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.

Molecular mechanisms of retinal ganglion cell degeneration in glaucoma and future prospects for cell body and axonal protection

“…Intracellular Ca 2+ influx also affects mitochondrial activity, such as the release of cytochrome C and ROS, and results in the activation of several apoptotic pathways. Our previous studies on the downstream intracellular Ca 2+ influx led us to propose that the activation of proapoptotic molecules, such as NF-κB p65 and p38, c-Jun N -terminal kinase (JNK), and c-Jun, plays a role in NMDA-induced neurotoxicity (Kitaoka et al, 2004; Munemasa et al, 2005, 2006; Takada et al, 2011). An inflammatory response, i.e., the upregulation of IL-1β, is also observed in the glia and RGCs after NMDA administration, suggesting the involvement of inflammation in response to excitotoxicity.…”