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



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.



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.



Gly blocks infarction by inhibiting IFNγ-mediated T cell activity, which is at least partly modulated by HMGB1 activity.
Department of Anesthesia, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, People's Republic of China.|Department of Neurosurgery and Stanford Stroke Center, Stanford University, 1201 Welch Rd, Stanford, CA, 94305, USA.|Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430006, People's Republic of China.
Xiaoxing
X
Xiong
Department of Neurosurgery and Stanford Stroke Center, Stanford University, 1201 Welch Rd, Stanford, CA, 94305, USA.|Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430006, People's Republic of China.
Lijuan
L
Gu
Department of Neurosurgery and Stanford Stroke Center, Stanford University, 1201 Welch Rd, Stanford, CA, 94305, USA.
Yan
Y
Wang
Department of Neurosurgery and Stanford Stroke Center, Stanford University, 1201 Welch Rd, Stanford, CA, 94305, USA.
Ying
Y
Luo
Department of Neurosurgery and Stanford Stroke Center, Stanford University, 1201 Welch Rd, Stanford, CA, 94305, USA.|Department of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510280, People's Republic of China.
Hongfei
H
Zhang
Department of Neurosurgery and Stanford Stroke Center, Stanford University, 1201 Welch Rd, Stanford, CA, 94305, USA.
Jessica
J
Lee
Department of Surgery, Stanford University, Stanford, CA, 94305, USA.
Sheri
S
Krams
Department of Anesthesia, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, People's Republic of China. smzhu20088@163.com.
Shengmei
S
Zhu
Department of Neurosurgery and Stanford Stroke Center, Stanford University, 1201 Welch Rd, Stanford, CA, 94305, USA. hzhao@stanford.edu.
Heng
0000-0003-4180-653X
H
Zhao
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000473:pathology; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy*; D049109:Cell Proliferation / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D019695:Glycyrrhizic Acid / Q000627:therapeutic use*; D024243:HMGB1 Protein / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D011923:Rats, Nude; D017207:Rats, Sprague-Dawley; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D024243:HMGB1 Protein; D003208:Concanavalin A; D019695:Glycyrrhizic Acid; D010751:Phosphopyruvate Hydratase
Cerebral ischemia; Glycyrrhizin; HMGB1; T cells