Ellagic acid improves electrocardiogram waves and blood pressure against global cerebral ischemia rat experimental models

Authors

  • Mahin Dianat Faculty Member, Physiology Research Center and Department of Physiology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

Keywords:

Global cerebral ischemia, Ellagic acid, Rat, ECG, Blood pressure, MDA

Abstract

Background: Global cerebral ischemia (GCIR) arises in patients that are shown a variety of clinical difficulty including cardiac arrest, asphyxia, and shock. In spite of advances in understanding of the brain, ischemia and protective effects to improve ischemic injury still remain unknown. The aim of our study was to investigate the effect of ellagic acid (EA) pretreatment in the rat models of global cerebral ischemia reperfusion.

Methods: This experimental study was conducted in 2014 at the Physiology Research Center of the Ahvaz Jundishapur University of Medical Sciences in Ahvaz, Iran. Adult male Wistar rats (250-300 g) were used in this study. GCIR was induced by bilateral vertebral and common carotid arteries occlusion (4-VO). 32 rats were divided randomly to four groups: 1) So (Sham) received normal saline as vehicle of EA, 2) EA, 3) normal saline + GCIR, and 4) EA + GCIR. After anesthesia (a mix of xylazine and ketamine), animal subjected to 20 minutes of ischemia followed by 30 minutes of reperfusion in related groups. EA (100 mg/kg, dissolved in normal saline) or 1.5 ml/kg normal saline was administered (gavage, 10 days) to the related groups. EEG was recorded from NTS in GCIR treated groups.

Results: Present data showed that: 1) EEG in GCIR treated groups was flattened; 2) Blood pressure, voltage of QRS and P-R interval were reduced significantly in the ischemic groups compared to before ischemia, and pretreatment with EA prevented this reduction; and 3) MDA level and heart rate was increased by GCIR and pretreatment with EA reduced MDA level and restored the HR to normal level.

Conclusion: Results indicate that global cerebral ischemia-reperfusion impairs certain heart functions and ellagic acid as an antioxidant can restore these parameters. The results of this study suggest the possible utility of ellagic acid in patients with brain stroke.

References

WHO, Fact sheet N°310. 2014 [updated 2014; cited]; Available from:

http://www.who.int/mediacentre/factsheets/fs310/en/index.html.

Schweizer S, Meisel A, Märschenz S. Epigenetic mechanisms in cerebral ischemia. J Cereb Blood Flow Metab.

; 33 (9): 1335-46. doi: 10.1038/jcbfm.2013.93. PMID: 23756691, PMCID: PMC3764391.

Salazar J, Wityk R, Grega M, Borowicz L, Doty J, Petrofski J, et al. Stroke after cardiac surgery: short- and

long-term outcomes. Ann Thorac Surg. 2001; 72 (4): 1195–1201. PMID: 11603436.

Li P, Su L, Li X, Di W, Zhang X, Zhang C, et al. Remote limb ischemic postconditioning protects mouse brain

against cerebral ischemia/reperfusion Injury via up regulating expression of Nrf2, HO-1, NQO-1 in mice. Int J

Neurosci. 2015; 1-28. doi:10.3109/00207454. PMID: 26000916.

Stedman TL. Stedman's Medical Dictionary. 28th ed.: Lippincott Williams & Wilkins; 2006.

Klein KU, Stadie A, Fukui K, Schramm P, Werner C, Oertel J, et al. Measurement of cortical microcirculation

during intracranial aneurysm surgery by combined laser-Doppler flowmetry and photospectrometry.

Neurosurgery. 2011; 69 (2):391-8. doi: 10.1227/NEU.0b013e3182178bc9. PMID: 21430590.

McGinnis W, Audhya T, Edelson S. Proposed Toxic and Hypoxic Impairment of a Brainstem Locus in Autism.

Int J Environ Res Public Health .2013; 10 (12): 6955–7000. doi: 10.3390/ijerph10126955. PMID: 24336025 ,

PMCID: PMC3881151.

Liu JH, Yan J, Chang XR, et al. Effect of electroacupuncture after electrolytic damage nucleus tractus solitarii.

Zhongyiyao Linchuang Zazhi. 2010; 22 (5): 414–416.

