Activation of c-Jun-N-terminal kinase in a rat model of intracerebral hemorrhage: the role of iron.
Iron accumulates in the brain and contributes to brain injury after intracerebral hemorrhage (ICH). The c-Jun-N-terminal kinase (JNK) signaling pathway mediates cell death after ischemic stroke, however, the involvement of JNK in ICH is not well known. This study investigated whether the JNK signaling pathway is activated by iron after ICH. Male Sprague-Dawley rats received an infusion of autologous whole blood (as a model of ICH) or ferrous iron into the right basal ganglia and control rats had an infusion of saline. Some ICH rats were treated with either deferoxamine (DFX), an iron chelator, or vehicle. Activation of JNK was measured by Western blot analysis and immunohistochemistry. Free iron in cerebrospinal fluid (CSF) and behavioral outcomes following ICH were also examined. We found that activated JNK in the brain were increased after ICH, and an intracerebral infusion of ferrous iron also upregulated brain activated JNK. Free iron accumulated in CSF and systemic administration of DFX after ICH reduces free iron contents in CSF, suppresses JNK activation and improves ICH-induced neurological deficits. Our results demonstrated that the JNK signaling pathway is activated after ICH and iron may contribute to this activation. DFX reduces free iron levels and attenuates activation of JNK suggesting iron chelation may be useful therapy for ICH patients.
Wan
Shu
S
Department of Neurosurgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Zhan
Renya
R
Zheng
Shusen
S
Hua
Ya
Y
Xi
Guohua
G
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000201:enzymology; D002543:Cerebral Hemorrhage / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D003676:Deferoxamine / Q000627:therapeutic use; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D007839:Functional Laterality; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D007501:Iron / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017262:Siderophores / Q000627:therapeutic use; D013997:Time Factors
D017262:Siderophores; D007501:Iron; D048031:JNK Mitogen-Activated Protein Kinases; D003676:Deferoxamine