Evidence that intracellular cyclophilin A and cyclophilin A/CD147 receptor-mediated ERK1/2 signalling can protect neurons against in vitro oxidative and ischemic injury.
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.
Boulos
Sherif
S
Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Australian Neuromuscular Research Institute, WA, Australia. sboulos@cyllene.uwa.edu.au
Meloni
Bruno P
BP
Arthur
Peter G
PG
Majda
Bernadette
B
Bojarski
Christina
C
Knuckey
Neville W
NW
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D051926:Basigin / Q000378:metabolism*; D001555:Benzene Derivatives / Q000633:toxicity; D015153:Blotting, Western; D002545:Brain Ischemia / Q000473:pathology*; D002478:Cells, Cultured; D021984:Cyclophilin A / Q000378:metabolism / Q000502:physiology*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D000860:Hypoxia / Q000473:pathology; D007150:Immunohistochemistry; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D009474:Neurons / Q000473:pathology*; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000502:physiology*; D010957:Plasmids / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
D001555:Benzene Derivatives; D018076:DNA, Complementary; D016877:Oxidants; D012333:RNA, Messenger; D051926:Basigin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D021984:Cyclophilin A; D005947:Glucose; C007164:cumene hydroperoxide