title: Tetramethylpyrazine suppresses HIF-1alpha, TNF-alpha, and activated caspase-3 expression in middle cerebral artery occlusion-induced brain ischemia in rats.
abstract: OBJECTIVE
  To examine the detailed mechanisms underlying the inhibitory effect of tetramethylpyrazine (TMPZ) in inflammatory and apoptotic responses induced by middle cerebral artery occlusion (MCAO) in rats.
  
  
  METHODS
  MCAO-induced focal cerebral ischemia in rats was used in this study. The hypoxia-inducible factor-1alpha(HIF-1alpha), activation of caspase-3, and TNF-alpha mRNA transcription in ischemic regions were detected by immunoblotting and RT-PCR, respectively. Anti-oxidative activity was investigated using a thiobarbituric acid-reactive substance (TBARS) test in rat brain homogenate preparations.
  
  
  RESULTS
  We showed the statistical results of the infarct areas of solvent- and TMPZ (20 mg/kg)-treated groups at various distances from the frontal pole in MCAO-induced focal cerebral ischemia in rats. Treatment with TMPZ (20 mg/kg) markedly reduced the infarct area in all regions, especially in the third to fifth sections. MCAO-induced focal cerebral ischemia was associated with increases in HIF-1alpha and the activation of caspase-3, as well as TNF-alpha transcription in ischemic regions. These expressions were markedly inhibited by treatment with TMPZ (20 mg/kg). However, TMPZ (0.5-5 mmol/L) did not significantly inhibit TBARS reaction in rat brain homogenates.
  
  
  CONCLUSIONS
  The neuroprotective effect of TMPZ may be mediated at least by a portion of the inhibition of HIF-1alpha and TNF-alpha activations, followed by the inhibition of apoptosis formation (active caspase-3), resulting in a reduction in the infarct volume in ischemia-reperfusion brain injury. Thus, TMPZ treatment may represent an ideal approach to lowering the risk of or improving function in ischemia- reperfusion brain injury-related disorders.
authors.affiliation: Department of Anesthesiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 110, Taiwan, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chang
authors.forename: George
authors.initials: G
authors.lastname: Hsiao
authors.forename: Seu-Hwa
authors.initials: SH
authors.lastname: Chen
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Chen
authors.forename: Jiing-Han
authors.initials: JH
authors.lastname: Lin
authors.forename: Kuang-Hung
authors.initials: KH
authors.lastname: Lin
authors.forename: Duen-Suey
authors.initials: DS
authors.lastname: Chou
authors.forename: Joen-Rong
authors.initials: JR
authors.lastname: Sheu
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001157:Arterial Occlusive Diseases / Q000201:enzymology / Q000378:metabolism*; D002545:Brain Ischemia / Q000201:enzymology / Q000378:metabolism*; D053148:Caspase 3 / Q000096:biosynthesis*; D004789:Enzyme Activation / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D008297:Male; D020768:Middle Cerebral Artery / Q000502:physiology*; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011719:Pyrazines; D014409:Tumor Necrosis Factor-alpha; D053148:Caspase 3; C017953:tetramethylpyrazine