Multiple functional therapeutic effects of DL-3-n-butylphthalide in the cuprizone model of demyelination

Abstract Aims Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). The disease mechanisms driving progressive MS remain unresolved. Without this information, current therapeutic strategies are unsatisfactory in preventing disease progression. Our previous work revealed that DL-3-n-butylphthalide (NBP) treatment reduced demyelination in an ethidium bromide mouse model of demyelination. Here, we examine the effect of NBP in the cuprizone model of demyelination by evaluating the pathologic, functional, and behavioral consequences of treatment with NBP. Materials and methods Forty mice were divided randomly into 4 groups: a normal diet group, a cuprizone diet group, and two NBP groups (10 and 20 mg/kg). CNS infiltration by microglia, axon health and myelination were assessed using immunohistochemistry and electron microscopy, and the levels of cytoplasmic complexes were assessed by Western blotting. Key findings The results showed the neuroprotective effects of the NBP included suppressing the microglia activation through inhibition of nuclear factor-κB (NF-κB) expression, thus decreasing activation of the NF-κB signaling pathway. In particular, myelin density was increased due to an increased mean number of mature oligodendrocytes (OLs) in the high-dose NBP (20 mg/kg) subgroup through reduced oligodendrocyte apoptosis. Meanwhile, increased expression of myelin sheath proteins, including proteolipid protein (PLP) and myelin basic protein (MBP), was observed in the same subgroup. Significance These data suggest that NBP may not only have anti-inflammatory properties but also promote the survival of OLs in a mouse cuprizone model of demyelination. NBP may have a potential role in the treatment of MS.