Liu AJ, Ling G, Wu J, Shen FM, Wang DS, Lin LL, et al. Arterial baroreflex function is an important

determinant of acute cerebral ischemia in rats with middle cerebral artery occlusion. Life Sci. 2008; 83 (11-12):

-93. doi: 10.1016/j.lfs.2008.06.021. PMID: 18647611.

Sottiurai VS, Herbert L, Hatter D. Revascularization of cerebral ischemia after previous bilateral extra cranialintracranial bypass procedures. J Vasc Surg.1997; 26(1):160-3. PMID: 9240338.

Li LX, Campbell K, Zhao S, Knuckey NW, Meloni BP.The effect of blood pressure (37 vs 45 mmHg) and

carotid occlusion duration (8 vs 10 min) on CA1-4 neuronal damage when using isoflurane in a global cerebral

ischemia rat model. Brain Res Bull. 2011; 86(5-6):390-4. doi: 10.1016/j.brainresbull.2011.09.005. PMID:

Pomfy M, Franko J.Validation of a four-vessel occlusion model for transient global cerebral ischemia in dogs. J

Hirnforsch. 1999; 39(4):465-71. PMID: 10841444

Zhang F, Iadecola C.Temporal characteristics of the protective effect of aminoguanidine on cerebral ischemic

damage. Brain Res. 1998; 802 (1-2): 104-10. PMID: 9748524.

Kannan MM, Quine SD. Ellagic acid ameliorates isoproterenol induced oxidative stress: Evidence from

electrocardiological, biochemical and histological study. Eur J Pharmacol. 2011; 659(1):45-52. doi:

1016/j.ejphar.2011.02.037. PMID: 21385579.

Juan A. Ascacio-Valdés, José J. Buenrostro-Figueroa, Antonio Aguilera-Carbó, Arely Prado-Barragán, Raúl

Rodríguez-Herrera and Cristóbal N. Aguilar. Ellagitannins: Biosynthesis, biodegradation and biological

properties. Journal of Medical Plants Research.2011; 5(19):4696-4703. Available from:

http://www.academicjournals.org/JMPR.

Xue R, He J, Wang N, Yao F, Lv J, Wu G. Relationship between transmembrane signal transduction pathway

and DNA repair and the mechanism after global cerebral ischemia-reperfusion in rats. Neurosci Bull. 2009; 25

(3): 115-21. doi: 10.1007/s12264-009-8818-9. PMID: 19448685.

Pang X, Li T, Feng L, Zhao J, Zhang X, Liu J. Ellagic acid-induced thrombotic focal cerebral ischemic model

in rats. J Pharmacol Toxicol Methods. 2014; 69 (3): 217-22. doi: 10.1016/j.vascn.2014.01.001. PMID:

Dianat M, Veisi A, Ahangarpour A, Fathi Moghaddam H.The effect of hydro-alcoholic celery

(Apiumgraveolens) leaf extract on cardiovascularparameters and lipid profile in animal model of hypertension

induced by fructose. Avicenna J Phytomed. 2015; 5 (3): 203-9. PMID: 26101753. PMCID: PMC4469955.

Yonekura I, Kawahara N, Nakatomi H, Furuya K, Kirino T. A model of global cerebral ischemia in C57 BL/6

mice. J Cereb Blood Flow Metab.2004; 24 (2): 151-8. doi: 10.1097/01.WCB.0000096063.84070.C1. PMID:

Beltz J, McNeil C, Fisher M,et al. Investigation of the antihyperalgesic effects of the pomegranate extract

ellagic acid. AANA J. 2008; 76 (5): 365–366. Abstract A6.

Girish C, Koner B, Jayanthi S, Ramachandra R, Rajesh B, Pradhan S. Hepatoprotective activity of picroliv,

curcumin and ellagic acid compared to silymarin on paracetamol induced liver toxicity in mice.Fundam Clin

Pharmacol. 2009; 23 (6): 735-45. doi: 10.1111/j.1472-8206.2009.00722.x. PMID: 19656205.

Mansouri M, Naghizadeh B, Ghorbanzadeh B, Farbood Y. Central and peripheral antinociceptive effects of

ellagic acid in different animal models of pain. European Journal of Pharmacology. 2013; 707 (1-3): 46-53.

doi: 10.1016/j.ejphar.2013.03.031. PMID: 23528359.

