β expression. More importantly, RVG/siPdcd4 injection attenuated synaptic plasticity impairment and protected mice from CRS-induced depressive behavior. These findings suggest that RVG/siPdcd4 complex is a potential therapeutic medicine for depression.
Highlights
Major depressive disorder (MDD) is one of the most common psychiatric disorders and causes a leading disease burden [1]
programmed cell death 4 (Pdcd4) Small interfering RNA (siRNA) upregulates brain-derived neurotrophic factors (BDNF) expression and suppresses inflammatory response in cells of nerve system Our recent research found that Pdcd4 is an endogenous suppressor of BDNF, meaning that silencing Pdcd4 will increase the expression of BDNF in nerve cells [15]
Overexpression of Pdcd4 in mouse hippocampal neuron cell line HT-22 significantly decreased the expression of BDNF, while knocking-down of Pdcd4 by siPdcd4 increased the expression of BDNF which detected by western blot and Enzyme-Linked Immunosorbent Assay (ELISA) (Fig. 1b, c)
Summary
Major depressive disorder (MDD) is one of the most common psychiatric disorders and causes a leading disease burden [1]. There is evidence that the dysfunction or mutation of BDNF gene leads to susceptibility to environment stress, while BDNF recombinant protein injection corrects mice depressive behaviors which are caused by chronic stress [4,5,6,7]. The pro-inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in peripheral and central nervous system are significantly increased in patients with depression [11] These studies suggest that the combination of promoting BDNF expression in depressive patients and inhibiting proinflammation plays a critical role in antidepressant development. Designing a method to target the molecule which plays a key role in BDNF expression and neuroinflammation is highly desirable
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