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(S)-1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) reduces rat myocardial apoptosis against ischemia and reperfusion injury by activation of phosphatidylinositol 3-kinase/Akt signaling and anti-inflammatory action in vivo.
J Pharmacol Exp Ther. 2009 Aug; 330(2):440-8.JP

Abstract

We examined our hypothesis that (S)-1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) inhibits apoptosis in myocardial ischemia and reperfusion (I/R) injury in vivo via activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and by reducing inflammation during I/R. To do this, we induced a 30-min period of ischemia by occlusion of the left anterior descending coronary artery of the rat followed by a 2-h (for phosphorylation of Akt), 6-h (for biochemical analysis), or 24-h (for functional analysis) period of reperfusion to determine the effect of CKD712 treatment. Pretreatment with CKD712 significantly improved myocardial function as evidenced by an increase in the +/-dP/dt and a decrease in the infarct size, which were antagonized by a PI3K inhibitor, wortmannin (WT). Interestingly, CKD712 increased the phosphorylation of Akt and cAMP-response element-binding protein and increased the expression of the Bcl-2 gene, but it reduced the expression of the Bax gene. CKD712 decreased not only the expression but also the activity of the caspase-3 protein in the myocardium after reperfusion. Thus, all of the antiapoptotic effects of CKD712 were significantly inhibited by WT. Furthermore, the antiapoptotic effects of CKD712 and its inhibition by WT in myocardium after reperfusion were confirmed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining. Finally, CKD712 was found to reduce the serum levels of the high-mobility group box 1 protein, tumor necrosis factor-alpha, and the cardiac troponin I protein in addition to tissue levels of malondialdehyde and myeloperoxidase activity in I/R hearts. Taken together, both the activation of PI3K/Akt and its anti-inflammatory action prevent apoptosis in myocardial I/R injury by CKD712.

Authors+Show Affiliations

Department of Pharmacology, Institute of Health Sciences, School of Medicine Gyeongsang National University, Jinju 660-751, Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

19458286

Citation

Jin, Yong Chun, et al. "(S)-1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) Reduces Rat Myocardial Apoptosis Against Ischemia and Reperfusion Injury By Activation of Phosphatidylinositol 3-kinase/Akt Signaling and Anti-inflammatory Action in Vivo." The Journal of Pharmacology and Experimental Therapeutics, vol. 330, no. 2, 2009, pp. 440-8.
Jin YC, Lee YS, Kim YM, et al. (S)-1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) reduces rat myocardial apoptosis against ischemia and reperfusion injury by activation of phosphatidylinositol 3-kinase/Akt signaling and anti-inflammatory action in vivo. J Pharmacol Exp Ther. 2009;330(2):440-8.
Jin, Y. C., Lee, Y. S., Kim, Y. M., Seo, H. G., Lee, J. H., Kim, H. J., Yun-Choi, H. S., & Chang, K. C. (2009). (S)-1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) reduces rat myocardial apoptosis against ischemia and reperfusion injury by activation of phosphatidylinositol 3-kinase/Akt signaling and anti-inflammatory action in vivo. The Journal of Pharmacology and Experimental Therapeutics, 330(2), 440-8. https://doi.org/10.1124/jpet.108.150342
Jin YC, et al. (S)-1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) Reduces Rat Myocardial Apoptosis Against Ischemia and Reperfusion Injury By Activation of Phosphatidylinositol 3-kinase/Akt Signaling and Anti-inflammatory Action in Vivo. J Pharmacol Exp Ther. 2009;330(2):440-8. PubMed PMID: 19458286.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - (S)-1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) reduces rat myocardial apoptosis against ischemia and reperfusion injury by activation of phosphatidylinositol 3-kinase/Akt signaling and anti-inflammatory action in vivo. AU - Jin,Yong Chun, AU - Lee,Young Soo, AU - Kim,Young Min, AU - Seo,Han Geuk, AU - Lee,Jae Heun, AU - Kim,Hye Jung, AU - Yun-Choi,Hye Sook, AU - Chang,Ki Churl, Y1 - 2009/05/20/ PY - 2009/5/22/entrez PY - 2009/5/22/pubmed PY - 2009/8/20/medline SP - 440 EP - 8 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 330 IS - 2 N2 - We examined our hypothesis that (S)-1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) inhibits apoptosis in myocardial ischemia and reperfusion (I/R) injury in vivo via activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and by reducing inflammation during I/R. To do this, we induced a 30-min period of ischemia by occlusion of the left anterior descending coronary artery of the rat followed by a 2-h (for phosphorylation of Akt), 6-h (for biochemical analysis), or 24-h (for functional analysis) period of reperfusion to determine the effect of CKD712 treatment. Pretreatment with CKD712 significantly improved myocardial function as evidenced by an increase in the +/-dP/dt and a decrease in the infarct size, which were antagonized by a PI3K inhibitor, wortmannin (WT). Interestingly, CKD712 increased the phosphorylation of Akt and cAMP-response element-binding protein and increased the expression of the Bcl-2 gene, but it reduced the expression of the Bax gene. CKD712 decreased not only the expression but also the activity of the caspase-3 protein in the myocardium after reperfusion. Thus, all of the antiapoptotic effects of CKD712 were significantly inhibited by WT. Furthermore, the antiapoptotic effects of CKD712 and its inhibition by WT in myocardium after reperfusion were confirmed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining. Finally, CKD712 was found to reduce the serum levels of the high-mobility group box 1 protein, tumor necrosis factor-alpha, and the cardiac troponin I protein in addition to tissue levels of malondialdehyde and myeloperoxidase activity in I/R hearts. Taken together, both the activation of PI3K/Akt and its anti-inflammatory action prevent apoptosis in myocardial I/R injury by CKD712. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/19458286/_S__1__alpha_naphthylmethyl__67_dihydroxy_1234_tetrahydroisoquinoline__CKD712__reduces_rat_myocardial_apoptosis_against_ischemia_and_reperfusion_injury_by_activation_of_phosphatidylinositol_3_kinase/Akt_signaling_and_anti_inflammatory_action_in_vivo_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=19458286 DB - PRIME DP - Unbound Medicine ER -