Ceruloplasmin protects injured spinal cord from iron-mediated oxidative damage.
CNS injury-induced hemorrhage and tissue damage leads to excess iron, which can cause secondary degeneration. The mechanisms that handle this excess iron are not fully understood. We report that spinal cord contusion injury (SCI) in mice induces an "iron homeostatic response" that partially limits iron-catalyzed oxidative damage. We show that ceruloplasmin (Cp), a ferroxidase that oxidizes toxic ferrous iron, is important for this process. SCI in Cp-deficient mice demonstrates that Cp detoxifies and mobilizes iron and reduces secondary tissue degeneration and functional loss. Our results provide new insights into how astrocytes and macrophages handle iron after SCI. Importantly, we show that iron chelator treatment has a delayed effect in improving locomotor recovery between 3 and 6 weeks after SCI. These data reveal important aspects of the molecular control of CNS iron homeostasis after SCI and suggest that iron chelator therapy may improve functional recovery after CNS trauma and hemorrhagic stroke.
Rathore
Khizr I
KI
Center for Research in Neuroscience, The Research Institute of the McGill University Health Center, Montreal, Quebec, Canada H3G 1A4.
Kerr
Bradley J
BJ
Redensek
Adriana
A
López-Vales
Rubèn
R
Jeong
Suh Young
SY
Ponka
Prem
P
David
Samuel
S
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D002570:Ceruloplasmin / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D006470:Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D007501:Iron / Q000378:metabolism / Q000633:toxicity*; D019189:Iron Metabolism Disorders / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D016896:Treatment Outcome
D000975:Antioxidants; D018696:Neuroprotective Agents; D007501:Iron; D002570:Ceruloplasmin