Increase in Endogenous Brain Superoxide Dismutase as a Potential Mechanism of Lipopolysaccharide-Induced Brain Ischemic Tolerance

Abstract

A low dose (0.5 mg/kg) of lipopolysaccharide (LPS), administered 72 hours before 60-minute middle cerebral artery occlusion, induced a delayed neuroprotection proven by the significant decrease (-35%) of brain infarct volume in comparison with control, whereas infarct volumes remained unchanged in rats treated 12, 24, or 168 hours before ischemia. This delayed neuroprotective effect of LPS was induced only with low doses (0.25 to 1 mg/kg), whereas this effect disappeared with a higher dose (2 mg/kg). The delayed neuroprotection of LPS was induced in the cortical part of the infarcted zone, not in the subcortical part. The beneficial effect of LPS on consequences of middle cerebral artery occlusion was suppressed by dexamethasone (3 mg/kg) and indomethacin (3 mg/ kg) administered 1 hour before LPS, whereas both drugs had no direct effect on infarct volume by themselves, suggesting that activation of inflammatory pathway is involved in the development of LPS-induced brain ischemic tolerance. Preadministration of cycloheximide, an inhibitor of protein synthesis, also blocked LPS-induced brain ischemic tolerance suggesting that a protein synthesis is also necessary as a mediating mechanism. Superoxide dismutase (SOD) could be one of the synthesized proteins because lipopolysaccharide increased SOD brain activity 72 hours, but not 12 hours, after its administration, which paralleled the development of brain ischemic tolerance. In contrast, catalase brain activity remained unchanged after LPS administration. The LPS-induced delayed increase in SOD brain content was suppressed by a previous administration of indomethacin. These data suggest that the delayed neuroprotective effect of low doses of LPS is mediated by an increased synthesis of brain SOD that could be triggered by activation of inflammatory pathway.

Decreased infarct size after focal cerebral ischemia in mice chronically infected with Toxoplasma gondii

“…However, it appears that the LPS dose used in these models may be a determinant in the observed degeneration. In fact, although high LPS doses may increase cytokines and oxidative stress, low doses of peripheral LPS have a neuroprotective effect (Bordet et al, 2000). This is consistent with our recent study in which we observed an increase in brain NGF and GSH levels 3 days after peripheral LPS treatment (Arsenijevic et al, 2007b;Hernadfalvi et al, 2007).…”

“…Although both animal models and clinical studies showed that infections promote neuronal death following cerebral ischemic injury (Sacco, 2001;Emsley and Tyrrell, 2002), activation of the immune system can also result in neuroprotection (Bordet et al, 2000). In fact, the effect of infection on ischemic damage may largely depend on the regulation of reactive oxygen species by pro-inflammatory and anti-inflammatory cytokines as well as by the main antioxidant state regulators, namely superoxide dismutase (SOD) (Guegan et al, 1998;Murakami et al, 1998), glutathione (GSH) (Nicholls and Budd, 2000;Schulz et al, 2000;Droge, 2002), uncoupling protein-2 (UCP2) (Arsenijevic et al, 2000b;Mattiasson et al, 2003) and nerve growth factor (NGF) (Brodie, 1996;Guegan et al, 1999;Villoslada et al, 2000).…”

Neuroanesthesia and Intensive Care Isoflurane tolerance against focal cerebral ischemia is attenuated by adenosine A1 receptor antagonists

“…Both the uncorrected and corrected infarct volumes in three isofluranetreated groups were smaller than those of the Control group (uncorrected volume 287.2 ± 90.3 mm 3 and corrected volume 217.3 ± 79.5 mm 3 ). A significant reduction was observed in the Isoflurane group (uncorrected volume 137.4 ± 84.8 mm 3 and corrected volume 106.5 ± 60.0 mm 3 ) and the Vehicle+Isoflurane group (uncorrected volume 138.0 ± 84.2 mm 3 and corrected volume 104.7 ± 60.9 mm 3 ), (P < 0.01). The infarct volumes of DPCPX+Isoflurane group (uncorrected volume 250.1 ± 102.8 mm 3 and corrected volume 191.0 ± 80.0 mm 3 ) were significantly larger than those of the Isoflurane and Vehicle+Isoflurane groups (P < 0.01).…”

“…A significant reduction was observed in the Isoflurane group (uncorrected volume 137.4 ± 84.8 mm 3 and corrected volume 106.5 ± 60.0 mm 3 ) and the Vehicle+Isoflurane group (uncorrected volume 138.0 ± 84.2 mm 3 and corrected volume 104.7 ± 60.9 mm 3 ), (P < 0.01). The infarct volumes of DPCPX+Isoflurane group (uncorrected volume 250.1 ± 102.8 mm 3 and corrected volume 191.0 ± 80.0 mm 3 ) were significantly larger than those of the Isoflurane and Vehicle+Isoflurane groups (P < 0.01). Eight-cyclopentyl-1,3-dipropulxanthine treatment without isoflurane preconditioning in the DPCPX group did not change the infarct volume compared with the Control group.…”

“…A pharmacological agent to induce cerebral ischemic tolerance before surgery would be valuable. Unfortunately most pharmacological or chemical agents that induce cerebral tolerance, such as lipopolysaccharide, 3 tumour necrosis factor-α, 4 and interleukin-1, 5 are limited in their application to patients due to their toxicity.…”