Intervention timing and effect of PJ34 on astrocytes during oxygen-glucose deprivation/reperfusion and cell death pathways

Abstract

Poly (ADP-ribose) polymerase-1 (PARP-1) plays as a double edged sword in cerebral ischemia-reperfusion, hinging on its effect on the intracellular energy storage and injury severity, and the prognosis has relationship with intervention timing. During ischemia injury, apoptosis and oncosis are the two main cell death pathway sin the ischemic core. The participation of astrocytes in ischemia-reperfusion induced cell death has triggered more and more attention. Here, we examined the protective effects and intervention timing of the PARP-1 inhibitor PJ34, by using a mixed oxygen-glucose deprivation/reperfusion (OGDR) model of primary rat astrocytes in vitro, which could mimic the ischemia-reperfusion damage in the "ischemic core". Meanwhile, cell death pathways of various PJ34 treated astrocytes were also investigated. Our results showed that PJ34 incubation (10 μmol/L) did not affect release of lactate dehydrogenase (LDH) from astrocytes and cell viability or survival 1 h after OGDR. Interestingly, after 3 or 5 h OGDR, PJ34 significantly reduced LDH release and percentage of PI-positive cells and increased cell viability, and simultaneously increased the caspase-dependent apoptotic rate. The intervention timing study demonstrated that an earlier and longer PJ34 intervention during reperfusion was associated with more apparent protective effects. In conclusion, earlier and longer PJ34 intervention provides remarkable protective effects for astrocytes in the "ischaemic core" mainly by reducing oncosis of the astrocytes, especially following serious OGDR damage.

Poly(ADP-Ribose) Polymerase Inhibitor PJ34 Reduces Brain Damage after Stroke in the Neonatal Mouse Brain

“…The presence of clasmatodendrotic astrocytes in the cortical infarct eight days after ischemia suggests that tissue damage is still in progress as previously reported in the neonatal ischemic rat [23], and PJ34 reverses this effect at the rostral extremity. In primary astrocyte cultures submitted to oxygen-glucose deprivation and re-oxygenation, PJ34 was associated with protective effects [24], and combined targeting of either PARP-1/PARP-2 or PARP-12/PARP-3 inhibition after s. aureus injury attenuated astrocyte inflammatory responses more effectively compared to knock-down of either PARP alone [25].…”