The Bu Shen Yi Sui Formula Promotes Axonal Regeneration via Regulating the Neurotrophic Factor BDNF/TrkB and the Downstream PI3K/Akt Signaling Pathway

Abstract

Axonal damage is recognized as an important pathological feature in the chronic progressive neurological disorder multiple sclerosis (MS). Promoting axonal regeneration is a critical strategy for the treatment of MS. Our clinical and experimental studies have shown that the Bu Shen Yi Sui formula (BSYS) promotes axonal regeneration in MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS, but the exact mechanism has not been thoroughly elucidated to date. In this study, we investigated the effects of BSYS and its two decomposed formulas—the Bu Shen formula (BS) and the Hua Tan Huo Xue formula (HTHX)—on brain-derived neurotrophic factor (BDNF)/TrkB and related signaling pathways to explore the mechanism by which axonal regeneration is promoted in vitro and in vivo . Damaged SH-SY5Y cells incubated with low serum were treated with BSYS-, BS-, and HTHX-containing serum, and EAE mice induced by the myelin oligodendrocyte glycoprotein (MOG) 35–55 peptide were treated with BSYS. The results showed that the BSYS-containing serum markedly increased cell viability and increased the levels of growth associated protein (GAP)-43, phosphorylated (p)-cAMP-response element binding protein (CREB), BDNF, TrkB, and p-PI3K. The BS and HTHX treatments also induced the protein expression of GAP-43 and p-extracellular signal-regulated kinase (ERK) in the cells. Furthermore, the effects of BSYS on cell viability, GAP-43, p-CREB, and neurite outgrowth were clearly inhibited by LY294002, a specific antagonist of the PI3K signaling pathways. The addition of U0126 and U73122, antagonists of the ERK and PLCγ pathway, respectively, significantly inhibited cell viability and GAP-43 protein expression. Moreover, BSYS treatment significantly increased the expression of the 68-, 160-, and 200-kDa neurofilaments (NFs) of proteins and the BDNF, TrkB, PI3K, and Akt mRNA and proteins in the brain or spinal cord of mice at different stages. These results indicated that BSYS promotes nerve regeneration, and its mechanism is mainly related to the upregulation of the BDNF/TrkB and PI3K/Akt signaling pathways. BS and HTHX also promoted nerve regeneration, and this effect involved the ERK pathway.

Bu-Shen-Yi-Sui Capsule, an Herbal Medicine Formula, Promotes Remyelination by Modulating the Molecular Signals via Exosomes in Mice with Experimental Autoimmune Encephalomyelitis

“…This suggests that BSYSC can improve the clinical performance of EAE mice, reduce perivascular inflammatory infiltration, and promote myelin regeneration. These results are consistent with our previous studies [22,26].…”

“…Injection of BDNF-transfected bone marrow stem cells reduces demyelination and facilitates remyelination, thus decreasing the severity of clinical EAE symptoms. Previous studies have found that BSYSC can upregulate the expression of BDNF and TrkB protein and mRNA in the brain and spinal cord of EAE mice [ 22 ]. Let-7 is one of the most abundant miRs expressed in the brain.…”

“…Except for Fritillariae Thunbergii Bulbus, which was crushed into a fine powder, the other nine herbs were immersed in distilled water for 30 min and boiled for 2 h. Inspissation of the filtered solution was performed under reduced pressure at 70°C, and then, the dried powder was uniformly mixed with Fritillariae Thunbergii Bulbus. To ensure the quality and stability of BSYSC, the characteristic chemical fingerprint and the main chemical components of BSYSC were identified using ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) [9,22]. The same batch of BSYSC was used throughout our study.…”

“…The main chemical constituents in BSYSC-containing serum were determined by UPLC-MS/MS. [9,22] The same serum containing BSYSC was used in the cultured OPCs study.…”

Apremilast Regulates the Teff/Treg Balance to Ameliorate Uveitis via PI3K/AKT/FoxO1 Signaling Pathway

“…PI3K/AKT are often dysregulated in autoimmune disease, and the expression of a constitutively active form of AKT leads to autoimmunity. Some autoimmune diseases, such as rheumatoid arthritis ( 50 ) and multiple sclerosis ( 51 ) show increased activity of the PI3K/AKT pathway ( 31 ). However, few studies have determined the function of the PI3K/AKT/FoxO1 pathway in the pathogenesis of uveitis.…”