Apoptosis plays a role in the process of tissue damage after myocardial infarction (MI). This study was designed to investigate the possible effect of cerebrolysin against apoptosis triggered by oxidative cell stress in myocardial ischemia induced by isoproterenol in rat. Rats were pretreated with cerebrolysin 5 mL/kg intraperitoneally for 7 days and intoxicated with isoproterenol (ISO, 85 mg/kg, sc) on the last 2 days. Hearts were excised and stained to detect the infarction size. Serum levels of cardiotoxicity indices as creatine kinase isoenzyme (CK-MB) and troponin I (cTnI) as well as the cardiac oxidative stress parameters as thiobarbituric acid reactive substances and superoxide dismutase were estimated. The expression of prodeath gene p53 and antideath gene Bcl-2 was also assessed from the excised heart tissues. Leakage of cardiac enzymes, elevated oxidative stress markers, and apoptotic indices confirmed the MI occurring as a consequence of isoproterenol-induced ischemia. Cerebrolysin pretreatment caused significant attenuation of the oxidative stress-induced apoptosis in the ischemic myocardial tissue. These findings provided an evidence that cerebrolysin could protect rat myocardium against ischemic insult that was attributed to its antioxidant as well as its anti-apoptotic properties.
Acikel M , Buyukokuroglu ME , Erdogan F , Akosy H , Bozkurt E , Senocak H : Protective effect of dantrolene against myocardial injury induced by isoproterenol in rats: biochemical and histological findings. Int. J. Cardiol. 98, 389–394 (2005)
Bialik S , Geenen DL , Sasson IE , Cheng R , Horner JW , Evans SM , Lord EM , Koch CJ , Kitsis RN : Myocyte apoptosis during acute myocardial infarction in the mouse localizes to hypoxic regions but occurs independently of p53. J. Clin. Invest. 100, 1363–1372 (1997)
Cheng W , Kajstura J , Nitahara JA , Li B , Reiss K , Liu Y , Clark WA , Krajewski S , Reed JC , Olivetti G , Anversa P : Programmed myocyte cell death affects the viable myocardium after infarction in rats. Exp. Cell Res. 226, 316–327 (1996)
Deviatkina TA , Vazhnichaia EM , Lytsenko RV : Characteristics of lipid peroxidation in various tissues during acute stress and its correction by pyracetam and cerebrolysin. Eksp. Klin. Farmakol. 634, 38–41 (2000)
Formichi P , Radi E , Battisti C , Di Maio G , Muresanu D , Federico A : Cerebrolysin administration reduces oxidative stress-induced apoptosis in lymphocytes from healthy individuals. J. Cell Mol. Med. 1611, 2840–2843 (2012)
Galang N , Sasaki H , Maulik N : Apoptotic cell death during ischemia/reperfusion and its attenuation by antioxidant therapy. Toxicology 148, 111–118 (2000)
Garg V , Taylor T , Warren M , Venable P , Sciuto K , Shibayama J , Zaitsev A : β-Adrenergic stimulation and rapid pacing mutually promote heterogeneous electrical failure and ventricular fibrillation in the globally ischemic heart. Am. J. Physiol. Heart Circ. Physiol. 308, H1155–H1170 (2015)
Gasparyan AY : Cardiovascular risk and inflammation: pathophysiological mechanisms, drug design, and targets. Curr. Pharm. Des. 18, 1447–1449 (2012)
Gonzalez ME , Francis L , Castellano O : Antioxidant systemic effect of short-term cerebrolysin administration. J. Neural. Transm. Suppl. 53, 333–341 (1998)
Gustafsson AB , Gottlieb RA : Heart mitochondria: gates of life and death. Cardiovasc. Res. 77, 334–343 (2008)
Hartbauer M , Hutter-Paier B , Skofitsch G , Windisch M : Antiapoptotic effects of the peptidergic drug cerebrolysin on primary cultures of embryonic chick cortical neurons. J. Neural. Transm. 108, 459–473 (2001)
Heiss WD , Brainin M , Bornstein NM , Tuomilehto J , Hong Z : Cerebrolysin in patients with acute ischemic stroke in Asia: results of a double-blind, placebo-controlled randomized trial. Stroke 433, 630–636 (2012)
