Delayed tolerance with repetitive transient focal ischemic preconditioning in the mouse

Background and Purpose - Transient ischemic attacks have long been regarded as a risk factor for the incidence of stroke but may reduce the severity of stroke by inducing ischemic tolerance. The present objective was to develop an ischemic preconditioning (IPC) model of delayed tolerance in the mouse based on repetitive, transient middle cerebral artery occlusion (MCAO). Methods - Mice anesthetized with halothane or isoflurane underwent IPC, which consisted of repetitive MCAO at 45-minute intervals by the intraluminal filament technique. A 90-minute test MCAO was performed 24 to 96 hours later. Results - Using an IPC of 2 5-minute MCAO episodes, the reduction in infarct volume from the test MCAO was maximal with a 72-hour delay in striatum (70%) and cerebral cortex (64%) when halothane was used for surgical anesthesia. With isoflurane anesthesia, the reduction in infarct volume was less prominent in striatum (34%) and not significant in cortex (9%) despite similar levels of arterial pressure and decreases in cortical perfusion. Neuronal cell death was rare 6 days after this IPC stimulus alone with halothane or isoflurane. Increasing the severity of IPC to 3 5-minute bouts or 1 15-minute bout of MCAO in the presence of isoflurane anesthesia augmented the reduction in infarct volume in striatum and cortex, but it also augmented selective neuronal cell death in striatum after the IPC stimulus alone. Conclusions - These data demonstrate that a repetitive focal IPC stimulus can be titrated to induce delayed tolerance in both striatum and cortex of the mouse without inducing neuronal death by itself.