Endogenous zinc mediates apoptotic programmed cell death in the developing brain.
Endogenous zinc can mediate the apoptotic programmed cell death (PCD) in the developing brain. Intensive accumulation of labile zinc occurs in almost all neurons undergoing PCD in the developing rat brain. Based on the greater frequency of neurons with intensive zinc accumulation compared to apoptotic neurons, it is inferred that cytosolic zinc accumulation precedes apoptotic PCD. To determine the role of intracellular labile zinc in developmental apoptosis, we subcutaneously injected the membrane-permeant zinc chelator, N,N,N',N-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) into postnatal rats for 7 days after birth. TPEN chelated intraneuronal zinc without modulating the expression of the zinc-regulating proteins, ZnT-1, ZnT-3, and synaptophysin. The frequency of apoptotic neurons significantly decreased in TPEN-treated rat brains compared with that in normal postnatal rats. Activating cleavages of caspase-9 and -3, and mitochondrial pro-apoptotic Bax expression were reduced, whereas expression of anti-apoptotic Bcl-2 was increased. Thus, intracerebral zinc chelation may arrest PCD in the developing brain by interfering with the caspase-dependent apoptotic pathway. The present study demonstrates that intracellular zinc acts as a key mediator of developmental apoptosis and therefore provides the first in vivo evidence that endogenous labile zinc causes neuronal apoptosis.
Cho
Eunsil
E
Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
Hwang
Jung-Jin
JJ
Han
Seung-Hee
SH
Chung
Sun Ju
SJ
Koh
Jae-Young
JY
Lee
Joo-Yong
JY
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000166:cytology* / Q000187:drug effects / Q000254:growth & development*; D020169:Caspases / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005029:Ethylenediamines / Q000494:pharmacology; D005260:Female; D020287:In Situ Nick-End Labeling / Q000379:methods; D007279:Injections, Subcutaneous / Q000379:methods; D051379:Mice; D008813:Mice, Inbred ICR; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D011247:Pregnancy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D002614:Chelating Agents; D005029:Ethylenediamines; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D020169:Caspases; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine