We previously reported that
cyclophilin A protein is up-regulated in cortical neuronal cultures following several preconditioning treatments. In the present study, we have demonstrated that adenoviral-mediated over-expression of
cyclophilin A in rat cortical neuronal cultures can protect neurons from oxidative stress (induced by
cumene hydroperoxide) and in vitro
ischemia (induced by
oxygen glucose deprivation). We subsequently demonstrated that cultured neurons, but not astrocytes, express the recently identified putative
cyclophilin A receptor, CD147 (also called
neurothelin,
basigin and
EMMPRIN), and that administration of purified
cyclophilin A protein to neuronal cultures induces a rapid but transient phosphorylation of the
extracellular signal-regulated kinase (ERK) 1/2. Furthermore, administration of purified
cyclophilin A protein to neuronal cultures protects neurons from oxidative stress and in vitro
ischemia. Interestingly, we detected up-regulation of
cyclophilin A mRNA, but not
protein in the hippocampus following a 3-min period of sublethal global
cerebral ischemia in the rat. Despite our in vivo findings, our in vitro data show that
cyclophilin A has both intracellular- and extracellular-mediated neuroprotective mechanisms. To this end, we propose
cyclophilin A's extracellular-mediated neuroprotection occurs via CD147 receptor signalling, possibly by activation of ERK1/2 pro-survival pathways. Further characterization of
cyclophilin A's neuroprotective mechanisms may aid the development of a neuroprotective
therapy.