Protective Effect of Thalidomide Against N-Methyl-D-Aspartate-Induced Retinal Neurotoxicity

Thalidomide, an inhibitor of tumor necrosis factor-a (TNF-alpha) 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-alpha 6 and 24 hr after an NMDA injection. Western blot analysis revealed a significant increase in nuclear factor-kappa B (NF-kappa B) 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-kappa B p65, p-JNK, and p-p38 after NMDA injection. Innmuno-histochemical analysis showed that thalidomide attenuated NF-kappa B p65 immunoreactivity in the GCL induced by NMDA treatment. In the NMDA-treated group, translocation of NF-kappa B 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. (C) 2011 Wiley-Liss, Inc.