A significant number of laboratories observed that poly (ADP-ribose) polymerase (PARP)
inhibitors, administered a few hours after ischemic or traumatic brain injury, may drastically reduce
the subsequent neurological damage. It has also been shown that PARP inhibitors, administered for 24
hours to rats with permanent middle cerebral artery occlusion (MCAO), may reduce the number of
dying neurons for a long period after surgery, thus suggesting that these agents could reduce the delayed brain damage
and the neurological and cognitive impairment (dementia) frequently observed a few months after a stroke. In organotypic
hippocampal slices exposed to N-methyl-N'-nitro-N'-nitrosoguanidine (MNNG), an alkylating agent able to activate
PARP, a selective and delayed degeneration of the CA1 pyramidal cells which was anatomically similar to that observed
after a short period of oxygen and glucose deprivation (OGD) has been described. Biochemical and electrophysiological
approaches showed that MNNG exposure caused an increased expression and function of the calcium permeable α-amino-
3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) channels in the CA1 but not in the CA3 hippocampal region.
PARP inhibitors prevented this increase and reduced CA1 cell death. The AMPA receptor antagonist 2,3-dihydroxy-6-
nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione or the selective Ca2+ permeable AMPA channel blocker 1-Naphthyl
acetyl spermine (NASPM), also reduced the MNNG-induced CA1 pyramidal cell death. Since activation of PARP-1
facilitate the expression of Ca2+ permeable channels and the subsequent delayed cell death, PARP inhibitors administered
a few hours after a stroke may not only reduce the early post-ischemic brain damage but also the late neuronal death
frequently occurring after severe stroke.
Keywords: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, cell death, Dementia, Neuroprotection,
Poly(ADP-ribose) polymerases, stroke.
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