Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.4.2.30 (
PARP
)
13,611
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID: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. 2038 May 52
Poly(adenosine diphosphate ribose) polymerases (PARPs) are multifunctional proteins which play a role in many cellular processes. Namely, PARP1 and PARP2 have been shown to be involved in DNA repair, and therefore are valid targets in cancer treatment with
PARP
inhibitors, such as rucaparib, currently in clinical trials. Proton magnetic resonance spectroscopy (
1
H-
MRS
) was used to study the impact of rucaparib in vitro and ex vivo in liver tissue from mice, via quantitative analysis of nicotinamide adenosine diphosphate (NAD
+
) spectra, to assess the potential of
MRS
as a biomarker of the
PARP
inhibitor response. SW620 (colorectal) and A2780 (ovarian) cancer cell lines, and PARP1 wild-type (WT) and PARP1 knock-out (KO) mice, were treated with rucaparib, temozolomide (methylating agent) or a combination of both drugs.
1
H-
MRS
spectra were obtained from perchloric acid extracts of tumour cells and mouse liver. Both cell lines showed an increase in NAD
+
levels following
PARP
inhibitor treatment in comparison with temozolomide treatment. Liver extracts from PARP1 WT mice showed a significant increase in NAD
+
levels after rucaparib treatment compared with untreated mouse liver, and a significant decrease in NAD
+
levels in the temozolomide-treated group. The combination of rucaparib and temozolomide did not prevent the NAD
+
depletion caused by temozolomide treatment. The
1
H-
MRS
results show that NAD
+
levels can be used as a biomarker of
PARP
inhibitor and methylating agent treatments, and suggest that in vivo measurement of NAD
+
would be valuable.
...
PMID:PARP inhibitor rucaparib induces changes in NAD levels in cells and liver tissues as assessed by MRS. 2854 72
