Inhibition Of NDRG2-related Apoptosis Is Involved In An Astrocyte-specific Neuroprotection Induced By Sevoflurane Preconditioning

Background: Mechanism study of sevoflurane preconditioning–induced cerebral ischemic tolerance is mostly focused on the death and survival of neuron, while the involvement of other cell types(i.e. astrocyte) is negalected. NDRG2 is a gene that mainly expressed in astrocyte in central nervous system and plays an important role in regulating astrocyte proliferation and reactivity. Our previous work showed that NDRG2 might participate in brain ischemia. This study investigates the role of astroglial NDRG2 in the neuroprotection of sevoflurane preconditioning against cerebral ischemic/reperfusion injury both in vivo and in vitro.Methods: At 2h after sevoflurane(2%) preconditioning for 1h, rats were subjected to MCAO for 120 min. Neurobehavioral scores(n=10), infarct volumes(n=10), astrocyte reactivity(n=6), cellular apoptosis(n=6), and NDRG2 expression(n=6) were determined at 24 h after reperfusion. In vitro, cultural astrocytes were exposed to OGD for 4h at 2hafter 2% sevoflurane preconditioing(1h). Cellular viability(n=8), LDH release(n=8), apoptosis(n=6), and NDRG2 expression(n=6) were evaluated in the presence or absence of NDRG2-specific si RNA or NDRG2 overexpression plasmid.Results: Sevoflurane preconditioning improved neurological function(12.75[11.38~13.50] vs. 7.0[6.5~8.5]), reduced ischemic infarct volume(25.7±5.7% vs. 48.3±8.9%), decreased apoptosis(TUNEL–positive cells reduced to 31.2 ± 5.3% and cleaved Caspase-3 reduced to 1.42 ± 0.21 fold) and inhibited NDRG2 expression(1.28±0.15 fold) and nuclear translocation(2.21±0.29 fold) at ischemic penumbra. Similar effects were observed in cultural astrocytes exposed to OGD. NDRG2 knockdown by si RNA attenuated OGD–induced injury(cell viability increased to 80.5±4.1%; LDH release reduced to 30.5±4.0%) and cellular apoptosis(cleaved Caspase-3 reduced to 1.55±0.21 fold; TUNEL–positive cells reduced to 18.2±4.3%), whereas NDRG2 overexpression reversed the protective effects of sevoflurane preconditioning.Conclusion: Sevoflurane preconditioning inhibits NDRG2 up-regulation and nuclear translocation in astrocytes, and represses NDRG2-related cellular apoptosis to induce cerebral ischemic tolerance via antiapoptosis, which represents one new mechanism of sevoflurane preconditioning and provides a novel target for neuroprotection.