Tissue-type transglutaminase and the effects of cystamine on intracerebral hemorrhage-induced brain edema and neurological deficits.
Neurodegeneration occurs after intracerebral hemorrhage (ICH) and tissue-type transglutaminase (tTG) has a role in neurodegenerative disorders. The present study investigated tTG expression after ICH and the effects of a tTG inhibitor, cystamine, on ICH-induced brain edema and neurological deficits. This study has two parts. In the first, male Sprague-Dawley rats received an intracaudate injection of 100 microL autologous whole blood or a needle insertion (sham). Rats were killed 3 days later and the brains used for immunohistochemistry, Western blots and real-time quantitative polymerase chain reaction. In the second set, ICH rats were treated intraperitoneally with either a tTG inhibitor, cystamine, or vehicle. Rats underwent behavioral testing and were killed at day-3 for measurement of brain swelling. tTG positive cells were found in the ipsilateral basal ganglia after ICH and most of those cells were neuron-like. Western blot analysis showed a 3-fold increase in tTG in the ipsilateral basal ganglia (p<0.01 vs. sham) after ICH. tTG mRNA levels were also significantly higher (8.5-fold increase vs. sham). Cystamine treatment attenuated ICH-induced brain swelling (day 3: 14.4+/-3.2 vs. 21.4+/-4.0% in vehicle-treated rats, p<0.01), neuronal death and improved functional outcome (forelimb placing score: 47+/-23 vs. 17+/-16% in vehicle-treated rats, p<0.05). ICH induces perihematomal tTG upregulation and cystamine, a tTG inhibitor, reduces ICH-induced brain swelling and neurological deficits.
Okauchi
Masanobu
M
R5018 Biomedical Science Research Building, Department of Neurosurgery, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, Michigan 48109-2200, USA.
Xi
Guohua
G
Keep
Richard F
RF
Hua
Ya
Y
D000818:Animals; D001479:Basal Ganglia / Q000201:enzymology*; D015153:Blotting, Western; D001923:Brain Chemistry; D001929:Brain Edema / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology*; D002543:Cerebral Hemorrhage / Q000201:enzymology / Q000503:physiopathology*; D003538:Cystamine / Q000494:pharmacology* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D007150:Immunohistochemistry; D008297:Male; D009410:Nerve Degeneration; D016133:Polymerase Chain Reaction; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D003538:Cystamine