Figure 21-15 During ischemia, depletion of adenosine triphosphate leads to neuronal depolarization and the subsequent release of supranormal quantities of neurotransmitters, especially glutamate. Excessive stimulation of ligand-gated channels and the simultaneous opening of voltage-dependent Ca²⁺ channels permits rapid entry of Ca²⁺ into neurons. Stimulation of metabotropic glutamate receptors (mGlu) generates inositol triphosphate (IP₃ ), which causes release of Ca²⁺ from the endoplasmic reticulum (ER)/mitochondria. Activation of the α-amino-3-hydroxy-5-methyl-4-isoxazopropionic acid (AMPA)-gated subset of glutamate receptors also permits excessive entry of sodium (Na⁺ ). Excessive free Ca²⁺ results in the activation of numerous enzymes: protease activation causes breakdown of the cytoskeleton of the neuron; lipases damage plasma membrane lipids and release arachidonic acid, which is metabolized by cyclooxy-genases and lipoxygenases to yield free radicals and other mediators of cell injury; activation of nitric oxide synthase (NOS) leads to release of nitric oxide (NO) and, in turn, the generation of peroxynitrite, a highly reactive free radical; and activated endonucleases damage DNA, thereby rendering the neuron susceptible to apoptosis. Injury to mitochondria leads to energy failure, free radical generation, and the release of cytochrome c (Cyt c) from mitochondria; the latter is one of the means by which neuronal apoptosis is initiated. NMDA, N-methyl-D-aspartate; ROS, reactive oxygen species; VGCC, voltage-gated calcium channels.