Upregulation of ciliary neurotrophic factor in astrocytes by aspirin: Implications for remyelination in multiple sclerosis

Ciliary neurotrophic factor (CNTF) is a promyelinating trophic factor and mechanisms by which CNTF expression could be increased in the brain are poorly understood. Aspirin, acetylsalicylic acid, is one of the most widely-used analgesics. Interestingly, aspirin increased mRNA and protein expression of CNTF in primary mouse and human astrocytes in a dose- and time-dependent manner. Aspirin induced the activation of protein kinase A (PKA), but not protein kinase C (PKC). H-89, an inhibitor of PKA, abrogated aspirin-induced expression of CNTF. The activation of cAMP response element binding (CREB) protein, but not NF-kB, by aspirin, the abrogation of aspirin-induced expression of CNTF by siRNA knockdown of CREB, the presence of a consensus CRE in the promoter of CNTF, and the recruitment of CREB and CREB-binding protein to the CNTF promoter by aspirin suggest that aspirin increases the expression of CNTF gene via the activation of CREB. Furthermore, we demonstrate that aspirin-induced astroglial CNTF was also functionally active and that supernatants of aspirin-treated astrocytes of wild type, but not CNTF null, mice increased myelin-associated proteins in oligodendrocytes and protected oligodendrocytes from TNF-a insult. These results highlight a new and novel myelinogenic property of aspirin, which may be of benefit for multiple sclerosis and other demyelinating disorders.