Cheng CH, Yi P, Chang H, Tsai Y, Chang F. Kappa-opioid receptors in the caudal nucleus tractus solitarius

mediate 100 Hz electro acupuncture-induced sleep activities in rats. Evid Based Complement Alternat Med.

;2012:715024. doi: 10.1155/2012/715024. PMID: 22454676, PMCID: PMC3290910.

Sarkaki A, Eidypour Z, Motamedi F, keramati K, Farbood Y. Motor disturbances and thalamic electrical power

of frequency bands' improve by grape seed extract in animal model of Parkinson's disease. Avicenna J

Phytomed. 2012; 2 (4): 222–232. PMID: 25050252, PMCID: PMC4075680.

Pulsinelli W, Brierley J. A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke. 1979;

: 267–272. doi: 10.1161/01.STR.10.3.267.

Greene E. Anatomy of the rat. Transactions Am Philosophical. Philadelphia, USA. 1935: 127–9.

Diler A, Ziylan Y, Uzum G, Lefauconnier J, Seylaz J, Pinard E. Passage of spermidine across the blood–brain

barrier in short recirculation periods following global cerebral ischemia: effects of mild hyperthermia. Neurosci

Res. 2002; 43 (4): 335-342. doi: 10.1016/S0168-0102(02)00059-7. PMID: 12135777. 28) Leeuwenburgh C, Heinecke J. Oxidative stress and antioxidants in exercise. Curr Med Chem. 2001; 8 (7): 829- 38. doi: 10.2174/0929867013372896. PMID: 11375753.

Satoh K. Serum lipid peroxide in cerebrovascular disorders determined by new colorimetric Method. Clin Chim

Acta. 1978; 90 (1): 37-43. PMID: 719890.

Sumiyoshi M, Kitazato K, Yagi K, Miyamoto T, Kurashiki Y, Matsushita N, et al. The accumulation of brain

water-free sodium is associated with ischemic damage independent of the blood pressure in female rats. Brain

Res. 2015; 1616:37-44. doi: 10.1016/j.brainres.2015.04.051. PMID: 25957792.

Herguido M, Carceller F, Madero R, Roda J. Animal survival related to acute blood pressure response in global

cerebral ischemia in rats. Neurol Res. 1997; 19 (4): 417-9. PMID: 9263223.

Smith J, Baumert M, Nalivaiko E, McEvoy R, Catcheside P. Arousal in obstructive sleep apnoea patients is

associated with ECG RR and QT interval shortening and PR interval lengthening. J Sleep Res. 2009; 18 (2):

-95. doi: 10.1111/j.1365-2869.2008.00720.x. PMID: 19645965.

Seki Y, Tomizawa T, Khechinashvili N, Soda K. Contribution of solvent water to the solution X-ray scattering

profile of proteins. Biophys Chem. 2002; 28; 95(3):235-52. PMID: 12062383.

Kim J, Kim SH, Choi H. Dehydroepiandrosterone supplements increases malate dehydrogenase activity and

decreases NADPH-dependent antioxidant enzyme activity in rat hepatocellular carcinogenesis. Nutr Res Pract.

; 2 (2): 80-4. doi: 10.4162/nrp.2008.2.2.80. PMCID: PMC2815321.

Peters J, Ihle P. ECG-synchronized thoracic vest inflation during autonomic blockade, myocardial ischemia, or

cardiac arrest. J Appl Physiol . 1992; 73 (6): 2263-73. PMID: 1490933.

Chakkarapani E, Dingley J, Aquilina K, Osredkar D, Liu X, Thoresen M. Effects of xenon and hypothermia on

cerebrovascular pressure reactivity in newborn global hypoxic-ischemic pig model. J Cereb Blood Flow Metab.

; 33 (11): 1752-60. doi: 10.1038/jcbfm.2013.123. PMID: 23899927, PMCID: PMC3824173.

Katsanos A, Korantzopoulos P, Tsivgoulis G, Kyritsis AP, Kosmidou M, Giannopoulos S. Electrocardiographic

abnormalities and cardiac arrhythmias in structural brain lesions. Int J Cardiol. 2013; 167 (2): 328-34. doi:

1016/j.ijcard.2012.06.107. PMID: 22809542.

