Endotoxin preconditioning prevents cellular inflammatory response during ischemic neuroprotection in mice.
OBJECTIVE
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.
Rosenzweig
Holly L
HL
Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239, USA.
Lessov
Nikola S
NS
Henshall
David C
DC
Minami
Manabu
M
Simon
Roger P
RP
Stenzel-Poore
Mary P
MP
D000818:Animals; D001921:Brain / Q000276:immunology / Q000473:pathology; D002545:Brain Ischemia / Q000276:immunology* / Q000473:pathology*; D004195:Disease Models, Animal; D004731:Endotoxins; D020244:Infarction, Middle Cerebral Artery / Q000276:immunology* / Q000473:pathology*; D019194:Ischemic Preconditioning; D007962:Leukocytes / Q000502:physiology; D008070:Lipopolysaccharides; D008262:Macrophage Activation; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000502:physiology; D009000:Monocytes / Q000502:physiology; D020556:Neutrophil Infiltration
D004731:Endotoxins; D008070:Lipopolysaccharides; C044101:endotoxin, Escherichia coli