Zinc translocation accelerates infarction after mild transient focal ischemia.
Excess release of chelatable zinc (Zn(2+)) from central synaptic vesicles may contribute to the pathogenesis of selective neuronal cell death following transient forebrain ischemia, but a role in neurodegeneration after focal ischemia has not been defined. Adult male Long-Evans rats subjected to middle cerebral artery occlusion (MCAO) for 30 min followed by reperfusion developed delayed cerebral infarction reaching completion 3 days after the insult. One day after the insult, many degenerating cerebral neurons exhibited increased intracellular Zn(2+), and some labeled with the antibody against activated caspase-3. I.c.v. administration of the Zn(2+) chelator, EDTA saturated with equimolar Ca(2+) (CaEDTA), 15 min prior to ischemia attenuated subsequent Zn(2+) translocation into cortical neurons, and reduced infarct volume measured 3 days after ischemia. Although the protective effect of CaEDTA at this endpoint was substantial (about 70% infarct reduction), it was lost when insult severity was increased (from 30 to 60 min MCAO), or when infarct volume was measured at a much later time point (14 days instead of 3 days after ischemia). These data suggest that toxic Zn(2+) translocation, from presynaptic terminals to post-synaptic cell bodies, may accelerate the development of cerebral infarction following mild transient focal ischemia.
Lee
J-M
JM
Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 S Euclid Avenue, Saint Louis, MO 63110, USA.
Zipfel
G J
GJ
Park
K H
KH
He
Y Y
YY
Hsu
C Y
CY
Choi
D W
DW
D000634:Aminoquinolines; D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002544:Cerebral Infarction / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002614:Chelating Agents / Q000494:pharmacology; D005456:Fluorescent Dyes; D007150:Immunohistochemistry; D002546:Ischemic Attack, Transient / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D017729:Presynaptic Terminals / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D009435:Synaptic Transmission / Q000502:physiology; D013687:Telencephalon / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D014105:Tosyl Compounds; D015032:Zinc / Q000378:metabolism*
D000634:Aminoquinolines; D002614:Chelating Agents; D005456:Fluorescent Dyes; D014105:Tosyl Compounds; C061730:N-(6-methoxy-8-quinolyl)-4-toluenesulfonamide; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D015032:Zinc