Ghrelin inhibits hydrogen peroxide-induced apoptotic cell death of oligodendrocytes via ERK and p38MAPK signaling.

Here, we examined the protective effect of ghrelin on apoptotic cell death induced by hydrogen peroxide (H₂O₂) in primary oligodendrocyte cultures. Ghrelin receptor, growth hormone secretagogue receptor 1a, was expressed in mature oligodendrocytes. H₂O₂ (1 mm) treatment induced apoptotic cell death of oligodendrocytes, which was significantly inhibited by ghrelin treatment. Ghrelin also reduced cytochrome c release, and caspase-3 activation increased by H₂O₂ treatment. Furthermore, the protective effect of ghrelin against H₂O₂-induced oligodendrocyte cell death was mediated through growth hormone secretagogue receptor 1a. Both ERK and p38MAPK were activated (peaked at 8 h in ERK and 1 h in p38MAPK) by H₂O₂ treatment, whereas c-Jun N-terminal kinase and Akt were not. Interestingly, ghrelin further increased ERK activation and decreased p38MAPK activation after H₂O₂ treatment. Next, we tried to elucidate the role of ERK and p38MAPK activation in H₂O₂-induced apoptotic cell death of oligodendrocytes using pharmacological inhibitors. We found that the inhibition of apoptotic cell death of oligodendrocytes by ghrelin was abolished by ERK inhibitor, PD98059 (20 μM), whereas cell survival was increased by p38MAPK inhibitor, SB203580 (10 μM). These results thus indicate that ghrelin inhibits H₂O₂ -induced oligodendrocytes cell death in part by increasing ERK activation and decreasing p38MAPK activation, and ghrelin may represent a potential therapeutic agent for protecting oligodendrocytes in central nervous system injuries.