Tetramethylpyrazine suppresses HIF-1alpha, TNF-alpha, and activated caspase-3 expression in middle cerebral artery occlusion-induced brain ischemia in rats.
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.
Chang
Yi
Y
Department of Anesthesiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 110, Taiwan, China.
Hsiao
George
G
Chen
Seu-Hwa
SH
Chen
Yi-Cheng
YC
Lin
Jiing-Han
JH
Lin
Kuang-Hung
KH
Chou
Duen-Suey
DS
Sheu
Joen-Rong
JR
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*
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