Cerebrovascular hemodynamics and ischemic tolerance: Lipopolysaccharide-induced resistance to focal cerebral ischemia is not due to changes in severity of the initial ischemic insult, but is associated with preservation of microvascular perfusion

Lipopolysaccharide (LPS), administered 72 hours before middle cerebral arte ry (MCA) occlusion, confers significant protection against ischemic injury. For example, in the present study, LPS (0.9 mg/kg intravenously) induced a 31% reduction in infarct volume (compared with saline control) assessed 24 hours after permanent MCA occlusion. To determine whether LPS induces true tolerance to ischemia, or merely attenuates initial ischemic severity by a ugmenting collateral blood flow, local CBF was measured autoradiographicall y 15 minutes after MCA occlusion. Local CBF did not differ significantly be tween LPS- and saline-pretreated rats (e.g., 34 +/- 10 and 29 +/- 15 mL.100 g(-1).min(-1) for saline and LPS pretreatment in a representative region o f ischemic cortex), indicating that the neuroprotective action of LPS is no t attributable to an immediate reduction in the degree of ischemia induced by MCA occlusion, and that LPS does indeed induce a state of ischemic toler ance. In contrast to the similarity of the initial ischemic insult between tolerant (LPS-pretreated) and nontolerant (saline-pretreated) rats, microva scular perfusion assessed either 4 hours or 24 hours after MCA occlusion wa s preserved at significantly higher levels in the LPS-pretreated rats than in controls. Furthermore, the regions of preserved perfusion in tolerant an imals were associated with regions of tissue sparing. These results suggest that LPS-induced tolerance to focal ischemia is at least partly dependent on the active maintenance of microvascular patency and hence the prevention of secondary ischemic injury.