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Eur J Pharmacol. 2019 Feb 5;844:156-164. doi: 10.1016/j.ejphar.2018.11.031. Epub 2018 Nov 29.

Protective effects of tetramethylpyrazine analogue Z-11 on cerebral ischemia reperfusion injury.

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Department of Pharmacy, Qingdao Municipal Hospital, Qingdao 266071, China.
Department of Neurology, Eighth People's Hospital Affiliated to Qiingdao University, Qingdao 266003, China.
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China.


The aim of our study was to investigate the effects of a new synthetic compound (E) -1- (E) -1- (2- hydroxy -5- chlorophenyl) -3- (3, 5, 6- three methyl pyrazine -2- based) -2- propylene -1 ketone, Z-11, a tetramethylpyrazine analogue, on cerebral ischemia reperfusion injury and the underlying mechanism. 240-260 g adult male Wistar rats were subjected to middle cerebral artery occlusion for 2 h, followed by 22 h of reperfusion. Z-11 (1.7, 3.4 and 6.8 mg/kg, i.p.), Edaravone (3 mg/kg, i.p.) and DMSO (1‰, i.p.) was administered at 2 h after the onset of ischemia. The rats' neurological score, infarct volume, and body weight change were tested, and some oxidative stress markers such as superoxide dismutase (SOD) activity, glutathione (GSH) and malondialdehyde (MDA) contents were evaluated after 22 h of reperfusion. Results showed that neurologic deficit, infarct volume and body weight change were ameliorated after cerebral ischemia reperfusion, and that Z-11 exhibits an excellent effect at a dosage of 6.8 mg/kg. This dose also reduced the content of MDA, and upregulated SOD activity and GSH content. Similarly, 6.8 mg/kg Z-11 treatment inhibited the reactive oxygen species content and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, with the protein levels of Ras-related C3 botulinum toxin substrate1(Rac-1) and mitogenic oxidase (Nox2) downregulated even further. Moreover, the protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream anti-oxidant protein heme oxygenase-1 (HO-1) were upregulated. This indicates that Z-11 could play a protective role in cerebral ischemia-reperfusion injury, and that the protective effect of Z-11 may be related to improvements in the antioxidant capacity of brain tissue. The mechanisms are associated with enhancing oxidant defence systems via the activation of Nrf2/HO-1 and Rac-1/NADPH oxidase pathways.


Cerebral ischemia; Reactive oxygen species; Tetramethylpyrazine

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