Novel treatment of excitotoxicity: targeted disruption of intracellular signalling from glutamate receptors.
Glutamate signalling plays key physiological roles in excitatory neurotransmission and CNS plasticity, but also mediates excitotoxicity, the process responsible for triggering neurodegeneration through glutamate receptor overactivation. Excitotoxicity is thought to be a key neurotoxic mechanism in neurological disorders, including brain ischemia, CNS trauma and epilepsy. However, treating excitotoxicity using glutamate receptor antagonists has not proven clinically viable, necessitating more sophisticated approaches. Increasing knowledge of the composition of the postsynaptic density at glutamatergic synapses has allowed us to extend our understanding of the molecular mechanisms of excitotoxicity and to dissect out the distinct signalling pathways responsible for excitotoxic damage. Key molecules in these pathways are physically linked to the cytoplasmic face of glutamate receptors by scaffolding proteins that exhibit binding specificity for some receptors over others. This imparts specificity to physiological and pathological glutamatergic signalling. Recently, we have capitalized on this knowledge and, using targeted peptides to selectively disrupt intracellular interactions linked to glutamate receptors, have blocked excitotoxic signalling in neurones. This therapeutic approach circumvents the negative consequences of blocking glutamate receptors, and may be a practical strategy for treating neurological disorders that involve excitotoxicity.
Aarts
Michelle M
MM
Toronto Western Research Institute, McPav 11-416, 399 Bathurst Street, Toronto, Ont., Canada M5T 2S8. maarts@uhnres.utoronto.ca
Tymianski
Michael
M
D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D005544:Forecasting; D006801:Humans; D009422:Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate