FIGURE 5.

Overview of the neuroprotective activity of N-methyl-d-aspartate. Activation of NMDA receptors results in the influx of extracellular calcium intracellularly and the immediate release (within two minutes) of brain-derived neurotrophic factor (BDNF). Extracellular BDNF then binds to and activates its cognate receptor, TrkB. Thus, coactivation of NMDA and TrkB receptors occurs within ten minutes (see Marini et al., 1998). The influx of calcium and possibly other second messenger systems leads to the phosphorylation of I-kB, the inhibitor of NF-kB. Once phosphorylated, I-kB is rapidly degraded by the ubiquitin-proteosome-mediated pathway resulting in the release of NF-kB. Activated NF-kB translocates to the nucleus where it binds to the 5'- flanking region of exon 3 of the bdnf gene and likely to the promoter of the bcl-2 gene to activate gene transcription to protect vulnerable neurons against the excitotoxic effects of glutamate acting on NMDA receptors. The question marks indicate gaps in knowledge of the interaction between NMDA and TrkB receptors and the signal transduction pathways that mediate the survival effects of coactivation of NMDA and TrkB receptors.