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PI3K/Akt pathway contributes to neuroprotective effect of Tongxinluo against focal cerebral ischemia and reperfusion injury in rats.
J Ethnopharmacol. 2016 Apr 02; 181:8-19.JE

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE

Tongxinluo (TXL), a compound prescription, is formulated according to the collateral disease doctrine of traditional Chinese medicine, and is widely used for the treatment of cardio-cerebrovascular diseases in China.

AIM OF THE STUDY

We aimed to investigate the neuroprotective effect of TXL on focal cerebral ischemia and reperfusion injury in rats by attenuating its brain damage and neuronal apoptosis, and to assess the potential role of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway in this protection.

MATERIALS AND METHODS

Adult Male Sprague-Dawley rats (n=120) were randomly divided into 5 groups: sham, cerebral ischemia and reperfusion (I/R), cerebral ischemia and reperfusion plus TXL (1.6g/kg/day) (TXL1.6), TXL1.6 plus LY294002 and dimethyl sulfoxide (DMSO) (TXL1.6+LY294002), TXL1.6 plus DMSO (TXL1.6+vehicle). Prior to the grouping, TXL1.6 was selected to be the optimal dose of TXL by evaluating the neurological deficits score of five group rats (Sham, I/R, TXL0.4, TXL0.8 and TXL1.6, n=30) at 0, 1, 3, 5, and 7 days after reperfusion. Rats, being subjected to middle cerebral artery occlusion (MCAO) for 90min followed by 24h reperfusion, were the cerebral ischemia/reperfusion models. At 24h after reperfusion, cerebral infarct area was measured via tetrazolium staining and neuronal damage was showed by Nissl staining. The double staining of Terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick end labeling (TUNEL) staining and immunofluorescence labeling with NeuN, was performed to evaluate neuronal apoptosis. Proteins involved in PI3K/Akt pathway were detected by Western blot.

RESULTS

The results showed that TXL markedly improved neurological function, reduced cerebral infarct area, decreased neuronal damage, and significantly attenuated neuronal apoptosis, while these effects were eliminated by inhibition of PI3K/Akt with LY294002. We also found that TXL up-regulated the expression levels of p-PDK1, p-Akt, p-c-Raf, p-BAD and down-regulated Cleaved caspase 3 expression notably, which were partially reversed by LY294002. Additionally, the increment of p-PTEN level on which LY294002 had little effect was also detected in response to TXL treatment.

CONCLUSIONS

These findings demonstrated that TXL provided neuroprotection against cerebral ischemia/reperfusion injury and neuronal apoptosis, and this effect was mediated partly by activation of the PI3K/Akt pathway.

Authors+Show Affiliations

Department of Integrative Medicine, Zhongshan Hospital, Laboratory of Neurology, Institute of Integrative Medicine, Fudan University, 180 Fenglin Road, Shanghai 200032, China.Department of Integrative Medicine, Zhongshan Hospital, Laboratory of Neurology, Institute of Integrative Medicine, Fudan University, 180 Fenglin Road, Shanghai 200032, China.Department of Integrative Medicine, Zhongshan Hospital, Laboratory of Neurology, Institute of Integrative Medicine, Fudan University, 180 Fenglin Road, Shanghai 200032, China.Department of Integrative Medicine, Zhongshan Hospital, Laboratory of Neurology, Institute of Integrative Medicine, Fudan University, 180 Fenglin Road, Shanghai 200032, China.Department of Integrative Medicine, Zhongshan Hospital, Laboratory of Neurology, Institute of Integrative Medicine, Fudan University, 180 Fenglin Road, Shanghai 200032, China.Department of Integrative Medicine, Zhongshan Hospital, Laboratory of Neurology, Institute of Integrative Medicine, Fudan University, 180 Fenglin Road, Shanghai 200032, China.Department of Integrative Medicine, Zhongshan Hospital, Laboratory of Neurology, Institute of Integrative Medicine, Fudan University, 180 Fenglin Road, Shanghai 200032, China.Department of Integrative Medicine, Zhongshan Hospital, Laboratory of Neurology, Institute of Integrative Medicine, Fudan University, 180 Fenglin Road, Shanghai 200032, China.Department of Integrative Medicine, Zhongshan Hospital, Laboratory of Neurology, Institute of Integrative Medicine, Fudan University, 180 Fenglin Road, Shanghai 200032, China.Department of Integrative Medicine, Zhongshan Hospital, Laboratory of Neurology, Institute of Integrative Medicine, Fudan University, 180 Fenglin Road, Shanghai 200032, China. Electronic address: dingfangcai@163.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26805466

