Excitotoxicity in Cerebral Ischemia

  • Domenico E. Pellegrini-Giampietro
  • Elena Meli
  • Flavio Moroni


The hypothesis that cerebral ischemia may recognize an excitoxic pathophysiological component is supported by a number of consolidated arguments, including the neuroprotective activity of glutamate receptor antagonists in experimental animal models and the use of anti-excitotoxic agents in clinical trials for stroke. Despite the dramatic results in the preclinical setting, phase III clinical trials with neuroprotective drugs have been generally unsuccessful so far. Several complicating variables have been put forward to explain this discrepancy, including population heterogeneity, morphological and functional differences between human and animal brain, and side-effects of the tested compounds that prevent reaching effective plasma concentrations. Fine-tuning in the design of clinical trials, the use of imaging techniques for the evaluation of human brain injury, and the development of more appropriate experimental animal models are among the strategies that need to be utilized in future clinical studies. Also, drugs with a better therapeutic index and aimed at alternative targets in the excitotoxic cascade appear to be required. In our laboratory, we have recently investigated two alternative mechanisms promoted by extracellular glutamate that lead to post-ischemic neuronal damage: (1) the stimulation of mGlu1 receptors and (2) the overactivation of poly(ADP-ribose) polymerase.


cerebral ischemia stroke glutamate receptors free radicals poly(ADP-ribose) polymerase 


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Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Domenico E. Pellegrini-Giampietro
    • 1
  • Elena Meli
    • 1
  • Flavio Moroni
    • 1
  1. 1.Dipartimento di Fannacologia Preclinica e ClinicaFirenzeItaly

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