Hockenbery DM , Zutter M , Hickey W , Nahm M , Korsmeyer SJ : Bcl-2 protein is topographically restricted in tissues characterized by apoptotic cell death. Proc. Natl. Acad. Sci. U. S. A. 88, 6961–6965 (1991)
Hutter-Paier B , Grygar E , Frühwirth M , Temmel I , Windisch M : Further evidence that Cerebrolysin® protects cortical neurons from neurodegeneration in vitro. J. Neural. Transm. Suppl. 53, 363–372 (1998)
Keshavarz M , Emamghoreishi M , Nekooeian AA , Warsh JJ , Zare HR : Increased Bcl-2 protein levels in rat primary astrocyte culture following chronic lithium treatment. Iran J. Med. Sci. 38, 255–262 (2013)
Krijnen PAJ , Nijmeijer R , Meijer CJLM , Visser CA , Hack CE , Niessen HWM : Apoptosis in myocardial ischaemia and infarction. J. Clin. Pathol. 55, 801–811 (2002)
Li H , Xie YH , Yang Q , Wang SW , Zhang BL , Wang JB , Cao W , Bi LL , Sun JY , Miao S , Hu J , Zhou XX , Qiu PC : Cardioprotective effect of paeonol and danshensu combination on isoproterenol-induced myocardial injury in rats. PLoS One 7, e48872 (2012)
Li WG , Zaheer A , Coppey L , Oskarsson HJ : Activation of JNK in the remote myocardium after large myocardial infarction in rats. Biochem. Biophys. Res. Commun. 246, 816–820 (1998)
Lie JT , Pairolero PC , Holley KE , Titus JL : Macroscopic enzyme mapping verification of large, homogeneous, experimental myocardial infarcts of predictable size and location in dogs. J. Thorac. Cardiovasc. Surg. 69, 599–605 (1975)
Lowry OH , Rosebrough NJ , Farr AL , Randall RJ : Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193, 265–275 (1951)
Mathew S , Menon PVG , Kurup PA : Effect of administration of vitamin A, ascorbic acid and nicotinamide adenine dinucleotide + flavin adenine dinucleotide on severity of myocardial infarction induced by isoproterenol in rats. Indian J. Exp. Biol. 23, 500–504 (1985)
Misao J , Hayakawa Y , Ohno M , Kato S , Fujiwara T , Fujiwara H : Expression of Bcl-2 protein, an inhibitor of apoptosis, and Bax, an accelerator of apoptosis, in ventricular myocytes of human hearts with myocardial infarction. Circulation 94, 1506–1512 (1996)
Miyashita T , Krajewski S , Krajewska M , Wang HG , Lin HK , Liebermann DA , Hoffman B , Reed JC : Tumor suppressor p53 is a regulator of Bcl-2 and Bax gene expression in vitro and in vivo. Oncogene 9, 1799–1805 (1994)
Ohkawa H , Ohishi N , Yagi K : Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem. 95, 351–358 (1979)
Oltvai ZN , Milliman CL , Korsmeyer SJ : Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74, 609–619 (1993)
Ornellas DS , Nascimento DS , Christoph DH , Guggino WB , Morales MM : Aldosterone and high-NaCl diet modulate ClC-2 chloride channel gene expression in rat kidney. Pflügers Arch. 444, 193–201 (2002)
Palojoki E , Saraste A , Eriksson A , Pulkki K , Kallajoki M , Voipio-Pulkki LM , Tikkanen I : Cardiomyocyte apoptosis and ventricular remodeling after myocardial infarction in rats. Am. J. Physiol. Heart Circ. Physiol. 280, H2726–H2731 (2001)
Panda S , Kar A , Banerjee T , Sharma N : Combined effects of quercetin and atenolol in reducing isoproterenol-induced cardiotoxicity in rats: possible mediation through scavenging free radicals. Cardiovasc. Toxicol. 12, 235–242 (2012)
Patocková J , Krsiak M , Marhol P , Tůmová E : Cerebrolysin inhibits lipid peroxidation induced by insulin hypoglycemia in the brain and heart of mice. Physiol. Res. 52, 455–460 (2003)
Rathore N , John S , Kale M , Bhatnagar D : Lipid peroxidation and antioxidant enzymes in isoproterenol induced oxidative stress in rat tissues. Pharmacol. Res. 38, 297–303 (1998)
