Concept of excitotoxicity via glutamate receptors

Abstract

Since its inception, the concept of glutamate excitotoxicity has provided a foundational framework for understanding the role played by excitatory amino acids in disease states of the brain. At the same time, it has served as a guiding principle in the development and evaluation of new anti-excitotoxic drugs, many of which show promise as neuroprotective therapies in a number of neurological conditions. The discovery that glutamate receptors on the cell surface can engage, through second messengers such as calcium (Ca2+), nitric oxide (NO), and inositol phospholipids, downstream intracellular signaling cascades involved in cell death helped uncover the complexity of the excitotoxic cascade. The identification of numerous intracellular effectors of excitotoxicity has provided a physiological and pharmacological basis for understanding the cellular and molecular mechanisms behind glutamate-mediated nerve cell injury and its role in neuropsychiatric diseases. More recently, knowledge of the molecular biology of glutamate receptors has allowed, for the first time, the identification of differences in the pattern of expression of glutamate receptors in human populations afflicted by neuropsychiatric diseases. This knowledge will be useful in uncovering genes that may confer individual susceptibility to excitotoxic damage and, as a result, predisposition to the development of certain mental and neurological diseases. In this chapter, the role of glutamate receptor overactivation in excitotoxic cell injury as well as potential neuroprotective therapies for limiting glutamate-mediated neurotoxicity in disease states of the central nervous system will be discussed.