Glutamate antagonists: deadly liaisons with cancer.

Abstract

Four decades ago, it was demonstrated that the amino acid glutamate, when introduced directly into the central nervous system (CNS), could trigger convulsions (1, 2) by an excitatory (depolarizing) action on neural membrane (3). About the same time, others reported that s.c. glutamate can kill neurons in the retina (4) or brain (5, 6), and that the neuroexcitatory action of glutamate was responsible for the cell killing effect (7). From these early findings, glutamate gradually became recognized for its beneficial role as the predominant excitatory neurotransmitter in the mammalian CNS, and also for its detrimental potential as an “excitotoxic” molecule (8) that can destroy neurons throughout the entire CNS. A large family of glutamate transmitter receptors was then identified (9), which are classified as either ionotropic or metabotropic. The ionotropic subfamily is further divided into three subtypes, referred to as N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and Kainate receptors. In recent decades, it has been shown that glutamate excitotoxicity is responsible for neuronal degeneration in anoxia (10) and in essentially all other acute brain injury conditions (e.g., stroke, hypoglycemia, epilepsy, and head trauma), and the excitotoxic action of glutamate has been shown in many cases to involve abnormal uptake or intracellular mobilization of Ca2+ (11). Substantial evidence has also been generated implicating abnormal glutamate signaling and/or excitotoxicity in the pathogenesis of numerous more chronic CNS diseases, such as Parkinson's and Alzheimer's disease (12), but also multiple sclerosis (13).