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The chronic protective effects of limb remote preconditioning and the underlying mechanisms involved in inflammatory factors in rat stroke.

Wei D, Ren C, Chen X, Zhao H - PLoS ONE (2012)

Bottom Line: LRP reduced brain injury size both at 2 days and 60 days post-stroke and improved behavioral outcomes for up to 2 months.In addition, LRP decreased iNOS and nitrotyrosine protein expression after stroke.In conclusion, LRP executes long-term protective effects against stroke and may block brain injury by inhibiting activities of the galectin-9/Tim-3 pathway, iNOS, and nitrotyrosine.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Stanford University, Stanford, California, United States of America.

ABSTRACT
We recently demonstrated that limb remote preconditioning (LRP) protects against focal ischemia measured 2 days post-stroke. Here, we studied whether LRP provides long-term protection and improves neurological function. We also investigated whether LRP transmits its protective signaling via the afferent nerve pathways from the preconditioned limb to the ischemic brain and whether inflammatory factors are involved in LRP, including the novel galectin-9/Tim-3 inflammatory cell signaling pathway, which induces cell death in lymphocytes. LRP in the left hind femoral artery was performed immediately before stroke. LRP reduced brain injury size both at 2 days and 60 days post-stroke and improved behavioral outcomes for up to 2 months. The sensory nerve inhibitors capsaicin and hexamethonium, a ganglion blocker, abolished the protective effects of LRP. In addition, LRP inhibited edema formation and blood-brain barrier (BBB) permeability measured 2 days post-stroke. Western blot and immunostaining analysis showed that LRP inhibited protein expression of both galectin-9 and T-cell immunoglobulin domain and mucin domain 3 (Tim-3), which were increased after stroke. In addition, LRP decreased iNOS and nitrotyrosine protein expression after stroke. In conclusion, LRP executes long-term protective effects against stroke and may block brain injury by inhibiting activities of the galectin-9/Tim-3 pathway, iNOS, and nitrotyrosine.

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LRP attenuated edema induced by stroke.A. Diagram of the dissected regions of the ischemic penumbra and core for BBB leakage measurement. The penumbra (I) is defined as the ischemic region spared by LRP, while the core (II) is the ischemic part that developed into the infarction. The same regions were also dissected for Western blotting. B. LRP inhibited BBB leakage. Evans blue was injected 2 h before the rat was euthanized. The ischemic penumbra and core, as well as the corresponding non-ischemic hemisphere were dissected for Evans blue detection. LRP reduced BBB leakage at 48 h after stroke in the penumbra but not in the core (n = 6/group). * vs. control ischemia, P<0.05. C. LRP mitigated edema after stroke. The ischemic and non-ischemic hemispheres from each rat brain were separated, weighed for wet weight, baked at 90±2°C for 1 wk, and weighed again for dry weight. Water contained in the brain tissues was calculated and is presented in the bar graph (n = 6–7/group). *** vs. contralateral hemisphere, P<0.001; ### vs. sham and control ischemia, P<0.001.
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pone-0030892-g003: LRP attenuated edema induced by stroke.A. Diagram of the dissected regions of the ischemic penumbra and core for BBB leakage measurement. The penumbra (I) is defined as the ischemic region spared by LRP, while the core (II) is the ischemic part that developed into the infarction. The same regions were also dissected for Western blotting. B. LRP inhibited BBB leakage. Evans blue was injected 2 h before the rat was euthanized. The ischemic penumbra and core, as well as the corresponding non-ischemic hemisphere were dissected for Evans blue detection. LRP reduced BBB leakage at 48 h after stroke in the penumbra but not in the core (n = 6/group). * vs. control ischemia, P<0.05. C. LRP mitigated edema after stroke. The ischemic and non-ischemic hemispheres from each rat brain were separated, weighed for wet weight, baked at 90±2°C for 1 wk, and weighed again for dry weight. Water contained in the brain tissues was calculated and is presented in the bar graph (n = 6–7/group). *** vs. contralateral hemisphere, P<0.001; ### vs. sham and control ischemia, P<0.001.

Mentions: BBB permeability at 2 days post-stroke was measured by Evans blue. The level of Evans blue was robustly increased at 48 hours after stroke in the ischemic penumbra (Fig. 3A), but much higher levels were detected in the core than in the penumbra. LRP blocked BBB leakage in the penumbra at 48 hours but had no effect in the core (Fig. 3A).


