title: Tetramethylpyrazine improves the recovery of spinal cord injury via Akt/Nrf2/HO-1 pathway.
abstract: Spinal cord injury (SCI) is one of the most severe traumatic conditions, resulting in postoperative complications. Our results and other reports have shown that tetramethylpyrazine (TMP) is able to exhibit neuro-protective effects after SCI. In the current study, we aimed to examine the possible mechanism underlying the neuro-protective effect of TMP in rat model of SCI. TMP improved locomotor functions and decreased permeability of blood-spinal cord barrier in rats with SCI, as evidenced by increase of Basso-Beattie-Bresnahan scores and decrease of Evans blue leakage. In addition, TMP decreased the expression of several proinflammatory cytokines, including IL-1β, TNFα and IL-18, reduced TUNEL-positive cells and caspase 3 and 9 activities, decreased thiobarbituric acid reactive substances content and increased glutathione level and superoxide dismutase activity in rats. All these effects were inhibited by zinc protoporphyrin IX (ZnPP), an inhibitor of HO-1, and LY294002, an inhibitor of Akt. Moreover, TMP inhibited the decrease of mRNA expression of HO-1 which was suppressed by ZnPP and LY294002. TMP inhibited the decrease of Akt phosphorylation in rats after SCI, which was suppressed by LY294002, but not ZnPP. Furthermore, LY294002, but not ZnPP, significantly inhibited TMP-induced increase of mRNA expression of Nrf2 and DNA binding activity of Nrf2 in HO-1 promoters in rat model of SCI. The data suggested that TMP induced neuro-protective effects against injury of spinal cord through the activation of Akt/Nrf2/HO-1 signaling pathway. These results have appointed a new path toward the understanding of pathogenesis and TMP-related therapy of SCI and associated neurodegenerative diseases.
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zeng
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China. Electronic address: weixin_li111@163.com.
authors.forename: Weixin
authors.initials: W
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D002867:Chromones; D016207:Cytokines; D009025:Morpholines; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495637:Nfe2l2 protein, rat; D011719:Pyrazines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051547:Heme Oxygenase-1; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; C017953:tetramethylpyrazine
keywords: Akt; HO-1; Nrf2; Spinal cord injury; Tetramethylpyrazine