Recurrent mild cerebral ischemia: Enhanced brain injury following acute compared to subacute recurrence in the rat

Abstract

Background: In the current study, a transient cerebral ischemia producing selective cell death was designated a mild ischemic insult. A comparable insult in humans is a transient ischemic attack (TIA) that is associated with functional recovery but can have imaging evidence of minor ischemic damage including cerebral atrophy. A TIA also predicts a high risk for early recurrence of a stroke or TIA and thus multiple ischemic insults are not uncommon. Not well understood is what the effect of differing recovery times between mild ischemic insults has on their pathophysiology. We investigated whether cumulative brain damage would differ if recurrence of a mild ischemic insult occurred at 1 or 3 days after a first insult. Results: A transient episode of middle cerebral artery occlusion via microclip was produced to elicit mild ischemic changes-predominantly scattered necrosis. This was followed 1 or 3days later by a repeat of the same insult. Brain damage assessed histologically 7days later was substantially greater in the 1day recurrent group than the 3days recurrent group, with areas of damage consisting predominantly of regions of incomplete infarction and pannecrosis in the 1day group but predominantly regions of selective necrosis and smaller areas of incomplete infarction in the 3days group (P<0.05). Enhanced injury was reflected by greater number of cells staining for macrophages/microglia with ED1 and greater alterations in GFAP staining of reactive astrocytes in the 1day than 3days recurrent groups. The differential susceptibility to injury did not correspond to higher levels of injurious factors present at the time of the second insult such as BBB disruption or increased cytokines (tumor necrosis factor). Microglial activation, with potential for some beneficial effects, appeared greater at 3days than 1day. Also blood analysis demonstrated changes that included an acute increase in granulocytes and decrease in platelets at 1day compared to 3days post transient ischemia. Conclusions: Dynamic changes in multiple inflammatory responses likely contribute to the time dependence of the extent of damage produced by recurrent mild ischemic insults. The time of mild stroke recurrence is crucial with early recurrence producing greater damage than subacute recurrence and this supports urgency for determining and implementing optimal stroke management directly after a TIA.