Fig. 6.

Hypothetical scheme accounting for NMDA-triggered neurodegeneration. With brief (5 min) exposure (thick arrows), the neurons die through enduring NO formation, which is the product of a self-perpetuating cycle involving Na⁺-channel activity, which causes glutamate release and then further stimulation of NMDA receptors. The neuronal cell death resulting from this pathway manifests a prolonged (3–4 hr) delay, and it takes ∼16 hr to become maximal. NO generated from iNOS can also kill the neurons. A possible mechanism for NO-induced cell death is through peroxynitrite (ONOO⁻) formation after reaction with superoxide anions (·O⁻₂). The sites of action of the inhibitors used experimentally (identified inparentheses) are indicated. When the initial stimulation of NMDA receptors is more prolonged (e.g., 40 min), the neurons die more quickly (within 4–6 hr) and in a mechanistically distinct manner (thin arrows) that requires glutamate release (now independent of TTX-sensitive Na⁺ channels) and NMDA receptor stimulation, but the associated effector mechanism is NO-independent (despite abundant NO generation). This mechanism is presumed to be Ca²⁺-dependent, and it may involve activation of catabolic enzymes, such as phospholipases, proteases, and nucleases. The broken lines signify alternative routes through which Na⁺ channels and glutamate, in principle, could mediate neuronal death, although these were not visible in the experimental paradigms examined.AMPA_R, AMPA receptors; mGluR, metabotropic glutamate receptors.