Apurinic/apyrimidinic endonuclease APE1 is required for PACAP-induced neuroprotection against global cerebral ischemia

R. Anne Stetler, Yanqin Gao, R. Suzanne Zukin, Peter S. Vosler, Lili Zhang, Feng Zhang, Guodong Cao, Michael V. L. Bennett, Jun Chen

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Inducible DNA repair via the base-excision repair pathway is an important prosurvival mechanisma ctivated in response to oxidative DNA damage. Elevated levels of the essential base-excision repair enzyme apurinic/apyrimidinic endonuclease1(APE1)/redox effector factor-1 correlate closely with neuronal survival against ischemic insults, depending on the CNS region, protective treatments, and degree of insult. However, the precise mechanisms by which this multifunctional protein affords protection and is activated by upstream signaling pathways in postischemic neurons are not well delineated. Here we show that intracerebral administration of pituitary adenylate cyclase-activating polypeptide (PACAP), an endogenously occurring small neuropeptide, induces expression of APE1 in hippocampal neurons. Induction of APE1expression requires PKA-and p38-dependent phosphorylation of cAMP response-element binding and activating transcription factor 2, which leads to transactivation of the APE1 promoter. We further show that PACAP markedly reduces oxidative DNA stress and hippocampal CA1 neuronal death following transient global ischemia. These effects occurred,atleastinpart,viaenhanced APE1expression.Furthermore, the DNA repair function of APE1 was required for PACAP-mediated neuroprotection. Thus, induction of DNA repair enzymes may be a uniquestrategy for neuroprotection agains thippocampa linjury.

Original languageEnglish (US)
Pages (from-to)3204-3209
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number7
DOIs
StatePublished - Feb 16 2010

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DNA-(Apurinic or Apyrimidinic Site) Lyase
Pituitary Adenylate Cyclase-Activating Polypeptide
Brain Ischemia
DNA Repair
Activating Transcription Factor 2
DNA Repair Enzymes
Neurons
Response Elements
Neuropeptides
Transcriptional Activation
DNA Damage
Oxidation-Reduction
Oxidative Stress
Ischemia
Phosphorylation
Neuroprotection
DNA
Enzymes
Proteins

Keywords

  • Activating transcription factor 2
  • cAMP response-element binding
  • Delayed neurodegeneration
  • DNA repair
  • Oxidative stress

ASJC Scopus subject areas

  • General

Cite this

Apurinic/apyrimidinic endonuclease APE1 is required for PACAP-induced neuroprotection against global cerebral ischemia. / Stetler, R. Anne; Gao, Yanqin; Zukin, R. Suzanne; Vosler, Peter S.; Zhang, Lili; Zhang, Feng; Cao, Guodong; Bennett, Michael V. L.; Chen, Jun.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 7, 16.02.2010, p. 3204-3209.

Research output: Contribution to journalArticle

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abstract = "Inducible DNA repair via the base-excision repair pathway is an important prosurvival mechanisma ctivated in response to oxidative DNA damage. Elevated levels of the essential base-excision repair enzyme apurinic/apyrimidinic endonuclease1(APE1)/redox effector factor-1 correlate closely with neuronal survival against ischemic insults, depending on the CNS region, protective treatments, and degree of insult. However, the precise mechanisms by which this multifunctional protein affords protection and is activated by upstream signaling pathways in postischemic neurons are not well delineated. Here we show that intracerebral administration of pituitary adenylate cyclase-activating polypeptide (PACAP), an endogenously occurring small neuropeptide, induces expression of APE1 in hippocampal neurons. Induction of APE1expression requires PKA-and p38-dependent phosphorylation of cAMP response-element binding and activating transcription factor 2, which leads to transactivation of the APE1 promoter. We further show that PACAP markedly reduces oxidative DNA stress and hippocampal CA1 neuronal death following transient global ischemia. These effects occurred,atleastinpart,viaenhanced APE1expression.Furthermore, the DNA repair function of APE1 was required for PACAP-mediated neuroprotection. Thus, induction of DNA repair enzymes may be a uniquestrategy for neuroprotection agains thippocampa linjury.",
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