Evaluation of cyclosporine A in a stroke model in the immature rat brain.
The effects of ischemia-reperfusion on opening of the mitochondrial permeability transition pore (mPTP) and its blockade in the immature brain are not fully understood. Presently, we evaluated the effect of cyclosporine A (CsA) on cell death and mPTP opening in a model of transient focal ischemia induced by permanent left middle cerebral artery, and homolateral transient common carotid artery occlusion (50 min) in P7 rats. CsA (10mg/kg) was administered 14 h before induction of ischemia and effects were analyzed at 30-40 min and 48 h after reperfusion. CsA administration reduced infarct size, DNA fragmentation and apoptotic bodies, and inflammatory responses in mild but not severe injury. CsA increased the Ca(2+) load required to open the mPTP (78.4 ± 19.2 vs. 50.2 ± 19.9 nmol.mg(-)(1) protein, p < 0.05) in limiting the decoupling of the respiratory chain by unchanged state 3 but reduced state 4, and attenuated early calpain-mediated alpha-spectrin proteolysis. In conclusion, CsA mediates inhibition of mPTP opening and has a tendency to protect immature rat brain against mild ischemic injury. This article is part of a Special Issue entitled "Interaction between repair, disease, & inflammation."
Leger
Pierre-Louis
PL
UMR-CNRS 7102, Université P&M Curie-Paris6, 75005 Paris, France.
De Paulis
Damien
D
Branco
Sonia
S
Bonnin
Philippe
P
Couture-Lepetit
Elisabeth
E
Baud
Olivier
O
Renolleau
Sylvain
S
Ovize
Michel
M
Gharib
Abdallah
A
Charriaut-Marlangue
Christiane
C
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000473:pathology* / Q000648:ultrastructure; D020520:Brain Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000209:etiology; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D016572:Cyclosporine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D007839:Functional Laterality; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D008407:Mast Cells / Q000473:pathology; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow; D013049:Spectrin / Q000378:metabolism; D018608:Ultrasonography, Doppler / Q000379:methods
D005904:Glial Fibrillary Acidic Protein; D007166:Immunosuppressive Agents; D013049:Spectrin; D016572:Cyclosporine; D002118:Calcium