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

Abstract

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.

Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor

“…Independent of its anti-inflammatory actions, INO-1001 and other PARP inhibitors can interrupt a programmed cell death pathway that is triggered by DNA damage [41-43]. Accordingly, prior studies have shown salutary effects of PARP inhibitors given shortly (within 60 minutes) after TBI [16,44-47]. A key and novel aspect of the present study is that PARP inhibition was not initiated until 20 - 24 hours after TBI.…”

The 70 kDa heat shock protein protects against experimental traumatic brain injury

“…Recent work in TBI and related brain injuries has implicated, among other processes, matrix metalloproteinases (MMPs) in the breakdown of the extracellular matrix (ECM) and BBB, leading to brain edema and hemorrhage (Lescot et al, 2010 and Higashida et al, 2011). MMPs are first expressed as pro-proteins, which are cleaved by other activated MMPs and proteases in the extracellular space (Cunningham et al, 2005).…”

Neuroprotective potential of erythropoietin and its derivative carbamylated erythropoietin in periventricular leukomalacia

“…Several studies reported that PARP-1 gene interruption or pharmacological inhibition elicits neuroprotection (Jagtap and Szabo, 2005; Lescot et al, 2010; Veto et al, 2010). We examined the effects of EPO and CEPO on PARP-1 activity in these PVL models and found decreased PARP-1 activity in the white matter after treatment.…”