Key result
The PARP1 inhibitor veliparib cuts cerebral infarct area ~79% after ischemia-reperfusion in ARH3-deficient mice.
Why the study?
Excessive PAR accumulation due to ARH3 deficiency leads to cell death and neurodegeneration, and the potential protective effect of PARP1 inhibition was unclear.
Does PARP1 inhibition reduce cell death and injury in ARH3-deficient mice and human cells exposed to oxidative stress and ischemia/reperfusion?
Does PARP1 inhibition reduce cell death and injury in ARH3-deficient mice and human cells exposed to oxidative stress and ischemia/reperfusion?
Absolute Event Rate: 3.5% vs 17%
p-value: p=<0.01
PARP1 inhibition alleviates cell death and injury from oxidative stress and ischemia/reperfusion in ARH3-deficient models, suggesting a potential therapeutic strategy for patients with ARH3 deficiency.
PARP1 inhibition may attenuate injury in ARH3 deficiency; leaves open clinical translation pending human studies.
Poly(ADP-ribosyl)ation refers to the covalent attachment of ADP-ribose to protein, generating branched, long chains of ADP-ribose moieties, known as poly(ADP-ribose) (PAR). Poly(ADP-ribose) polymerase 1 (PARP1) is the main polymerase and acceptor of PAR in response to DNA damage. Excessive intracellular PAR accumulation due to PARP1 activation leads cell death in a pathway known as parthanatos. PAR degradation is mainly controlled by poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribose-acceptor hydrolase 3 (ARH3). Our previous results demonstrated that ARH3 confers protection against hydrogen peroxide (H2O2) exposure, by lowering cytosolic and nuclear PAR levels and preventing apoptosis-inducing factor (AIF) nuclear translocation. We identified a family with an ARH3 gene mutation that resulted in a truncated, inactive protein. The 8-year-old proband exhibited a progressive neurodegeneration phenotype. In addition, parthanatos was observed in neurons of the patient's deceased sibling, and an older sibling exhibited a mild behavioral phenotype. Consistent with the previous findings, the patient's fibroblasts and ARH3-deficient mice were more sensitive, respectively, to H2O2 stress and cerebral ischemia/reperfusion-induced PAR accumulation and cell death. Further, PARP1 inhibition alleviated cell death and injury resulting from oxidative stress and ischemia/reperfusion. PARP1 inhibitors may attenuate the progression of neurodegeneration in affected patients with ARH3 deficiency.
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Mashimo et al. (2019) studied ARH3 deficiency (progressive neurodegeneration) (n=6). PARP1 inhibition (veliparib / PJ34) vs. Control (vehicle) was evaluated on Infarct area in ARH3-/- mice after middle cerebral artery occlusion and 24-hour reperfusion (p=<0.01). In ARH3-deficient mice, the PARP1 inhibitor veliparib significantly reduced cerebral infarct area following ischemia/reperfusion injury compared to control (3.5% vs 17.0%).
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