Thioredoxin inhibits NMDA-induced neurotoxicity in the rat retina.
Thioredoxin (TRX) plays a variety of redox-related roles in organisms. To investigate its function as an endogenous redox regulator in NMDA-induced retinal neurotoxicity, we injected NMDA with TRX, mutant TRX or saline into the vitreous cavity of rat eyes. Retinal ganglion cells were rescued by TRX, compared with saline, when evaluated by retrograde labeling analysis at 7 days after NMDA injection. TRX, but not its mutant form, prevented NMDA-induced apoptosis in the retina, as measured by terminal deoxynucleotidyl transferase-mediated UTP nick-end labeling. The induction of caspase 3 and 9, but not caspase 8, by NMDA was significantly lower in TRX-treated eyes than in saline-treated eyes. NMDA-induced activation of the MAPKs, p38 kinase and c-Jun N-terminal kinase after 6 h and of the MAPK kinases (MKKs) MKK3/6 and MKK4 after 3 h was markedly suppressed in retinal ganglion cells by TRX but not by the mutant form. NMDA-induced increases in protein carbonylation, nitrosylation and lipid peroxidation were also suppressed in TRX-treated eyes. We concluded that the intravitreous injection of TRX effectively attenuated NMDA-induced retinal cell damage and that suppression of oxidative stress and inhibition of apoptotic signaling pathways were involved in this neuroprotection.
Inomata
Yasuya
Y
Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan.
Nakamura
Hajime
H
Tanito
Masaki
M
Teratani
Akie
A
Kawaji
Takahiro
T
Kondo
Norihiko
N
Yodoi
Junji
J
Tanihara
Hidenobu
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology* / Q000633:toxicity; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000633:toxicity; D018696:Neuroprotective Agents; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012160:Retina / Q000473:pathology; D012164:Retinal Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D012165:Retinal Ganglion Cells / Q000187:drug effects; D013879:Thioredoxins / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D016755:Proto-Oncogene Proteins c-jun; C002744:3-nitrotyrosine; D014443:Tyrosine; D013879:Thioredoxins; D016202:N-Methylaspartate; D020928:Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; C505528:Casp8 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases