Icaritin Promotes Myelination by Simultaneously Enhancing the Proliferation and Differentiation of Oligodendrocyte Precursor Cells.

Myelin repair, which is known as remyelination, is critical to the treatment of neurodegenerative diseases, and myelination depends on not only the differentiation of oligodendrocyte precursor cells toward oligodendrocytes but also the renewal of oligodendrocyte precursor cells under pathological conditions. However, simultaneously promoting the differentiation and proliferation of oligodendrocyte precursor cells in lesions remains an unmet challenge and might affect demyelinating diseases. Kidney-tonifying herbs of traditional Chinese medicine (TCM) are effective in improving the symptoms of degenerative patients. However, herbs or compounds with dual functions are unverified. The purpose of this study was to find a kidney-tonifying TCM that synchronously improved the differentiation and proliferation of oligodendrocyte precursor cells under pathological conditions. Compounds with dual functions were screened from highly frequently used kidney-tonifying TCM, and the effects of the obtained compound on remyelination were investigated in an in vitro oligodendrocyte precursor cell differentiation model under pathological conditions and in demyelinating mice in vivo. The compound icaritin, which is an active component of Yin-Yang-Huo (the leaves of Epimedium brevicornu Maxim), demonstrated multiple effects on the remyelination process, including enhancing oligodendrocyte precursor cell proliferation, facilitating the differentiation of neural progenitor cells toward oligodendrocyte precursor cells and further toward oligodendrocytes, and maturation of oligodendrocytes under corticosterone- or glutamate-induced pathological conditions. Importantly, icaritin effectively rescued behavioral functions and increased the formation of myelin in a cuprizone-induced demyelination mouse model. The multiple effects of icaritin make it a promising lead compound for remyelination therapy.

Bu Shen Yi Sui capsule promotes remyelination correlating with Sema3A/NRP-1, LIF/LIFR and Nkx6.2 in mice with experimental autoimmune encephalomyelitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Bu Shen Yi Sui capsule (BSYSC), based on traditional Chinese formula Liu Wei Di Huang pill, is effective for the treatment of multiple sclerosis (MS) in clinical experience and trials. Our previous studies confirmed that BSYSC had the neuroprotective effect in MS and its animal model, experimental autoimmune encephalomyelitis (EAE); however, its mechanism of action was not clear. Thus, the effect of BSYSC on remyelination and the underlying mechanisms were investigated in the EAE mice. MATERIALS AND METHODS: The EAE model was established by injecting subcutaneously myelin oligodendrocyte protein (MOG) 35-55 in mice. Mice were treated with BSYSC (3.02 g/kg) or vehicle daily by oral gavage for 40 days. The body weight and clinical score of mice were evaluated. Brain was observed by magnetic resonance imaging. The inflammation infiltrate of brain and spinal cord was determined by hematoxylin-eosin staining, while the structure of myelin sheath was visualized by transmission electron microscopy on days 23 and 40 post immunization (dpi), respectively. The protein and mRNA levels of platelets-derived growth factor receptor (PDGFR) α and 2', 3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) were measured by immunohistochemistry, western blot and quantitative real-time polymerase chain reaction. The protein expressions of semaphorins (Sema) 3A, Neuropilin (NRP) - 1, leukemia inhibitory factor (LIF), LIF receptor (LIFR) and Nkx6.2 were further investigated by western blot. RESULTS: BSYSC treatment improved the body weight and clinical score of EAE mice, alleviated inflammatory infiltration and nerve fiber injuries. It also protected the ultrastructural integrity of myelin sheath. BSYSC significantly increased expressions of PDGFRα and CNPase in mice with EAE on 40 dpi. Furthermore, BSYSC treatment increased the expressions of LIF, LIFR and Nkx6.2 and reduced Sema3A and NRP-1 in EAE mice on 40 dpi. CONCLUSIONS: The data demonstrated that BSYSC exhibited the neuroprotective effect against EAE by promoting oligodendrocyte progenitor cells (OPCs) proliferation and differentiation, thus facilitating remyelination. Sema3A/NRP-1, LIF/LIFR and Nkx6.2 are likely contributed to the effects of BSYSC on OPCs.