title: Protective effect of thalidomide against N-methyl-D-aspartate-induced retinal neurotoxicity.
abstract: Thalidomide, an inhibitor of tumor necrosis factor-α (TNF-α) production, has been indicated to be useful for many inflammatory and oncogenic diseases. In the present study, we examined whether thalidomide (50 mg/kg/day, p.o.) has a protective effect against N-methyl-D-aspartate (NMDA)-induced retinal neurotoxicity in rats. A morphometric analysis showed that systemic administration of thalidomide protects neural cells in the ganglion cell layer (GCL) in a dose-dependent manner and significantly decreases the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells in GCL and in the inner nuclear layer (INL). ELISA showed that thalidomide significantly suppressed the elevation of TNF-α 6 and 24 hr after an NMDA injection. Western blot analysis revealed a significant increase in nuclear factor-κB (NF-κB) p65 level in the retinas treated with NMDA at 24 hr after the injection, but not at 6 or 72 hr. Furthermore, an increase in p-JNK and p-p38 levels was also observed in the retina after NMDA injection. Thalidomide suppressed the increased expressions of NF-κB p65, p-JNK, and p-p38 after NMDA injection. Immunohistochemical analysis showed that thalidomide attenuated NF-κB p65 immunoreactivity in the GCL induced by NMDA treatment. In the NMDA-treated group, translocation of NF-κB p65 from the cytoplasm to the nucleus was detected in TUNEL-positive cells exposed to NMDA treatment. These results suggest new indications for thalidomide against neurodegenerative diseases.
authors.affiliation: 5th Year, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Takada
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Munemasa
authors.forename: Junko
authors.initials: J
authors.lastname: Kuribayashi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Fujino
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kitaoka
mesh_terms: D000818:Animals; D004347:Drug Interactions / Q000276:immunology; D020287:In Situ Nick-End Labeling / Q000379:methods; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012162:Retinal Degeneration / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013792:Thalidomide / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D018696:Neuroprotective Agents; D009498:Neurotoxins; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D016202:N-Methylaspartate