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Glycyrrhizin protects against focal cerebral ischemia via inhibition of T cell activity and HMGB1-mediated mechanisms

View Article: PubMed Central - PubMed

ABSTRACT

Background: Glycyrrhizin (Gly) protects against brain injury induced by stroke. We studied whether Gly achieves its protection by inhibiting T cell activity and high-mobility group box 1 (HMGB1) release in the ischemic brain.

Methods: Stroke was induced by transient middle cerebral artery occlusion in rats and mice. Gly was injected intraperitoneally before or after stroke. We measured infarction, neuroinflammatory cells, gene expressions of interferon-γ (IFNγ), IL-4, and IL-10 in CD4 T cells, HMGB1 release, and T cell proliferation in cultured splenocytes.

Results: Gly treatment reduced infarctions and neuroinflammation characterized by the infiltration of CD68-positive macrophages and myeloperoxidase-positive neutrophils, which corresponds to a reduction in the number of T cells and their subsets, CD4 and CD8 T cells, in the ischemic brain, as measured by flow cytometry. Unlike in wild-type animals, Gly did not offer protection in nude rats and severe combined immunodeficient (SCID) mice who had no T cells, while Gly reduced infarction in both nude rats and SCID mice whose T cells were reconstituted, suggesting that T cells should be the target of Gly. In addition, Gly administration inhibited T cell proliferation stimulated by ConA in in vitro assays and inhibited HMGB1 release from the ischemic brain. Furthermore, Gly attenuated gene expression of IFNγ, but not IL-4 and IL-10 in CD4 T cells. Lastly, HMGB1 promoted T cell proliferation stimulated by ConA, which was inhibited by the addition of Gly.

Conclusions: Gly blocks infarction by inhibiting IFNγ-mediated T cell activity, which is at least partly modulated by HMGB1 activity.

No MeSH data available.


Related in: MedlinePlus

Gly injection reduced infarct size after focal ischemia in wild-type rats. Infarct size in the ipsilateral hemisphere was measured 3 days after stroke onset using TTC staining, then normalized to the contralateral hemisphere and expressed as a percentage. a Gly injection reduced infarct size in focal ischemia with 100-min MCA suture occlusion. Representative infarcts stained with TTC are shown. MCAo only, the animals received no any treatment; vehicle, the stroke animals were injected with vehicle; Pre + Post, the drug was injected i.p. immediately before stroke onset and at 2 h; Post twice, Gly was injected twice immediately and 3.5 h post-reperfusion; and Post once, Gly was injected one time immediately after reperfusion. b Bar graphs represent the statistic results. *P < 0.05 vs vehicle; #P < 0.05 vs MCAo only; n = 9–13/group
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Fig1: Gly injection reduced infarct size after focal ischemia in wild-type rats. Infarct size in the ipsilateral hemisphere was measured 3 days after stroke onset using TTC staining, then normalized to the contralateral hemisphere and expressed as a percentage. a Gly injection reduced infarct size in focal ischemia with 100-min MCA suture occlusion. Representative infarcts stained with TTC are shown. MCAo only, the animals received no any treatment; vehicle, the stroke animals were injected with vehicle; Pre + Post, the drug was injected i.p. immediately before stroke onset and at 2 h; Post twice, Gly was injected twice immediately and 3.5 h post-reperfusion; and Post once, Gly was injected one time immediately after reperfusion. b Bar graphs represent the statistic results. *P < 0.05 vs vehicle; #P < 0.05 vs MCAo only; n = 9–13/group

Mentions: We first examined whether Gly injection reduced infarction induced by transient MCA occlusion in rats. The results showed that infarction was significantly reduced when Gly was injected twice i.p. into the animals, i.e., before MCA occlusion and 2 h after reperfusion (Fig. 1a). We further showed that Gly also resulted in reduction of infarct size when injected twice immediately at reperfusion and 3.5 h after reperfusion (Fig. 1b). Nevertheless, one injection of Gly immediately at reperfusion did not provide protection.Fig. 1


