Caspase inhibition by cardiotrophin-1 prevents neuronal death in vivo and in vitro.
Our previous studies showed that cardiotrophin-1 (CT-1), a cytokine in the interleukin-6 family, protected the developing rat brain against focal cerebral ischemia (FCI) in vivo and prevented cortical neuron death in vitro. However, the mechanisms by which CT-1 prevents neuronal death are not clearly understood. This in vivo study focused on whether CT-1 treatment prevented FCI-induced brain injuries in the postnatal day 7 (P7) rat through modulating activation of the initiator caspase-8 (C-8) and the downstream effector caspase-3 (C-3). FCI caused a significant increase in expressions of cleaved C-8 and C-3 and, meanwhile, a significant decrease in expression of microtubule-associated protein-2 (MAP2) in the left ischemic cortex of the P7 rat brain after FCI. Exogenous treatment of CT-1 significantly reduced the expression of cleaved C-8 or C-3 and attenuated the decline in MAP2 expression in the ischemic cortex from 12 to 24 hr after FCI. Subsequent in vitro experiments demonstrated that CT-1 treatment inhibited sodium nitroprusside (SNP)-induced activation of C-8 and C-3 and loss of MAP2-positive neurons in cortical neuron cultures. More importantly, CT-1 activated several pathways, including Janus kinase 2, signal transducers and activators of transcription 3, nuclear factor kappa B, mitogen-activated protein kinase (MAPK), and MAPK kinase in the cultures exposed to SNP. This is the first suggestion that CT-1 prevents neuronal injury in the developing central nervous system possibly through mediating multiple signal pathways, inhibiting activation of C-8 and C-3.
Peng
Hui
H
Atlantic Neonatal Research Institute, MidAtlantic Neonatology Associates, and Atlantic Health, Morristown, New Jersey, USA.
Sola
Augusto
A
Moore
James
J
Wen
Tongchun
T
D000818:Animals; D000831:Animals, Newborn; D020520:Brain Infarction / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D061945:Caspase Inhibitors; D016207:Cytokines; D008869:Microtubule-Associated Proteins; D020030:Nitric Oxide Donors; D011993:Recombinant Fusion Proteins; D009599:Nitroprusside; C092073:cardiotrophin 1; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases