Icariin mitigates depressive-like behavior in rats by regulating mitochondrial function

Abstract

Ethnopharmacological relevance: Epimedii Folium is a famous traditional Chinese medicine that has been utilized to treat depression, impotency and rheumatism for centuries in China. Icariin (ICA) is the primary flavonoid and quality control ingredient of Epimedii Folium.

Aims of the study: The objective of this investigation was to clarify the mechanisms through which ICA improved depressive-like behavior in prenatal stress (PS) offspring rats.

Materials and methods: Male offspring rats subjected to PS were utilized to investigate the antidepressant effect and possible mechanism of ICA. H&E staining, Nissl staining, ELISA, western blot, immunofluorescence staining and molecular docking were carried out in this work.

Results: ICA treatment markedly mitigated depressive-like behavior and hippocampal neuronal damage in PS offspring rats. The hippocampal synaptic plasticity of PS offspring rats was impaired, while the abnormal expressions of synaptic plasticity proteins and the synaptic ultrastructure were restored after the administration of ICA. Importantly, ICA treatment improved disrupted mitochondrial dynamics and morphology, thereby reversing the decline in ATP level and mitochondrial membrane potential (MMP) in the hippocampus of PS offspring rats. The reduction of MMP in PS rats further induced the apoptosis of hippocampal neurons, while this trend was markedly reversed after the treatment with ICA. Concurrently, ICA reversed the decrease of mitochondrial biogenesis proteins (SIRT1, PGC-1α, NRF1, and TFAM) and the interaction between SIRT1 and PGC-1α. Further studies found that treatment with ICA notably counteracted the reduction in SIRT1 deacetylase activity and the increase in PGC-1α acetylation level in the hippocampus of PS rats. Additionally, ICA enhanced mitophagy by activating the PINK1/Parkin signaling pathway.

Conclusion: ICA exerted anti-depressive effects in PS offspring rats, partly by improving mitochondrial dynamics, biogenesis, and mitophagy.

Keywords: Depression; Icariin; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Prenatal stress.