Glycyrrhizin protects against focal cerebral ischemia via inhibition of T cell activity and HMGB1-mediated mechanisms
Gly injection reduced infarct size after focal ischemia in wild-type rats. Infarct size in the ipsilateral hemisphere was measured 3 days after stroke onset using TTC staining, then normalized to the contralateral hemisphere and expressed as a percentage. a Gly injection reduced infarct size in focal ischemia with 100-min MCA suture occlusion. Representative infarcts stained with TTC are shown. MCAo only, the animals received no any treatment; vehicle, the stroke animals were injected with vehicle; Pre + Post, the drug was injected i.p. immediately before stroke onset and at 2 h; Post twice, Gly was injected twice immediately and 3.5 h post-reperfusion; and Post once, Gly was injected one time immediately after reperfusion. b Bar graphs represent the statistic results. *P < 0.05 vs vehicle; #P < 0.05 vs MCAo only; n = 9–13/group
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5016958&req=5

Fig1: Gly injection reduced infarct size after focal ischemia in wild-type rats. Infarct size in the ipsilateral hemisphere was measured 3 days after stroke onset using TTC staining, then normalized to the contralateral hemisphere and expressed as a percentage. a Gly injection reduced infarct size in focal ischemia with 100-min MCA suture occlusion. Representative infarcts stained with TTC are shown. MCAo only, the animals received no any treatment; vehicle, the stroke animals were injected with vehicle; Pre + Post, the drug was injected i.p. immediately before stroke onset and at 2 h; Post twice, Gly was injected twice immediately and 3.5 h post-reperfusion; and Post once, Gly was injected one time immediately after reperfusion. b Bar graphs represent the statistic results. *P < 0.05 vs vehicle; #P < 0.05 vs MCAo only; n = 9–13/group
Mentions: We first examined whether Gly injection reduced infarction induced by transient MCA occlusion in rats. The results showed that infarction was significantly reduced when Gly was injected twice i.p. into the animals, i.e., before MCA occlusion and 2 h after reperfusion (Fig. 1a). We further showed that Gly also resulted in reduction of infarct size when injected twice immediately at reperfusion and 3.5 h after reperfusion (Fig. 1b). Nevertheless, one injection of Gly immediately at reperfusion did not provide protection.Fig. 1

View Article: PubMed Central - PubMed

ABSTRACT

Background: Glycyrrhizin (Gly) protects against brain injury induced by stroke. We studied whether Gly achieves its protection by inhibiting T cell activity and high-mobility group box 1 (HMGB1) release in the ischemic brain.

Methods: Stroke was induced by transient middle cerebral artery occlusion in rats and mice. Gly was injected intraperitoneally before or after stroke. We measured infarction, neuroinflammatory cells, gene expressions of interferon-&gamma; (IFN&gamma;), IL-4, and IL-10 in CD4 T cells, HMGB1 release, and T cell proliferation in cultured splenocytes.

Results: Gly treatment reduced infarctions and neuroinflammation characterized by the infiltration of CD68-positive macrophages and myeloperoxidase-positive neutrophils, which corresponds to a reduction in the number of T cells and their subsets, CD4 and CD8 T cells, in the ischemic brain, as measured by flow cytometry. Unlike in wild-type animals, Gly did not offer protection in nude rats and severe combined immunodeficient (SCID) mice who had no T cells, while Gly reduced infarction in both nude rats and SCID mice whose T cells were reconstituted, suggesting that T cells should be the target of Gly. In addition, Gly administration inhibited T cell proliferation stimulated by ConA in in vitro assays and inhibited HMGB1 release from the ischemic brain. Furthermore, Gly attenuated gene expression of IFN&gamma;, but not IL-4 and IL-10 in CD4 T cells. Lastly, HMGB1 promoted T cell proliferation stimulated by ConA, which was inhibited by the addition of Gly.

Conclusions: Gly blocks infarction by inhibiting IFN&gamma;-mediated T cell activity, which is at least partly modulated by HMGB1 activity.

No MeSH data available.


Related in: MedlinePlus