Apurinic/apyrimidinic endonuclease 1 (APE1) contributes to resveratrol-induced neuroprotection against oxygen-glucose deprivation and re-oxygenation injury in HT22 cells: Involvement in reducing oxidative DNA damage

Abstract

Resveratrol, a naturally occurring polyphenolic compound, exhibits a neuroprotective role in models of central nervous system diseases, including cerebral ischemia/reperfusion injury. Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme that contributes to base excision repair of oxidative DNA damage and redox activation of transcription factors, associated with neuronal survival against hypoxic‑ischemic injury. It was hypothesized that resveratrol protects HT22 cells against oxygen‑glucose deprivation and re‑oxygenation (OGD/R)‑induced injuries through upregulation of APE1. It was demonstrated that resveratrol pretreatment significantly increased the viability of HT22 cells and decreased the release of lactate dehydrogenase (LDH), accompanied by the upregulation of APE1 mRNA, and protein levels, as well as the activity of APE1 under OGD/R conditions. In addition, resveratrol reversed OGD/R‑induced oxidative DNA damage as evidenced by the decreases in the levels of 8‑hydroxy‑2'‑deoxyguanosine and APE sites. However, APE1 knockdown using short hairpin RNA sequence targeting APE1 abolished resveratrol‑elicited beneficent effects against OGD/R‑induced cytotoxicity and oxidative stress. This was indicated by decreased cell viability, superoxide dismutase activity and glutathione levels, and increased LDH release and reactive oxygen species levels. The results of the present study indicate that APE1 contributes to the protective effects of resveratrol against neonatal hypoxic‑ischemic brain injuries, and suggest that DNA repair enzymes, including APE1, may be a unique strategy for neuroprotection against this disease.

Antioxidant and neuroprotective actions of resveratrol in cerebrovascular diseases

“…Leak et al have also revealed that the upregulation of APE1, either endogenously or through transgene overexpression, reduces oxidative DNA damage and protects neurons against acute ischemic damage ( Leak et al, 2015 ). Consistent with prior studies, Jia et al have found that RES obviously elevated the activity and level of APE1 ( Jia et al, 2017 ). On the other hand, previous research has shown that strand breaks of apurinic/apyrimidinic sites are considered a marker of oxidative DNA damage, and 8-OHdG is also the specific product of DNA oxidative damage ( Chen et al, 1997 ; Lan et al, 2003 ).…”

“…In addition, the knockdown of APE1 blocked the neuroprotective and antioxidant effects of RES. The above results further showed that RES exerted a neuroprotective role in ischemic stroke, which was related to the APE1-induced oxidative DNA damage reduction and antioxidant defense system enhancement ( Jia et al, 2017 ) ( Figure 3 ).…”

Curcumin exerts protective effects against hypoxia‑reoxygenation injury via the enhancement of apurinic/apyrimidinic endonuclease�1 in SH‑SY5Y cells: Involvement of the PI3K/AKT pathway

“…In addition, the overexpression of APE1 induced by an APE-mimicking peptide or adenovirus-mediated APE1 following reperfusion increased dNA repair, attenuated apoptosis and reduced the infarct volume (20,21). It has also been demonstrated that APE1 is an attractive target for neuroprotection and is involved in neuroprotection against cerebral I/R injury (22,23). Stetler et al (23) revealed that APE1 was required for pituitary adenylate cyclase-activating polypeptide (PAcAP)-induced neuroprotection against global cerebral ischemia.…”

Resveratrol decreases the expression of genes involved in inflammation through transcriptional regulation

“…Both the endonuclease and transcription factor binding activities of APE1/Ref-1 result in increased resilience of cells to proapoptotic stimuli (reviewed in [11]). Resveratrol (RESV), a naturally occurring polyphenolic compound found in red wine and grapes, reportedly affects the redox activity of APE1/Ref-1 [12][13][14][15]. RESV was shown to inhibit the redox and endonuclease activities of APE1/Ref-1 in in vitro assays.…”