In the present study, we tested this hypothesis in cultured primary cerebral cortical neurons and PC12 cells (pheochromocytoma of the rat adrenal medulla) using an in vitro ischemic model of oxygen-glucose deprivation (OGD). We chose relative short OGD durations as the ischemic stimulus in this study because we have been focusing on early ischemic BBB damage that occurs within the first 4.5 h after ischemia onset (i.e., the therapeutic time window of tPA thrombolysis for ischemic stroke; Hacke et al., 2008; Jin et al., 2012; Liu et al., 2012, 2016), and in these studies, we observed substantial neuronal death in the ischemic brain within several hours after stroke onset (Jin et al., 2012; Liu et al., 2012). Our data showed that OGD treatment significantly increased Nrdp1 expression in neuronal cells, and knockdown or overexpression of Nrdp1 augmented or attenuated OGD-induced neuronal death, respectively. Moreover, Nrdp1 upregulation was accompanied by increased ubiquitinization of USP8 and its degradation, and this change was associated with decreased HIF-1α levels in ischemic neurons.