Figure 8

Schematic representation of key steps in neuronal oxidative damage by UCB. UCB interaction with neurons causes the release of the neurotransmitter glutamate, which stimulates the NMDA glutamate-subtype receptor. Upon stimulation of NMDA receptors, neuronal nNOS is activated and NO· is produced. NO· leads to increased formation of cGMP through activation of soluble guanylate cyclase, and to disruption of the redox status. As a corollary of these events, mitochondrial function is impaired, ultimately leading to cell death. Inhibition of nNOS by l-NAME prevents downstream events from occurring, thus pointing to NO· as a key mediator in UCB-induced oxidative disruption. Preclusion of UCB-induced cell death by hemoglobin sequestration of NO· corroborates the involvement of this species in neuronal demise by UCB. Upstream blockade of NMDA receptors by MK-801 abrogates the neurotoxicity mediated by NO·, therefore indicating that excitotoxicity plays a key role in UCB-induced oxidative damage to neurons.