Abstract
Traumatic brain injury produces peroxynitrite, a powerful oxidant which triggers DNA strand breaks, leading to the activation of poly(ADP-ribose)polymerase-1 (PARP-1). We previously demonstrated that 3-aminobenzamide, a PARP inhibitor, is neuroprotective in a model of traumatic brain injury induced by fluid percussion in rat, suggesting that PARP-1 could be a therapeutic target. In order to confirm this hypothesis, we investigated the effects of PJ34 and INO-1001, two PARP inhibitors from structural classes other than benzamide, on the post-traumatic consequences. Pre- and post-treatments with PJ34 (30 mg/kg/day) and INO-1001 (10 mg/kg/day) decrease the neurological deficit at 3 days post-injury and this deficit is still reduced at 7 days. These neurological recovery-promoting effects are associated with the inhibition of PARP-1 activation caused by trauma, as demonstrated by abolishment of immunostaining of poly(ADP-ribose). Thus, the present work strengthens strongly the concept that PARP-1 inhibition may be a suitable approach for the treatment of brain trauma.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Brain / drug effects
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Brain / enzymology
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Brain / physiopathology
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Brain Injuries / complications
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Brain Injuries / drug therapy*
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Brain Injuries / physiopathology
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Collagen Type XI / antagonists & inhibitors*
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Collagen Type XI / metabolism
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Disease Models, Animal
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use
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Immunohistochemistry
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Indoles / pharmacology*
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Indoles / therapeutic use
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Male
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Nerve Degeneration / drug therapy*
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Nerve Degeneration / etiology
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Nerve Degeneration / physiopathology
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Neurons / drug effects
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Neurons / enzymology
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Neurons / pathology
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Neuroprotective Agents / pharmacology
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Neuroprotective Agents / therapeutic use
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Phenanthrenes / pharmacology*
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Phenanthrenes / therapeutic use
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Poly (ADP-Ribose) Polymerase-1
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Poly Adenosine Diphosphate Ribose / metabolism
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Poly(ADP-ribose) Polymerases
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Rats
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Rats, Sprague-Dawley
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Recovery of Function / drug effects
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Recovery of Function / physiology
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Solubility
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Treatment Outcome
Substances
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Collagen Type XI
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Enzyme Inhibitors
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INO 1001
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Indoles
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N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
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Neuroprotective Agents
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Phenanthrenes
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Poly Adenosine Diphosphate Ribose
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Parp1 protein, rat
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases