Noggin-mediated effects on metabolite profiles of microglia and oligodendrocytes after ischemic insult.

ABSTRACT

Recent studies show that shifts in energy metabolism in activated microglia are linked to their functions and immune responses in the ischemic brain. We previously reported that an antagonist of the bone morphogenetic protein, noggin, enhanced myelination in the ischemic brain during the chronic phase, and conditioned media (CM) from activated BV2 microglia treated with noggin after ischemia/reperfusion (I/R) increased the expression of myelin basic protein (MBP) in oligodendrocytes (MO3.13). To determine whether noggin induced changes in cell metabolism, metabolite profiles in BV2 and MO3.13 cells were analyzed by untargeted metabolomics using 1H nuclear magnetic resonance spectroscopy. Compared to vehicle-treated BV2 cells, noggin treatment (100 ng/mL for 3 h after I/R) suppressed the I/R-induced increase in intracellular glucose and lactate levels but increased extracellular levels of glucose and several amino acids. When MO3.13 cells were exposed to noggin CM from BV2 cells, most of the vehicle CM-induced changes in the levels of metabolites such as choline, formate, and intermediates of oxidative phosphorylation were reversed, while the glycerol level was markedly increased. An increase in glycerol level was also observed in the noggin-treated ischemic brain and was further supported by the expression of glycerol-3-phosphate dehydrogenase 1 (required for glycerol synthesis) in the cytoplasm of MBP-positive oligodendrocytes in the ischemic brains treated with noggin. These results suggest that noggin-induced changes in the metabolism of microglia provide a favorable environment for myelin synthesis in oligodendrocytes during the recovery phase after ischemic stroke.