Suppression of MIF-induced neuronal apoptosis may underlie the therapeutic effects of effective components of Fufang Danshen in the treatment of Alzheimer's disease

Abstract

Fufang Danshen (FFDS or Compound Danshen) consists of three Chinese herbs Danshen (Salviae miltiorrhizae radix et rhizome), Sanqi (Notoginseng radix et rhizome) and Tianranbingpian (Borneolum, or D-borneol), which has been show to significantly improve the function of the nervous system and brain metabolism. In this study we explored the possible mechanisms underlying the therapeutic effects of the combination of the effective components of FFDS (Tan IIA, NG-R1 and Borneol) in the treatment of Alzheimer's disease (AD) based on network pharmacology. We firstly constructed AD-related FFDS component protein interaction networks, and revealed that macrophage migration inhibitory factor (MIF) might regulate neuronal apoptosis through Bad in the progression of AD. Then we investigated the apoptosis-inducing effects of MIF and the impact of the effective components of FFDS in human neuroblastoma SH-SY5Y cells. We observed the characteristics of a “Pendular state” of MIF, where MIF (8 ng/mL) increased the ratio of p-Bad/Bad by activating Akt and the IKKα/β signaling pathway to assure cell survival, whereas MIF (50 ng/mL) up-regulated the expression of Bad to trigger apoptosis of SH-SY5Y cells. MIF displayed neurotoxicity similar to Aβ 1-42 , which was associated with the MIF-induced increased expression of Bad. Application of the FFDS composite solution significantly decreased the expression levels of Bad, suppressed MIF-induced apoptosis in SH-SY5Y cells. In a D-galactose- and AlCl 3 -induced AD mouse model, administration of the FFDS composite solution significantly improved the learning and memory, as well as neuronal morphology, and decreased the serum levels of INF-γ. Therefore, the FFDS composite solution exerts neuroprotective effects through down-regulating the level of Bad stimulated by MIF.