Ischemic postconditioning, including early and delayed
ischemic postconditioning, has been recognized as a simple and promising strategy in the treatment of
stroke. However, the effects of the combination of early and delayed
ischemic postconditioning, and the mechanisms underlying these effects, remain unclear. The aim of the present study was to determine whether the combination of early and delayed
ischemic postconditioning offers greater protection against
stroke, and enhances the production of brain‑derived
neurotrophic factor (
BDNF). A combination of early and delayed
ischemic postconditioning was established by repeated, transient occlusion and reperfusion of the ipsilateral common carotid artery in a rat model of
middle cerebral artery occlusion.
Infarct size, motor function, cerebral blood flow and
brain edema were then evaluated, in order to confirm the effects of combinative
ischemic postconditioning. TUNEL staining was used to analyze the rate of apoptosis of cells in the penumbral area.
BDNF, extracellular signal‑regulated
kinases 1/2 (ERK1/2) and cAMP response element‑binding
protein (CREB) expression was detected using immunofluorescence staining and western blot analysis. The results of the present study indicated that the combination of early and delayed
ischemic postconditioning further reduced the
infarct volume, stabilized cerebral blood disturbance and attenuated neuronal apoptosis, compared with either alone. However, combinative postconditioning exerted the same effect on neurological function and
brain edema, compared with early or delayed
ischemic postconditioning alone. Further investigation indicated that combinative
ischemic postconditioning increased the expression of
BDNF, and a significantly higher number of BDNF‑positive cells was observed in neurons and astrocytes from the combined group than in the early or delayed groups. Combinative
ischemic postconditioning also induced the phosphorylation of ERK1/2 and CREB in the cortex, following focal
ischemia. The results of the present study suggest that the combination of early and delayed
ischemic postconditioning may further reduce brain ischemic
reperfusion injury following focal
ischemia, compared with either treatment alone. In addition, it induces the production of
BDNF in neurons and astrocytes. Furthermore, the effects of combinative
ischemic postconditioning may be mediated by the activation of ERK1/2 and CREB.