title: Tetramethylpyrazine inhibits neutrophil activation following permanent cerebral ischemia in rats.
abstract: Experimental studies have demonstrated the beneficial effects of tetramethylpyrazine (TMP) against ischemic stroke and highlighted its crucial role in anti-inflammatory activity. This study provides evidence of an alternative target for TMP and sheds light on the mechanism of its anti-inflammatory action against ischemic brain injury. We report a global inhibitory effect of TMP on inflammatory cell intracerebral activation and infiltration in a rat model of permanent cerebral ischemia. The results of immunohistochemistry, enzymatic assay, flow cytometric analysis, and cytological analysis revealed that intraperitoneal TMP administration reduced neuronal loss, macrophage/microglia activation, brain parenchyma infiltrative neutrophils, and circulating neutrophils after cerebral ischemia. Biochemical studies of cultured neutrophils further demonstrated that TMP attenuated neutrophil migration, endothelium adhesion, spontaneous nitric oxide (NO) production, and stimuli-activated NO production after cerebral ischemia. In parallel with these anti-neutrophil phenomena, TMP also attenuated the activities of ischemia-induced inflammation-associated signaling molecules, including plasma high-mobility group box-1 protein (HMGB1) and neutrophil toll-like receptor-4 (TLR4), Akt, extracellular signal-regulated kinase (ERK), and inducible nitric oxide synthase. Another finding in this study was that the anti-neutrophil effect of TMP was accompanied by a further elevated expression of NF-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in neutrophils after cerebral ischemia. Taken together, our results suggest that both the promotion of endogenous anti-inflammatory defense capacity and the attenuation of pro-inflammatory responses via targeting of circulating neutrophils by elevating Nrf2/HO-1 expression and inhibiting HMGB1/TLR4, Akt, and ERK signaling might actively contribute to TMP-mediated neuroprotection against cerebral ischemia.
authors.affiliation: Department of Surgery, Feng Yuan Hospital, Taichung, Taiwan; Graduate Institute of Pharmaceutical Science and Technology, Central Taiwan University of Science and Technology, Taichung, Taiwan.
authors.forename: Cheng-Yi
authors.initials: CY
authors.lastname: Chang
authors.affiliation: School of Chinese Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Tsung-Kuei
authors.initials: TK
authors.lastname: Kao
authors.affiliation: Department of Veterinary Medicine, National Chung-Hsing University, Taichung, Taiwan.
authors.forename: Wen-Ying
authors.initials: WY
authors.lastname: Chen
authors.affiliation: Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan; Division of Urology, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Yen-Chuan
authors.initials: YC
authors.lastname: Ou
authors.affiliation: Division of Urology, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Jian-Ri
authors.initials: JR
authors.lastname: Li
authors.affiliation: Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Su-Lan
authors.initials: SL
authors.lastname: Liao
authors.affiliation: Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Shue-Ling
authors.initials: SL
authors.lastname: Raung
authors.affiliation: Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan; Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan. Electronic address: cjchen@vghtc.gov.tw.
authors.forename: Chun-Jung
authors.initials: CJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018375:Neutrophil Activation / Q000187:drug effects*; D011719:Pyrazines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018696:Neuroprotective Agents; D011719:Pyrazines; C017953:tetramethylpyrazine
keywords: Neutrophils; Stroke; Tetramethylpyrazine