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Poly(ADP-Ribose) Polymerase (PARP) and Excitotoxicity

  • Domenico E. Pellegrini-Giampietro
  • Alberto Chiarugi
  • Flavio Moroni
Part of the Molecular Biology Intelligence Unit book series (MBIU)

Abstract

Neuronal injury resulting from glutamate receptor-mediated excitotoxicity has been implicated in a wide spectrum of neurological disorders. Following dramatic results in the preclinical setting, anti-excitotoxic neuroprotective agents have been used in clinical trials for stroke and head injury, but the results have generally been unsuccessful. Hence, alternative targets in the excitotoxic cascade appear to be required. Poly(ADP-ribosyl)ation has been linked to the pathogenesis of numerous disorders of the CNS, including excitotoxicity and ischemic injury. A presumed cascade of glutamate receptor activation leading to excessive free radical formation, DNA damage and then overactivation of PARP-1 is based on studies with drugs that block these various steps. Along this classical view, experiments in our laboratory have shown that the intracellular depletion of ATP and NAD induced by PARP-1 overactivation leads to necrotic cell death in ischemic and excitotoxic models and that PARP-1 inhibitors are protective against necrotic but not apoptotic neuronal death. Therefore, it appears reasonable to propose PARP-1 inhibitors as useful therapeutic agents in pathological brain conditions where necrosis predominates.

Keywords

Neuronal Death Middle Cerebral Artery Occlusion Necrotic Cell Death Cereb Blood Flow Apoptotic Neuronal Death 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Landes Bioscience and Springer Science+Business Media 2006

Authors and Affiliations

  • Domenico E. Pellegrini-Giampietro
    • 1
  • Alberto Chiarugi
    • 1
  • Flavio Moroni
    • 1
  1. 1.Dipartimento di Farmacologia Preclinica e ClinicaUniversità degli Studi di FirenzeFirenzeItaly

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