PMID- 10559391
OWN - NLM
STAT- MEDLINE
DCOM- 19991202
LR  - 20191023
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 19
IP  - 22
DP  - 1999 Nov 15
TI  - Protection from oxidative stress-induced apoptosis in cortical neuronal cultures 
      by iron chelators is associated with enhanced DNA binding of hypoxia-inducible 
      factor-1 and ATF-1/CREB and increased expression of glycolytic enzymes, 
      p21(waf1/cip1), and erythropoietin.
PG  - 9821-30
AB  - Iron chelators are pluripotent neuronal antiapoptotic agents that have been shown 
      to enhance metabolic recovery in cerebral ischemia models. The precise 
      mechanism(s) by which these agents exert their effects remains unclear. Recent 
      studies have demonstrated that iron chelators activate a hypoxia signal 
      transduction pathway in non-neuronal cells that culminates in the stabilization 
      of the transcriptional activator hypoxia-inducible factor-1 (HIF-1) and increased 
      expression of gene products that mediate hypoxic adaptation. We examined the 
      hypothesis that iron chelators prevent oxidative stress-induced death in cortical 
      neuronal cultures by inducing expression of HIF-1 and its target genes. We report 
      that the structurally distinct iron chelators deferoxamine mesylate and mimosine 
      prevent apoptosis induced by glutathione depletion and oxidative stress in 
      embryonic cortical neuronal cultures. The protective effects of iron chelators 
      are correlated with their ability to enhance DNA binding of HIF-1 and activating 
      transcription factor 1(ATF-1)/cAMP response element-binding protein (CREB) to the 
      hypoxia response element in cortical cultures and the H19-7 hippocampal neuronal 
      cell line. We show that mRNA, protein, and/or activity levels for genes whose 
      expression is known to be regulated by HIF-1, including glycolytic enzymes, 
      p21(waf1/cip1), and erythropoietin, are increased in cortical neuronal cultures 
      in response to iron chelator treatment. Finally, we demonstrate that cobalt 
      chloride, which also activates HIF-1 and ATF-1/CREB in cortical cultures, also 
      prevents oxidative stress-induced death in these cells. Altogether, these results 
      suggest that iron chelators exert their neuroprotective effects, in part, by 
      activating a signal transduction pathway leading to increased expression of genes 
      known to compensate for hypoxic or oxidative stress.
FAU - Zaman, K
AU  - Zaman K
AD  - Department of Neurology, Harvard Medical School and The Beth Israel Deaconess 
      Medical Center, Boston, Massachusetts 02115, USA.
FAU - Ryu, H
AU  - Ryu H
FAU - Hall, D
AU  - Hall D
FAU - O'Donovan, K
AU  - O'Donovan K
FAU - Lin, K I
AU  - Lin KI
FAU - Miller, M P
AU  - Miller MP
FAU - Marquis, J C
AU  - Marquis JC
FAU - Baraban, J M
AU  - Baraban JM
FAU - Semenza, G L
AU  - Semenza GL
FAU - Ratan, R R
AU  - Ratan RR
LA  - eng
GR  - K08 NS01951/NS/NINDS NIH HHS/United States
GR  - R01 NS39170/NS/NINDS NIH HHS/United States
GR  - R29 NS34943/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Activating Transcription Factor 1)
RN  - 0 (Cdkn1a protein, rat)
RN  - 0 (Chelating Agents)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p21)
RN  - 0 (Cyclins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Hif1a protein, rat)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Transcription Factors)
RN  - 11096-26-7 (Erythropoietin)
RN  - 3G0H8C9362 (Cobalt)
RN  - 500-44-7 (Mimosine)
RN  - EC 1.1.1.27 (L-Lactate Dehydrogenase)
RN  - EC 4.1.2.13 (Fructose-Bisphosphate Aldolase)
RN  - EVS87XF13W (cobaltous chloride)
RN  - GAN16C9B8O (Glutathione)
RN  - J06Y7MXW4D (Deferoxamine)
SB  - IM
MH  - Activating Transcription Factor 1
MH  - Animals
MH  - Apoptosis/drug effects/*physiology
MH  - Cells, Cultured
MH  - Cerebral Cortex/*cytology/*physiology
MH  - Chelating Agents/pharmacology
MH  - Cobalt/pharmacology
MH  - Cyclic AMP Response Element-Binding Protein/*pharmacology
MH  - Cyclin-Dependent Kinase Inhibitor p21
MH  - Cyclins/*genetics
MH  - DNA-Binding Proteins/*metabolism
MH  - Deferoxamine/*pharmacology
MH  - Enzyme Induction/drug effects
MH  - Erythropoietin/*genetics
MH  - Fetus
MH  - Fructose-Bisphosphate Aldolase/biosynthesis/genetics
MH  - *Gene Expression Regulation/drug effects
MH  - Glutathione/metabolism
MH  - Glycolysis
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - L-Lactate Dehydrogenase/biosynthesis/genetics
MH  - Mimosine/pharmacology
MH  - Neurons/*cytology/drug effects/*physiology
MH  - Neuroprotective Agents
MH  - Nuclear Proteins/*metabolism
MH  - Oxidative Stress/*physiology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Transcription Factors/*metabolism
PMC - PMC6782985
EDAT- 1999/11/13 00:00
MHDA- 1999/11/13 00:01
PMCR- 2000/05/15
CRDT- 1999/11/13 00:00
PHST- 1999/11/13 00:00 [pubmed]
PHST- 1999/11/13 00:01 [medline]
PHST- 1999/11/13 00:00 [entrez]
PHST- 2000/05/15 00:00 [pmc-release]
AID - 3618 [pii]
AID - 10.1523/JNEUROSCI.19-22-09821.1999 [doi]
PST - ppublish
SO  - J Neurosci. 1999 Nov 15;19(22):9821-30. doi: 10.1523/JNEUROSCI.19-22-09821.1999.