Citation

Yu, Zhong-Hai, et al. "PI3K/Akt Pathway Contributes to Neuroprotective Effect of Tongxinluo Against Focal Cerebral Ischemia and Reperfusion Injury in Rats." Journal of Ethnopharmacology, vol. 181, 2016, pp. 8-19.
Yu ZH, Cai M, Xiang J, et al. PI3K/Akt pathway contributes to neuroprotective effect of Tongxinluo against focal cerebral ischemia and reperfusion injury in rats. J Ethnopharmacol. 2016;181:8-19.
Yu, Z. H., Cai, M., Xiang, J., Zhang, Z. N., Zhang, J. S., Song, X. L., Zhang, W., Bao, J., Li, W. W., & Cai, D. F. (2016). PI3K/Akt pathway contributes to neuroprotective effect of Tongxinluo against focal cerebral ischemia and reperfusion injury in rats. Journal of Ethnopharmacology, 181, 8-19. https://doi.org/10.1016/j.jep.2016.01.028
Yu ZH, et al. PI3K/Akt Pathway Contributes to Neuroprotective Effect of Tongxinluo Against Focal Cerebral Ischemia and Reperfusion Injury in Rats. J Ethnopharmacol. 2016 Apr 2;181:8-19. PubMed PMID: 26805466.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PI3K/Akt pathway contributes to neuroprotective effect of Tongxinluo against focal cerebral ischemia and reperfusion injury in rats. AU - Yu,Zhong-Hai, AU - Cai,Min, AU - Xiang,Jun, AU - Zhang,Zhen-Nian, AU - Zhang,Jing-Si, AU - Song,Xiao-Ling, AU - Zhang,Wen, AU - Bao,Jie, AU - Li,Wen-Wei, AU - Cai,Ding-Fang, Y1 - 2016/01/22/ PY - 2015/06/16/received PY - 2015/08/31/revised PY - 2016/01/18/accepted PY - 2016/1/26/entrez PY - 2016/1/26/pubmed PY - 2016/12/15/medline KW - Apoptosis KW - Cerebral ischemia and reperfusion injury KW - Neuroprotection KW - PI3K/Akt KW - Tongxinluo SP - 8 EP - 19 JF - Journal of ethnopharmacology JO - J Ethnopharmacol VL - 181 N2 - ETHNOPHARMACOLOGICAL RELEVANCE: Tongxinluo (TXL), a compound prescription, is formulated according to the collateral disease doctrine of traditional Chinese medicine, and is widely used for the treatment of cardio-cerebrovascular diseases in China. AIM OF THE STUDY: We aimed to investigate the neuroprotective effect of TXL on focal cerebral ischemia and reperfusion injury in rats by attenuating its brain damage and neuronal apoptosis, and to assess the potential role of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway in this protection. MATERIALS AND METHODS: Adult Male Sprague-Dawley rats (n=120) were randomly divided into 5 groups: sham, cerebral ischemia and reperfusion (I/R), cerebral ischemia and reperfusion plus TXL (1.6g/kg/day) (TXL1.6), TXL1.6 plus LY294002 and dimethyl sulfoxide (DMSO) (TXL1.6+LY294002), TXL1.6 plus DMSO (TXL1.6+vehicle). Prior to the grouping, TXL1.6 was selected to be the optimal dose of TXL by evaluating the neurological deficits score of five group rats (Sham, I/R, TXL0.4, TXL0.8 and TXL1.6, n=30) at 0, 1, 3, 5, and 7 days after reperfusion. Rats, being subjected to middle cerebral artery occlusion (MCAO) for 90min followed by 24h reperfusion, were the cerebral ischemia/reperfusion models. At 24h after reperfusion, cerebral infarct area was measured via tetrazolium staining and neuronal damage was showed by Nissl staining. The double staining of Terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick end labeling (TUNEL) staining and immunofluorescence labeling with NeuN, was performed to evaluate neuronal apoptosis. Proteins involved in PI3K/Akt pathway were detected by Western blot. RESULTS: The results showed that TXL markedly improved neurological function, reduced cerebral infarct area, decreased neuronal damage, and significantly attenuated neuronal apoptosis, while these effects were eliminated by inhibition of PI3K/Akt with LY294002. We also found that TXL up-regulated the expression levels of p-PDK1, p-Akt, p-c-Raf, p-BAD and down-regulated Cleaved caspase 3 expression notably, which were partially reversed by LY294002. Additionally, the increment of p-PTEN level on which LY294002 had little effect was also detected in response to TXL treatment. CONCLUSIONS: These findings demonstrated that TXL provided neuroprotection against cerebral ischemia/reperfusion injury and neuronal apoptosis, and this effect was mediated partly by activation of the PI3K/Akt pathway. SN - 1872-7573 UR - https://www.unboundmedicine.com/medline/citation/26805466/PI3K/Akt_pathway_contributes_to_neuroprotective_effect_of_Tongxinluo_against_focal_cerebral_ischemia_and_reperfusion_injury_in_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-8741(16)30025-3 DB - PRIME DP - Unbound Medicine ER -