The chronic protective effects of limb remote preconditioning and the underlying mechanisms involved in inflammatory factors in rat stroke.

Wei D, Ren C, Chen X, Zhao H - PLoS ONE (2012)

LRP attenuated edema induced by stroke.A. Diagram of the dissected regions of the ischemic penumbra and core for BBB leakage measurement. The penumbra (I) is defined as the ischemic region spared by LRP, while the core (II) is the ischemic part that developed into the infarction. The same regions were also dissected for Western blotting. B. LRP inhibited BBB leakage. Evans blue was injected 2 h before the rat was euthanized. The ischemic penumbra and core, as well as the corresponding non-ischemic hemisphere were dissected for Evans blue detection. LRP reduced BBB leakage at 48 h after stroke in the penumbra but not in the core (n = 6/group). * vs. control ischemia, P<0.05. C. LRP mitigated edema after stroke. The ischemic and non-ischemic hemispheres from each rat brain were separated, weighed for wet weight, baked at 90±2°C for 1 wk, and weighed again for dry weight. Water contained in the brain tissues was calculated and is presented in the bar graph (n = 6–7/group). *** vs. contralateral hemisphere, P<0.001; ### vs. sham and control ischemia, P<0.001.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3275571&req=5

pone-0030892-g003: LRP attenuated edema induced by stroke.A. Diagram of the dissected regions of the ischemic penumbra and core for BBB leakage measurement. The penumbra (I) is defined as the ischemic region spared by LRP, while the core (II) is the ischemic part that developed into the infarction. The same regions were also dissected for Western blotting. B. LRP inhibited BBB leakage. Evans blue was injected 2 h before the rat was euthanized. The ischemic penumbra and core, as well as the corresponding non-ischemic hemisphere were dissected for Evans blue detection. LRP reduced BBB leakage at 48 h after stroke in the penumbra but not in the core (n = 6/group). * vs. control ischemia, P<0.05. C. LRP mitigated edema after stroke. The ischemic and non-ischemic hemispheres from each rat brain were separated, weighed for wet weight, baked at 90±2°C for 1 wk, and weighed again for dry weight. Water contained in the brain tissues was calculated and is presented in the bar graph (n = 6–7/group). *** vs. contralateral hemisphere, P<0.001; ### vs. sham and control ischemia, P<0.001.
Mentions: BBB permeability at 2 days post-stroke was measured by Evans blue. The level of Evans blue was robustly increased at 48 hours after stroke in the ischemic penumbra (Fig. 3A), but much higher levels were detected in the core than in the penumbra. LRP blocked BBB leakage in the penumbra at 48 hours but had no effect in the core (Fig. 3A).

Bottom Line: LRP reduced brain injury size both at 2 days and 60 days post-stroke and improved behavioral outcomes for up to 2 months.In addition, LRP decreased iNOS and nitrotyrosine protein expression after stroke.In conclusion, LRP executes long-term protective effects against stroke and may block brain injury by inhibiting activities of the galectin-9/Tim-3 pathway, iNOS, and nitrotyrosine.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Stanford University, Stanford, California, United States of America.

ABSTRACT
We recently demonstrated that limb remote preconditioning (LRP) protects against focal ischemia measured 2 days post-stroke. Here, we studied whether LRP provides long-term protection and improves neurological function. We also investigated whether LRP transmits its protective signaling via the afferent nerve pathways from the preconditioned limb to the ischemic brain and whether inflammatory factors are involved in LRP, including the novel galectin-9/Tim-3 inflammatory cell signaling pathway, which induces cell death in lymphocytes. LRP in the left hind femoral artery was performed immediately before stroke. LRP reduced brain injury size both at 2 days and 60 days post-stroke and improved behavioral outcomes for up to 2 months. The sensory nerve inhibitors capsaicin and hexamethonium, a ganglion blocker, abolished the protective effects of LRP. In addition, LRP inhibited edema formation and blood-brain barrier (BBB) permeability measured 2 days post-stroke. Western blot and immunostaining analysis showed that LRP inhibited protein expression of both galectin-9 and T-cell immunoglobulin domain and mucin domain 3 (Tim-3), which were increased after stroke. In addition, LRP decreased iNOS and nitrotyrosine protein expression after stroke. In conclusion, LRP executes long-term protective effects against stroke and may block brain injury by inhibiting activities of the galectin-9/Tim-3 pathway, iNOS, and nitrotyrosine.

Show MeSH
Related in: MedlinePlus