Excitatory Amino Acid Induced Cytotoxicity in Cultured Neurons: Role of Intracellular Ca⁺⁺ Homeostasis

Abstract

In addition to its role as the major excitatory neurotransmitter, L-glutamate may have a toxic effect on neurons (Olney et al. 1971). This neurotoxic action depends on a multiplicity of factors such as concentration, exposure period, glutamate receptor expression, and a variety of intracellular events, the exact nature of which is not known. However, it is likely that different second messenger systems such as the inositol phosphates, cGMP and the intracellular Ca⁺⁺ concentration are of pivotal importance for initiation and propagation of reactions leading to neuronal damage and death (Siesjö 1988; Siesjö et al. 1989; Choi 1988). It is known that cerebral ischemia leads to loss of particular neurons (Ito et al. 1975) and it has been suggested that neurotransmitter glutamate could play a role in this neuronal degeneration (Jørgensen and Diemer 1982). In keeping with this, a variety of pathological conditions such as ischemia and hypoglycemia have been shown to be associated with an overflow of glutamate into the extracellular space in the brain (Benveniste et al. 1984; Drejer et al. 1985; Sandberg et al. 1986). That glutamate may indeed play an important role in ischemic brain damage is underlined by the finding that such damage to hippocampal CA1 pyramidal cells can be prevented by preischemic destruction of glutamatergic dentate gyrus granule cells (Johansen et al. 1986). Moreover, anoxic neuronal death in hippocampal cultures can be prevented by glutamate antagonists (Rothman 1984).