Effect of acute poly(ADP-ribose) polymerase inhibition by 3-AB on blood-brain barrier permeability and edema formation after focal traumatic brain injury in rats.
Recent evidence supports a crucial role for matrix metalloproteinase-9 (MMP-9) in blood-brain barrier (BBB) disruption and vasogenic edema formation after traumatic brain injury (TBI). Although the exact causes of MMP-9 upregulation after TBI are not fully understood, several arguments suggest a contribution of the enzyme poly(ADP-ribose)polymerase (PARP) in the neuroinflammatory response leading to MMP-9 activation. The objectives of this study were to evaluate the effect of PARP inhibition by 3-aminobenzamide (3-AB) (1) on MMP-9 upregulation and BBB integrity, (2) on edema formation as assessed by magnetic resonance imaging (MRI), (3) on neuron survival as assessed by (1)H magnetic resonance spectroscopy ((1)H-MRS), and (4) on neurological deficits at the acute phase of TBI. Western blots and zymograms showed blunting of MMP-9 upregulation 6 h after TBI. BBB permeability was decreased at the same time point in 3-AB-treated rats compared to vehicle-treated rats. Cerebral MRI showed less "free" water in 3-AB-treated than in vehicle-treated rats 6 h after TBI. MRI findings 24 h after TBI indicated predominant cytotoxic edema, and at this time point no significant differences were found between 3-AB- and vehicle-treated rats with regard to MMP-9 upregulation, BBB permeability, or MRI changes. At both 6 and 24 h, neurological function was better in the 3-AB-treated than in the vehicle-treated rats. These data suggest that PARP inhibition by 3-AB protected the BBB against hyperpermeability induced by MMP-9 upregulation, thereby decreasing vasogenic edema formation 6 h after TBI. Furthermore, our data confirm the neuroprotective effect of 3-AB at the very acute phase of TBI.
Lescot
Thomas
T
Equipe de recherche Pharmacologie de la Circulation Cérébrale (EA 2510), Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France. thomas.lescot@psl.aphp.fr
Fulla-Oller
Laurence
L
Palmier
Bruno
B
Po
Christelle
C
Beziaud
Tiphaine
T
Puybasset
Louis
L
Plotkine
Michel
M
Gillet
Brigitte
B
Meric
Philippe
P
Marchand-Leroux
Catherine
C
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001929:Brain Edema / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D010539:Permeability; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric
D001549:Benzamides; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C025160:3-aminobenzamide; D011065:Poly(ADP-ribose) Polymerases; D020780:Matrix Metalloproteinase 9