Endotoxin Preconditioning Prevents Cellular Inflammatory Response During Ischemic Neuroprotection in Mice

Abstract

Background and Purpose-Tolerance to ischemic brain injury is induced by several preconditioning stimuli, including lipopolysaccharide (LPS). A small dose of LPS given systemically confers ischemic protection in the brain, a process that appears to involve activation of an inflammatory response before ischemia. We postulated that LPS preconditioning modulates the cellular inflammatory response after cerebral ischemia, resulting in neuroprotection. Methods-Mice were treated with LPS (0.2 mg/kg) 48 hours before ischemia induced by transient middle cerebral artery occlusion (MCAO). The infarct was measured by 2,3,5-triphenyltetrazolium chloride staining. Microglia/macrophage responses after MCAO were assessed by immunofluorescence and flow cytometry. The effect of MCAO on white blood cells in the brain and peripheral circulation was measured by flow cytometry 48 hours after MCAO. Results-LPS preconditioning induced significant neuroprotection against MCAO. Administration of low-dose LPS before MCAO prevented the cellular inflammatory response in the brain and blood. Specifically, LPS preconditioning suppressed neutrophil infiltration into the brain and microglia/macrophage activation in the ischemic hemisphere, which was paralleled by suppressed monocyte activation in the peripheral blood. Conclusions-LPS preconditioning induces neuroprotection against ischemic brain injury in a mouse model of stroke. LPS preconditioning suppresses the cellular inflammatory response to ischemia in the brain and circulation. Diminished activation of cellular inflammatory responses that ordinarily exacerbate ischemic injury may contribute to neuroprotection induced by LPS preconditioning.

Toll-like receptor 3 agonist Poly I:C protects against simulated cerebral ischemia in vitro and in vivo

“…In several models of brain ischemia, systemic administration of the TLR4 ligand LPS induces tolerance to injury [24][25][26] that is most likely through induction of IFNβ and interferonstimulated genes through the TLR4 adapter molecule TRIF [7] . Poly I:C-induced tolerance to ischemic damage is similar to the phenomenon of LPS-induced tolerance to ischemic injury.…”

“…In contrast to the detrimental role of TLRs in response to ischemia, stimulation of TLR4 with low dose systemic administration of lipopolysaccharide (LPS) prior to ischemia provides robust neuroprotection accompanied by attenuated inflammatory response in the animal brain [9,10] . Mice lacking TLR4 show less IPC-induced neuroprotection than wild-type mice [11] .…”

Long-lasting protection in brain trauma by endotoxin preconditioning

“…Preconditioning in traumatic brain injury L Longhi et al occlusion (Rosenzweig et al, 2004(Rosenzweig et al, , 2007. To investigate the mechanisms involved in preconditioning in TBI, we first tested the hypothesis that TBI could be a condition susceptible to LPS-induced protection and explored the time window of such protection using functional and histological outcomes at 1 week after injury.…”

Endotoxin Preconditioning Protects against the Cytotoxic Effects of TNFα after Stroke: A Novel Role for TNFα in LPS-Ischemic Tolerance

“…Brain tissue was prepared for immunofluorescence as described previously (Rosenzweig et al, 2004). Brain sections were treated with anti-TNFR1 or anti-TRADD antibodies (Santa Cruz Biotechnology), which were detected with a Cy3-conjugated antibody (Jackson Immuno Research, PA, West Grove, USA).…”