The role of TrkB signaling-mediated synaptic plasticity in the antidepressant properties of catalpol, the main active compound of Rehmannia glutinosa Libosch

Abstract

Ethnopharmacological relevance: Rehmannia glutinosa Libosch. (RGL) is a famous ethnic medicine contained in antidepressant Chinese medicine formulas and is traditionally clinically used for depression. We have recently confirmed that RGL enhanced synaptic plasticity in a mouse model of Chinese medical syndrome and that catalpol may be the representatively pharmacological component responsible for its improvement in synaptic plasticity and treatment of depression. Impaired synaptic plasticity is closely linked to major depression. Tyrosine kinase receptor B (TrkB) signaling has recently been discovered as a key pathway for synaptic plasticity improvement and antidepressant discovery. However, to date, it is unknown whether the target of catalpol to improve synaptic plasticity involves TrkB and whether its antidepressant mechanism involves synaptic plasticity mediated by TrkB signaling.

Aim of study: This study aims to elucidate the potential antidepressant target and mechanisms of catalpol, the main active compound of RGL, through TrkB signaling-mediated synaptic plasticity.

Materials and methods: We have recently predicted through molecular networking strategy (including network pharmacology, molecular docking, and molecular dynamics simulation) that catalpol may exert its antidepressant effects by regulating TrkB signaling and thus modulating essential synaptic plasticity proteins. Then, this study used classic behavioral tests, targeted diagnostic reagents, Nissl and Golgi staining, immunohistochemical analysis, immunofluorescence analysis, Western blot, enzyme-linked immunosorbent assay, and Real-time PCR to confirm the potential target and signaling of catalpol to improve synaptic plasticity for the treatment of depression.

Results: The data showed that catalpol could improve synaptic plasticity and depressive behaviors, and its action pathway was predicted to involve TrkB signaling. Subsequently, the blockade of TrkB abolished the improvement of synaptic plasticity by catalpol and its antidepressant properties, which validated that TrkB signaling was the key pathway for catalpol to improve synaptic plasticity and exert antidepressant properties. Inhibition of COX-2 was likely to be a necessary facilitator for the antidepressant efficacy of catalpol via the TrkB target and TrkB-mediated synaptic plasticity.

Conclusion: TrkB signaling-mediated synaptic plasticity plays a key role in the antidepressant properties of catalpol. This study provides critical information for the development of new and targeted antidepressant therapies or treatment strategies by catalpol. However, considering the existence of sex differences in depression (female depression is 2-3 times than that of males) and not exploring the antidepressant sex specificity of catalpol is a limitation, we will investigate the sex specificity of the antidepressant effects and molecular mechanisms of catalpol on sex-specific animals in the future to provide a preclinical basis for more accurate and targeted medication of catalpol.

Keywords: Chinese medicine; SYP; Synaptic plasticity; Synaptic proteins; TrkB signaling; depression.