Remiao F , Carmo H , Carvalho FD , Bastos ML : Inhibition of glutathione reductase by isoproterenol oxidation products. J. Enzyme Inhib. 15, 47–61 (1999)
Ribeiro DA , Buttros JB , Oshima CT , Bergamaschi CT , Campos RR : Ascorbic acid prevents acute myocardial infarction induced by isoproterenol in rats: role of inducible nitric oxide synthase production. J. Mol. Histol. 402, 99–105 (2009)
Saraste A , Pulkki K , Kallajoki M , Henriksen K , Parvinen M , Voipio-Pulkki LM : Apoptosis in human acute myocardial infarction. Circulation 95, 320–323 (1997)
Senthil S , Sridevi M , Pugalendi KV : Cardioprotective effect of oleanolic acid on isoproterenol induced myocardial ischemia in rats. Toxicol. Pathol. 353, 418–423 (2007)
Seth SD , Maulik M , Katiyar CK , Maulik SK : Role of lipistat in protection against isoproterenol induced myocardial necrosis in rats: a biochemical and histological study. Indian J. Physiol. Pharmacol. 42, 101–106 (1998)
Sharma HS , Zimmermann-Meinzingen S , Sharma A , Johanson CE : Cerebrolysin attenuates blood-brain barrier and brain pathology following whole body hyperthermia in the rat. Acta Neurochir. Suppl. 106, 321–325 (2010)
Shen JG , Quo XS , Jiang B , Li M , Xin W , Zhao BL : Chinonin, a novel drug against cardiomyocyte apoptosis induced by hypoxia and reoxygenation. Biochim. Biophys. Acta 1500, 217–226 (2000)
Singal PK , Beamish RE , Dhalla NS : Potential oxidative pathways of catecholamines in the formation of lipid peroxides and genesis of heart disease. Adv. Exp. Med. Biol. 161, 391–401 (1983)
Soussi T , Caron de Fromentel C , Breugnot C , May E : Nucleotide sequence of a cDNA encoding the rat p53 nuclear oncoprotein. Nucleic Acids Res. 16, 11384 (1988)
Sugita Y , Kondo T , Kanazawa A , Itou T , Mizuno Y : Protective effects FPF1070 (cerebrolysin) on delayed neuronal death in the gerbil-detection of hydroxyl radicals with salicylic acid. No To Shinkei 45, 325–331 (1993)
Tosaki A , Woodward B , Yamamoto F , Hearse DJ : Isoproterenol and the genesis of reperfusion-induced arrhythmias in isolated rat heart: adrenoceptor or free radical-mediated mechanisms? J. Cardiovasc. Pharmacol. 15, 398–407 (1990)
Upaganlawar A , Patel V , Balaraman R : Tomato lycopene attenuates myocardial infarction induced by isoproterenol: Electrocardiographic, biochemical and anti-apoptotic study. Asian Pac. J. Trop. Biomed. 25, 345–351 (2012)
van der Laarse A : Hypothesis: troponin degradation is one of the factors responsible for deterioration of left ventricular function in heart failure. Cardiovasc. Res. 56, 8–14 (2002)
von Harsdorf R , Li PF , Dietz R : Signaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis. Circulation 99, 2934–2941 (1999)
Wang X : The expanding role of mitochondria in apoptosis. Genes Dev. 15, 2922–2933 (2001)
Winterbourn CC , Hawkins RE , Brian M , Carrell RW : The estimation of red cell superoxide dismutase activity. J. Lab. Clin. Med. 85, 337–342 (1975)
Xing S , Zhang J , Dang C , Liu G , Zhang Y , Li J , Fan Y , Pei Z , Zeng J : Cerebrolysin reduces amyloid-β deposits, apoptosis and autophagy in the thalamus and improves functional recovery after cortical infarction. J. Neurol. Sci. 337, 104–111 (2014)
Yue TL , Ma XL , Wang X , Romanic AM , Liu GL , Louden C , Gu JL , Kumar S , Poste G , Ruffolo RR Jr , Feuerstein GZ : Possible involvement of stress-activated protein kinase signaling pathway and Fas receptor expression in prevention of ischemia/reperfusion-induced cardiomyocyte apoptosis by carvedilol. Circ. Res. 82, 166–174 (1998)
Zhu J , Liu M , Kennedy RH , Liu SJ : TNF-α-induced impairment of mitochondrial integrity and apoptosis mediated by caspase-8 in adult ventricular myocytes. Cytokine 341, 96–105 (2006)