Chelation of neurotoxic zinc levels does not improve neurobehavioral outcome after traumatic brain injury.
Increases of synaptically released zinc and intracellular accumulation of zinc in hippocampal neurons after traumatic or ischemic brain injury is neurotoxic and chelation of zinc has been shown to reduce neurodegeneration. Although our previous studies showed that zinc chelation in traumatically brain-injured rats correlated with an increase in whole-brain expression of several neuroprotective genes and reduced numbers of apoptotic neurons, the effect on functional outcome has not been determined, and the question of whether this treatment may actually be clinically relevant has not been answered. In the present study, we show that treatment of TBI rats with the zinc chelator calcium EDTA reduces the numbers of injured, Fluoro-Jade-positive neurons in the rat hippocampus 24 h after injury but does not improve neurobehavioral outcome (spatial memory deficits) 2 weeks post-injury. Our data suggest that zinc chelation, despite providing short-term histological neuroprotection, fails to improve long-term functional outcome, perhaps because long-term disruptions in homeostatic levels of zinc adversely influence hippocampus-dependent spatial memory.
Department of Anesthesiology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0830, United States. hhellmic@utmb.edu
Helen L
HL
Hellmich
Kristine
K
Eidson
Jeremy
J
Cowart
Jeanna
J
Crookshanks
Deborah K
DK
Boone
Syed
S
Shah
Tatsuo
T
Uchida
Douglas S
DS
DeWitt
Donald S
DS
Prough
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000235:genetics / Q000523:psychology; D053148:Caspase 3 / Q000235:genetics; D002614:Chelating Agents / Q000627:therapeutic use*; D015913:Chelation Therapy / Q000379:methods*; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects; D015032:Zinc / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D051028:bcl-2-Associated X Protein / Q000235:genetics
C494828:Bax protein, rat; D002614:Chelating Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D053148:Caspase 3; D015032:Zinc