Pathways leading to apoptotic neurodegeneration following trauma to the developing rat brain.
Trauma triggers diffuse apoptotic neurodegeneration in the developing rat brain. To explore the pathogenesis of this phenomenon we investigated the involvement of three possible mechanisms: death receptor activation, activation of the intrinsic apoptotic pathway by cytochrome c release into the cytoplasm, and changes in trophic support provided by endogenous neurotrophins. We detected a decrease in the expression of bcl-2 and bcl-x(L), two antiapoptotic proteins that decrease mitochondrial membrane permeability, an increase in cytochrome c immunoreactivity in the cytosolic fraction, and an activation of caspase-9 in brain regions which show apoptotic neurodegeneration following percussion brain trauma in 7-day-old rats. Increase in the expression of the death receptor Fas was revealed by RT-PCR analysis, Western blotting, and immunohistochemistry, as was activation of caspase-8 in cortex and thalamus. Apoptotic neurodegeneration was accompanied by an increase in the expression of BDNF and NT-3 in vulnerable brain regions. The pancaspase inhibitor z-VAD.FMK ameliorated apoptotic neurodegeneration with a therapeutic time window of up to 8 h after trauma. These findings suggest involvement of intrinsic and extrinsic apoptotic pathways in neurodegeneration following trauma to the developing rat brain. Upregulation of neurotrophin expression may represent an endogenous mechanism that limits this apoptotic process.
Felderhoff-Mueser
Ursula
U
Department of Neonatology, Charité Children's Hospital, Humboldt University, 13353 Berlin, Germany.
Sifringer
Marco
M
Pesditschek
Stefanie
S
Kuckuck
Heike
H
Moysich
Axel
A
Bittigau
Petra
P
Ikonomidou
Chrysanthy
C
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics; D003574:Cytochrome c Group / Q000378:metabolism; D053938:DNA Fragmentation / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D020933:Neurotrophin 3 / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D051020:bcl-X Protein; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; C494813:Bcl2l1 protein, rat; D019208:Brain-Derived Neurotrophic Factor; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D020933:Neurotrophin 3; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051020:bcl-X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; D019938:Cyclin D1; C506435:Casp9 protein, rat; D053453:Caspase 9; D020169:Caspases