Glutamate receptors, neurotoxicity and neurodegeneration.
Glutamate excitotoxicity is a hypothesis that states excessive glutamate causes neuronal dysfunction and degeneration. As glutamate is a major excitatory neurotransmitter in the central nervous system (CNS), the implications of glutamate excitotoxicity are many and far-reaching. Acute CNS insults such as ischaemia and traumatic brain injury have traditionally been the focus of excitotoxicity research. However, glutamate excitotoxicity has also been linked to chronic neurodegenerative disorders such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease and others. Despite the continued research into the mechanisms of excitotoxicity, there are currently no pharmacological interventions capable of providing significant neuroprotection in the clinical setting of brain ischaemia or injury. This review addresses the current state of excitotoxic research, focusing on the structure and physiology of glutamate receptors; molecular mechanisms underlying excitotoxic cell death pathways and their interactions with each other; the evidence for glutamate excitotoxicity in acute neurologic diseases; laboratory and clinical attempts at modulating excitotoxicity; and emerging targets for excitotoxicity research.
Lau
Anthony
A
Division of Applied and Interventional Research, Toronto Western Research Institute, 399 Bathurst Street, Toronto, ON, Canada, M5T 2S8.
Tymianski
Michael
M
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000502:physiology; D020169:Caspases / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D016166:Free Radical Scavengers / Q000627:therapeutic use; D005609:Free Radicals / Q000378:metabolism; D018698:Glutamic Acid / Q000009:adverse effects* / Q000502:physiology; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects; D009410:Nerve Degeneration / Q000503:physiopathology*; D019636:Neurodegenerative Diseases / Q000503:physiopathology*; D020258:Neurotoxicity Syndromes / Q000503:physiopathology*; D009569:Nitric Oxide / Q000502:physiology; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000502:physiology; D017470:Receptors, Glutamate / Q000502:physiology*; D018092:Kainic Acid Receptors; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000627:therapeutic use; D015032:Zinc / Q000502:physiology
D000975:Antioxidants; D002118:Calcium; D002154:Calpain; D020169:Caspases; D016166:Free Radical Scavengers; D005609:Free Radicals; D018698:Glutamic Acid; D009569:Nitric Oxide; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D019831:Sodium-Calcium Exchanger; D015032:Zinc