A pathway of neuronal apoptosis induced by hypoxia/reoxygenation:: Roles of nuclear factor-κB and Bcl-2

As a model of the reperfusion injury found in stroke, we have exposed neurons to hypoxia followed by reoxygenation. Neurons treated with hypoxia/reoxygenation (H/R) respond by activating nuclear factor-kappa B (NF kappa B), releasing cytochrome c from their mitochondria, and ultimately dying. Further supporting an apoptotic mechanism, expression of the antiapoptotic Bcl-2 and Bcl-x proteins was increased following H/R. In this model, adenoviral-mediated transduction of I kappa B expression inhibited NF kappa B activation and significantly accelerated cytochrome c release and caspase-dependent neuronal death. At the same time, expression of mutated I kappa B prevented the increased expression of endogenous Bcl-2 and Bcl-x. In the presence of mutated I kappa B, singular overexpression of only Bcl-2 by adenoviral-mediated transduction significantly inhibited cytochrome c release, caspase-3-like activation, and cell death in response to H/R. These findings suggest a pathway where NF kappa B activation induces overexpression of Bcl-2 and Bcl-x, which function to prevent apoptotic cell death following H/R treatments.