Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia

Mikael J.L. Eliasson, Kenji Sampei, Allen S. Mandir, Patricia D. Hurn, Richard J. Traystman, Jun Bao, Andrew Pieper, Zhao Qi Wang, Ted M. Dawson, Solomon H. Snyder, Valina L. Dawson

Research output: Contribution to journalArticlepeer-review

Abstract

Nitric oxide (NO) and peroxynitrite, formed from NO and superoxide anion, have been implicated as mediators of neuronal damage following focal ischemia, but their molecular targets have not been defined. One candidate pathway is DNA damage leading to activation of the nuclear enzyme, poly(ADP- ribose) polymerase (PARP), which catalyzes attachment of ADP ribose units from NAD to nuclear proteins following DNA damage. Excessive activation of PARP can deplete NAD and ATP, which is consumed in regeneration of NAD, leading to cell death by energy depletion. We show that genetic disruption of PARP provides profound protection against glutamate-NO-mediated ischemic insults in vitro and major decreases in infarct volume after reversible middle cerebral artery occlusion. These results provide compelling evidence for a primary involvement of PARP activation in neuronal damage following focal ischemia and suggest that therapies designed towards inhibiting PARP may provide benefit in the treatment of cerebrovascular disease.

Original languageEnglish (US)
Pages (from-to)1089-1095
Number of pages7
JournalNature medicine
Volume3
Issue number10
DOIs
StatePublished - Oct 1997

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint

Dive into the research topics of 'Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia'. Together they form a unique fingerprint.

Cite this