tDCS enhances the protective effect of isoflurane preconditioning on perioperative stroke: a new mechanism associated with the nuclear protein Akirin2

Perioperative stroke (PS) is a major cause of surgery-related disability and mortality in noncardiac surgery. Preconditioning with isoflurane exhibits neuroprotective properties; transcranial direct current stimulation (tDCS), a promising technique for altering the function of neural systems, has also shown therapeutic potential for stroke. However, it remains unclear whether tDCS can enhance the protective effect of isoflurane preconditioning on perioperative stroke and the underlying mechanisms have also not been clarified. Middle cerebral artery occlusion (MCAO) under isoflurane anesthesia, a rat ischemia-reperfusion injury model and an in vitro oxygen-glucose deprivation (OGD) model of ischemic injury were performed. Isoflurane preconditioning and tDCS were administered daily for 7 days before MACO modeling. Adeno-associated virus, lentiviral vectors and small interfering RNA techniques were used to explore the underlying mechanisms. Our results showed that tDCS/DCS enhanced the inhibitory effects of isoflurane pretreatment on ischemia-induced neuronal death manifested by the reduced infarct volume in rats and the decreased LDH release after OGD injury. Moreover, isoflurane preconditioning in combination with tDCS/DCS further inhibited ischemia-mediated neuroinflammatory and oxidative stress response, two hallmarks of perioperative stroke. Mechanistically, we found that isoflurane preconditioning reversed a marked decrease in Akirin2 expression in both the cortex of MACO rats and cortical neurons subjected to OGD. Akirin2 functioned upstream of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and downstream of isoflurane to decrease OGD induced neuronal injury. Interestingly, tDCS/DCS can further upregulate the levels of Akirin2 in vitro and in vivo, compared with isoflurane pretreatment alone. In conclusion, tDCS treatment can enhance the neuroprotective effects of isoflurane preconditioning on perioperative stroke via the Akirin2-PTEN signaling pathway, highlighting its potential as a therapeutic means for applying in the perioperative period.