Glutamate Excitotoxicity

Our company was founded upon evidence that a very well established cell toxic pathway, glutamate excitotoxicity, can be controlled through the use of small molecule drugs. Glutamate is the predominant excitatory amino acid neurotransmitter in the mammalian central nervous system. Under normal conditions the function of glutamate is to tightly control the communication of information between neurons. However, it has been known for over 40 years that high glutamate exposure triggers central neuronal death, a process known as excitotoxicity.

An understanding of excitotoxicity requires emphasis to be placed on the extracellular concentrations of glutamate since it is this pool that can be toxic to susceptible neurons through activation of glutamate receptors. The intracellular concentrations of glutamate (5-10 mM) is normally 10,000-fold greater than the extracellular concentrations (<1-10 µM). Perturbations of this ratio can be toxic to neurons. Unlike many other neurotransmitters, there is no evidence that glutamate is metabolized extracellularly. Instead, it is cleared from the extracellular space by transport into neurons and astrocytes. This is the job of the glutamate transporters.

Based on the knowledge that excess synaptic glutamate is neurotoxic, numerous attempts have been made to block glutamate receptors during disease in order to prevent the triggering of cell death pathways. While glutamate receptor antagonists demonstrated early efficacy in modulating the glutamate pathway, they also demonstrated significant toxicity.

An alternative approach to blocking glutamate receptors is to decrease the levels of glutamate in the extracellular space. Indeed, both academic and pharmaceutical studies indicate that decreasing glutamate levels in the extracellular space can prevent neuronal degeneration. Based on this hypothesis Ruxton chose a novel target in the glutamate pathway, the glutamate transporter.