Hypoxic/ischemic preconditioning attenuate PKCδ-mediated injury in patients and mice with cerebral infarction

Abstract

Objective: cerebral ischemic/hypoxic preconditioning (I/HPC) is an endogenous strategy in which brief periods of sublethal ischemia/hypoxia render neural tissues resistant to subsequent ischemic/hypoxic damage. This phenomenon has been found in the brain, heart, liver, intestine, muscle, kidneys, and lung. However, whether HPC has a protective effect on secondary cerebral ischemic injury or protein kinase Cδ (PKCδ) within ischemic patients and animal models is still unclear. Methods: using a hypoxic preconditioned mouse model and a middle cerebral artery occlusion mouse model, combined with 2,3,5-triphenyl tetrazolium chloride (TTC) staining, SDS-polyacrylamide gel electrophoresis (SDS-PAGE), and Western blot, we observed changes in infarction size, density, edema ratio, and changes in PKCδ and membrane translocation within the ischemic cortex of the middle cerebral artery occlusion (MCAO) mice. Results: HPC can attenuate neurological deficits and cerebral ischemic injuries of mice following MCAO, including decreases in infarct size, edema ratio, densities of infarct area, and neuron loss. In addition, HPC inhibits PKCδ membrane translocation in the penumbra of the MCAO-induced ischemic cortex. We found that administration of PKCδ-specific inhibitor dV1-1 mimics the neuroprotective effects of HPC, and nonisoform-specific activation of PKC can partially abolish HPC-induced neuroprotection. Ischemic preconditioning decreased the levels of PKCδ in the serum of patients with cerebral infarction and reduced the cerebral nerve damage caused by ischemia. Conclusion: hypoxic/ischemic preconditioning attenuates PKCδ-mediated injury in patients and mice. These findings enrich our understanding of the signal transduction mechanism underlying cerebral HPC and provide clues to developing medicine against ischemia/ hypoxia-induced cerebral injuries.

Keywords

hypoxic preconditioning (HPC) / middle cerebral artery occlusion (MCAO) / protein kinase C (PKC) / penumbra / neuroprotection