Excitotoxic hypothesis

Excitotoxicity, or the “excitotoxic hypothesis,” to use the term coined by John Olney in 1978, suggests that a cell firing mechanism underlies glutamate neurotoxicity and that the toxic action may be mediated through glutamatergic or aspartergic neurotransmission (64). As a concept, excitotoxicity has gained wide acceptance and was long suggested to play a role in neuronal cell death associated with status epilepticus (SE) (8, 65). Glutamate and calcium play pivotal roles in the cascade of events leading to excitotoxic cell death (44, 55). Electron microscopy studies have helped establish at the ultrastructural level the involvement of mitochondria (18, 28) and changes in chromatin and cytoplasm that characterize excitotoxic cell death as a necrotic process (9). A lesser level of excessive excitation can also initiate molecular events leading to a delayed type of cell death, apoptosis.

Several mechanisms have been implicated as partially responsible for the neurochemical cellular alterations that supervene after excitotoxic stimuli (80). These events, when longlasting, lead the cell into a state of energy imbalance, with deterioration of the membrane potential, and cause neuronal and glial depolarization (37). Decreases in high-energy phosphate stores prevent glutamate reuptake, with consequent activation of N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and metabotropic glutamate receptors, the first two contributing to Ca²⁺ overload (74, 88). Mitochondrial depolarization after glutamate exposure has been reported to be an early event associated with intracellular Ca²⁺ loading (1, 31, 38, 40, 77). This event, suggested to be neuroprotective if acute and of moderate intensity (7, 86), seems to trigger necrotic cell death when longlasting and intense. Increases in mitochondrial Ca²⁺ contents may cause disruption of the inner membrane, disturbing electron chain transport and adenosine triphosphate (ATP) production (17). The distinction between a reversible, physiologic response to increased energy demand and a pathologic depolarization after mitochondrial damage is not always easy to make. It has recently been demonstrated that physiologic increases in conductance of mitochondrial membranes might develop as a response to increased synaptic activity (35). More important, this calcium-dependent change in mitochondrial conductance outlasts the period of stimulation by tens of seconds, and has been suggested to contribute to synaptic plasticity (35). During SE, however, such increases in conductance would presumably contribute to an earlier failure of mitochondrial activity. In addition, elevated cytosol Ca²⁺ leads to an increase in the activity of various proteases, phospholipases, and endonucleases (5). Caspases are aspartate-specific cysteine proteases normally existing as zymogens in cells. When cytochrome C is released from the inner mitochondrial membrane, it activates caspases, which might kill the cells (27). Although free radicals and arachidonic acid metabolites have been implicated as fundamental players in diverse processes of cell degeneration (16), they are not addressed further in this chapter.