Tetramethylpyrazine analogue CXC195 protects against cerebral ischemia/reperfusion-induced apoptosis through PI3K/Akt/GSK3β pathway in rats.
CXC195 showed strongest protective effects among the ligustrazine derivatives in cells and prevented apoptosis induced by H2O2 injury. We recently demonstrated that CXC195 protected against cerebral ischemia/reperfusion (I/R) injury by its antioxidant activity. However, whether the anti-apoptotic action of CXC195 is involved in cerebral I/R injury is unknown. Here, we investigated the role of CXC195 in apoptotic processes induced by cerebral I/R and the possible signaling pathways. Male Wistar rats were submitted to transient middle cerebral artery occlusion for 2h, followed by 24h reperfusion. CXC195 was injected intraperitoneally at 2h and 12h after the onset of ischemia. The number of apoptotic cells was measured by TUNEL assay, apoptosis-related protein cleaved caspase-3, Bcl-2, Bax and the phosphorylation levels of Akt and GSK3β in ischemic penumbra were assayed by western blot. The results showed that administration of CXC195 at the doses of 3mg/kg and 10mg/kg significantly inhibited the apoptosis by decreasing the number of apoptotic cells, decreasing the level of cleaved caspase-3 and Bax, and increasing the level of Bcl-2 in rats subjected to I/R injury. Simultaneously, CXC195 treatment markedly increased the phosphorylation of Akt and GSK3β. Blockade of PI3K activity by wortmannin, dramatically abolished its anti-apoptotic effect and lowered both Akt and GSK3β phosphorylation levels. Our study firstly demonstrated that CXC195 protected against cerebral I/R injury by reducing apoptosis in vivo and PI3K/Akt/GSK3β pathway involved in the anti-apoptotic effect.
Department of Pharmacology, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, Shandong 250012, People's Republic of China.
Lin
L
Chen
Department of Pharmacology, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, Shandong 250012, People's Republic of China.
Xinbing
X
Wei
Intensive Care Unit, Qianfoshan Hospital of Shandong University, 16766#, Jing Shi Road, Jinan, Shandong 250014, People's Republic of China.
Yunfeng
Y
Hou
Department of Pharmacology, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, Shandong 250012, People's Republic of China.
Xiaoqian
X
Liu
Department of Pharmacology, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, Shandong 250012, People's Republic of China.
Senpeng
S
Li
Department of Anesthesiology, Qilu Hospital, Shandong University, 107#, Wenhua Xi Road, Jinan, Shandong 250012, People's Republic of China.
Baozhu
B
Sun
Institute of Medicinal Chemistry, Shandong University School of Pharmaceutical Sciences, 44#, Wenhua Xi Road, Jinan, Shandong 250012, People's Republic of China.
Xinyong
X
Liu
Department of Pharmacology, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, Shandong 250012, People's Republic of China. Electronic address: liuhuiqing@sdu.edu.cn.
Huiqing
H
Liu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000378:metabolism* / Q000517:prevention & control; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
C552200:CXC 195; D018696:Neuroprotective Agents; D010879:Piperazines; D011719:Pyrazines; D058539:Phosphatidylinositol 3-Kinase; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3; C017953:tetramethylpyrazine
Apoptosis; Ischemia/reperfusion; PI3K/Akt/GSK3β pathway; Tetramethylpyrazine analogue CXC195