Post-ischemic brain damage: targeting PARP-1 within the ischemic neurovascular units as a realistic avenue to stroke treatment.
Stroke is the third leading cause of death in industrialized countries but efficacious stroke treatment is still an unmet need. Preclinical research indicates that different molecules afford protection from ischemic neurodegeneration, but all clinical trials conducted so far have inexorably failed. Critical re-evaluation of experimental data shows that all the components of the neurovascular unit, such as neurons, glia, endothelia and basal membranes, must be protected during the ischemic insult to obtain substantial and long-lasting neuroprotection. Here, we propose the nuclear enzyme poly(ADP-ribose) polymerase (PARP-1) as a key effector of cell death in the various elements of the neurovascular units, and assert that drugs inhibiting PARP-1 may therefore represent valuable tools for pharmacological treatment of stroke patients.
Moroni
Flavio
F
Department of Preclinical and Clinical Pharmacology, University of Florence, Italy. flavio.moroni@unifi.it
Chiarugi
Alberto
A
D001925:Brain Damage, Chronic / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D002545:Brain Ischemia / Q000150:complications* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D016923:Cell Death; D002560:Cerebrovascular Circulation; D002986:Clinical Trials as Topic; D003097:Collateral Circulation; D006801:Humans; D009474:Neurons / Q000473:pathology*; D018696:Neuroprotective Agents / Q000627:therapeutic use; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology*; D015533:Transcriptional Activation
D018696:Neuroprotective Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases