Synergistic Effects of Olfactory Ecto-Mesenchymal Stem Cell Supernatant and Ellagic Acid on Demyelination and Glial Modulation in a Chronic Multiple Sclerosis Model

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Stem cells as a source of neurotrophic factors and ellagic acid (EA) as an antioxidant reduce the progression of neurodegenerative diseases. In this study, we evaluated the effect of olfactory ecto-mesenchymal stem cell (EMSC) supernatant and EA on A1 astrocytes, M1 microglia, and demyelination in cuprizone model. To induce the chronic demyelination model, mice received a diet containing 0.2% cuprizone/kg of food for 12 weeks. EMSC supernatant was injected into the lateral ventricle of mice. EA was administered intraperitoneally daily at a dose of 80 mg/kg body weight for two weeks. Two weeks after injection, immunohistochemistry was performed to detect the presence of astrocytes (GFAP), microglia/macrophages (Iba-1), and oligodendrocytes (Olig2). The level of gene expression of EMSC (TGF-β and BDNF), astrocytes (C3 and GBP2) and microglia (iNOS, TNF-α and IL-6) was evaluated by qRT-PCR method. The results showed that injection of EMSC and EA increased the expression of TGF-β and BDNF genes as trophic factors. LFB images showed that supernatant and EA significantly improved remyelination, which was accompanied by an increase in oligodendrocyte population. The astrocyte population increased in the cuprizone group, while it decreased after supernatant and EA administration. The supernatant and EA decreased microglia after cuprizone induction. The qRT-PCR showed neurotoxic genes of A1 and M1 decreased after supernatant and EA administration. Here, we demonstrate that EMSC supernatant and EA could improve demyelination in neurodegenerative diseases such as MS by reducing microgliosis and astrocytosis in addition to increasing myelination.