title: 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.
abstract: 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.
authors.affiliation: Laboratory for Experimental Brain Research, Wallenberg Neuroscience Center, Lund University Hospital, Lund, Sweden. michelf@stanford.edu
authors.forename: Michel
authors.initials: M
authors.lastname: Ferrand-Drake
authors.forename: Changlian
authors.initials: C
authors.lastname: Zhu
authors.forename: Gunilla
authors.initials: G
authors.lastname: Gidö
authors.forename: Anker J
authors.initials: AJ
authors.lastname: Hansen
authors.forename: Jan-Olof
authors.initials: JO
authors.lastname: Karlsson
authors.forename: Ben A
authors.initials: BA
authors.lastname: Bahr
authors.forename: Naoufal
authors.initials: N
authors.lastname: Zamzami
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Pak H
authors.initials: PH
authors.lastname: Chan
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Wieloch
authors.forename: Klas
authors.initials: K
authors.lastname: Blomgren
mesh_terms: 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
chemical_list: 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