Cyclosporin A prevents calpain activation despite increased intracellular calcium concentrations, as well as translocation of apoptosis-inducing factor, cytochrome c and caspase-3 activation in neurons exposed to transient hypoglycemia.
Blockade of mitochondrial permeability transition protects against hypoglycemic brain damage. To study the mechanisms downstream from mitochondria that may cause neuronal death, we investigated the effects of cyclosporin A on subcellular localization of apoptosis-inducing factor and cytochrome c, activation of the cysteine proteases calpain and caspase-3, as well as its effect on brain extracellular calcium concentrations. Redistribution of cytochrome c occurred at 30 min of iso-electricity, whereas translocation of apoptosis-inducing factor to nuclei occurred at 30 min of recovery following 30 min of iso-electricity. Active caspase-3 and calpain-induced fodrin breakdown products were barely detectable in the dentate gyrus and CA1 region of the hippocampus of rat brain exposed to 30 or 60 min of insulin-induced hypoglycemia. However, 30 min or 3 h after recovery of blood glucose levels, fodrin breakdown products and active caspase-3 markedly increased, concomitant with a twofold increase in caspase-3-like enzymatic activity. When rats were treated with neuroprotective doses of cyclosporin A, but not with FK 506, the redistribution of apoptosis-inducing factor and cytochrome c was reduced and fodrin breakdown products and active caspase-3 immuno-reactivity was diminished whereas the extracellular calcium concentration was unaffected. We conclude that hypoglycemia leads to mitochondrial permeability transition which, upon recovery of energy metabolism, mediates the activation of caspase-3 and calpains, promoting cell death.
Ferrand-Drake
Michel
M
Laboratory for Experimental Brain Research, Wallenberg Neuroscience Center, Lund University Hospital, Lund, Sweden. michelf@stanford.edu
Zhu
Changlian
C
Gidö
Gunilla
G
Hansen
Anker J
AJ
Karlsson
Jan-Olof
JO
Bahr
Ben A
BA
Zamzami
Naoufal
N
Kroemer
Guido
G
Chan
Pak H
PH
Wieloch
Tadeusz
T
Blomgren
Klas
K
D000818:Animals; D051033:Apoptosis Inducing Factor; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002452:Cell Count; D016572:Cyclosporine / Q000494:pharmacology*; D003574:Cytochrome c Group / Q000378:metabolism; D018891:Dentate Gyrus / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005420:Flavoproteins / Q000378:metabolism; D007003:Hypoglycemia / Q000378:metabolism*; D007424:Intracellular Fluid / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008839:Microelectrodes; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000494:pharmacology
C494831:Aifm1 protein, rat; D051033:Apoptosis Inducing Factor; D003574:Cytochrome c Group; D005420:Flavoproteins; D008565:Membrane Proteins; D016572:Cyclosporine; D002154:Calpain; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D002118:Calcium; D016559:Tacrolimus