Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury.
Glutamate excitotoxicity plays an important role in the development of secondary injuries that occur following traumatic brain injury (TBI), and contributes significantly to expansion of the total volume of injury. Acute increases in extracellular glutamate levels have been detected in both experimental brain trauma models and in human patients, and can lead to over-stimulation of glutamate receptors, resulting in a cascade of excitotoxic-related mechanisms culminating in neuronal damage. These elevated levels of glutamate can be effectively controlled by the astrocytic glutamate transporters GLAST (EAAT1) and GLT-1 (EAAT2). However, evidence indicate these transporters and splice variant are downregulated shortly following the insult, which then precipitates glutamate-mediated excitotoxic conditions. Lack of success with glutamate receptor antagonists as a potential source of clinical intervention treatment following TBI has resulted in the necessity for a better understanding of the mechanisms that underlie the process of excitotoxicity, including the function and regulation of glutamate transporters. Such new insight should improve the likelihood of development of novel avenues for therapeutic intervention following TBI.
Department of Medicine, University of Montreal, Que., Canada.
Jae-Hyuk
JH
Yi
Alan S
AS
Hazell
D027322:Amino Acid Transport System X-AG / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D009498:Neurotoxins / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000378:metabolism
D027322:Amino Acid Transport System X-AG; D018691:Excitatory Amino Acid Antagonists; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D009498:Neurotoxins; D017470:Receptors, Glutamate; D018698:Glutamic Acid