Excitotoxicity is a process of neuronal injury mediated by excitatory amino acids (Olney and Sharpe 1969). Glutamate is the most abundant amino acid in the brain and is an essential neurotransmitter in the central nervous system. It plays a primary role in excitotoxicity (Arundine and Tymianski 2003). Overstimulation of glutamate receptors results in an excessive influx of calcium to mediate excito-toxic responses in nerve cells. Glutamate can act on many receptor types in the nervous system, including ionotropic and metabotropic receptors. Ionotropic NMDA-receptors are activated by the glutamate analogue N-methyl-D-aspartate (NMDA) and play a major role in excitotoxicity. a-amino-3-hydroxy-5-methyl-4-isoxalone propionic acid (AMPA) and kainate receptors are activated by AMPA and by kainate, respectively. These non-NMDA-type receptors are also involved in excessive intracellular calcium influx and excitotoxicity (Arundine and Tymianski 2003; Danbolt 2001). Ionotropic receptors are ion channel-linked receptors and cause ion-influx when stimulated. Metabotropic glutamate receptors (mGluR) are G-protein coupled receptors. Glutamate receptors may take part in excitotoxicity by modulating the function of other receptors either directly or indirectly. The Ca2+ influx following glutamate receptor activation in excitotoxicity can induce cell death by activating Ca2+-dependent enzyme systems, such as nitric oxide (NO) synthase (nNOS), calpains, and phospholipases. nNOS activation leads to the overproduction of NO through the conversion of L-arginine of L-citrulline. NO can exert many roles as a signaling molecule in neurons. Generation of excess NO can be neurotoxic (Dawson et al. 1993; Evans et al. 2001; Lankiewicz et al. 2000). NO can combine with O2- in the mitochondria to generate more toxic peroxynitrite (ONOO-), which can cause oxidative or nitrosa-tive injury to cellular proteins, lipids and DNA (Stamler et al. 2001). Injury to DNA causes a massive activation of poly (ADP-ribose) polymerase-1, which ultimately triggers cell death via the process of parthanatos (Mandir et al. 2000; Wang et al. 2004) (Fig. 5.1).

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