Fig. 3. Overview of the putative cellular targets of neuronal hypoxic preconditioning. Hypoxic preconditioning likely involves subinjurious stimulation occurring through pathways involved with hypoxic injury (fig. 2). The exact mechanisms of neuronal hypoxic preconditioning are slowly being unraveled; however, some of the known mediators are shown in the schematic mentioned earlier. Important receptor targets likely include ionotropic N -methyl-d-aspartate (NMDAR) glutamate (glu) receptors and adenosine triphosphate-dependent potassium channels (K-ATP) and G-protein-coupled adenosine (A1) receptors. Adenosine (A1) receptors (stimulated by adenosine [Ade]) likely act by reducing cellular activity during the subsequent insult. The downstream effectors distal to K-ATP signaling are unknown. Stimulation of excitatory receptors, exemplified by NMDA receptors, triggers the activation of cascades involved with cell survival and also produces reactive oxygen species (nitric oxide [NO] and superoxide [O²⁻]). The cell survival cascades include protein kinases such as mitogen-activated protein kinases (MAPK), protein kinase B (AKT), and protein kinase C (PKC; notably protein kinase Cϵ). The protein kinases can activate important transcription factors including phosphorylated cyclic-adenosine monophosphate response element-binding protein (pCREB). Hypoxia can also directly activate the hypoxia-inducible factor (HIF) by preventing HIF degradation allowing it to act as a transcription factor to upregulate effectors such as erythropoeitin and vascular endothelial growth factor. Finally, the activation of protein chaperones, including the heat shock proteins enhances protein stability and resists protein damage. This schematic does not portray all the targets of hypoxic preconditioning but conveys some of the important neuronal targets identified to date.