Khechinashvili G, Asplund K. Electrocardiographic changes in patients with acute stroke: a systematic review.

Cerebrovasc Dis. 2002; 14 (2): 67-76. PMID: 12187009.

Lindgren A, Wohlfart B, Pahlm O, Johansson BB. Electrocardiographic changes in stroke patients without

primary heart disease. Clin Physiol. 1994; 14 (2): 223-31. PMID: 8205753.

Aki H, Fujita M, Yamashita S, Fujimoto K, Kumagai K, Tsuruta R, et al. Elevation of jugular venous

superoxide anion radical is associated with early inflammation, oxidative stress, and endothelial injury in

forebrain ischemia-reperfusion rats. Brain Res. 2009; 1292: 180-90. doi: 10.1016/j.brainres.2009.07.054.

PMID: 19635469.

Kannan M, Quine S. Ellagic acid inhibits cardiac arrhythmias, hypertrophy and hyperlipidaemia during

myocardial infarction in rats. Metabolism. 2013; 62 (1): 52-61. doi: 10.1016/j.metabol.2012.06.003. PMID:

Woo M, Choi H, Seo M, Jeon H, Lee B. Ellagic acid suppresses lipid accumulation by suppressing early

adipogenic events and cell cycle arrest. Phytother Res. 2015; 29 (3): 398-406. doi: 10.1002/ptr.5264. PMID:

Sander D, Klingelhofer J. Extent of autonomic activation following cerebral ischemia is different in

hypertensive and normotensive humans. Arch Neurol. 1996; 53 (9): 890-4. doi:

1001/archneur.1996.00550090096015. PMID: 8815854.

Mohagheghi F, Khalaj L, Ahmadiani A, Rahmani B. Gemfibrozil pretreatment affecting antioxidant defense

system and inflammatory, but not Nrf-2 signaling pathways resulted in female neuroprotection and male

neurotoxicity in the rat models of global cerebral ischemia-reperfusion. Neurotox Res. 2013; 23(3):225-37. doi:

1007/s12640-012-9338-3. PMID: 22773136.

Akil E, Tamam Y, Akil M, Kaplan I, Bilik M, Acar A, et al. Identifying autonomic nervous system dysfunction

in acute cerebrovascular attack by assessments of heart rate variability and catecholamine levels. J Neurosci

Rural Pract. 2015; 6 (2): 145-50. DOI: 10.4103/0976-3147.153216. PMID: 25883469, PMCID: PMC4387800.

Diaz-Velez C, Garcia-Castineiras S, Mendoza-Ramos E, Hernandez-Lopez E. Increased malondialdehyde in

peripheral blood of patients with congestive heart failure. Am Heart J. 1996; 131 (1): 146-52. PMID: 8554002.

Han J, Kim C, Lim K, Kim J, Kim S, Yun YP, et al. Increases in blood pressure and heart rate induced by

caffeine are inhibited by (-)-epigallocatechin-3-O-gallate: involvement of catecholamines. J Cardiovasc

Pharmacol. 2011; 58(4):446-9. doi: 10.1097/FJC.0B013E31822D93CB. PMID: 21975870.

Yoshimura M, Watanabe Y, Kasai K, Yamakoshi J, Koga T. Inhibitory effect of an ellagic acid-rich

pomegranate extract on tyrosinase activity and ultraviolet-induced pigmentation. Biosci Biotechnol Biochem.

; 69 (12): 2368-73. doi: 10.1271/bbb.69.2368. PMID: 16377895.

Saenz de Tejada I, Carceller F, Fernandez A, Cuevas B, Ortes L, Giménez-Gallego G, et al. Kinins are

implicated of the hypotensive effect of acidic fibroblast growth factor. Eur J Med Res. 1997; 2 (7): 302-4.

PMID: 9233905

Powers W, Clarke W, Grubb RL Jr, Videen T, Adams HP Jr, Derdeyn C. Lower stroke risk with lower blood

pressure in hemodynamic cerebral ischemia. Neurology. 2014; 82 (12): 1027-32. doi:

1212/WNL.0000000000000238. PMID: 24532276, PMCID: PMC3962994.

Madias J. Mechanism of attenuation of the QRS voltage in heart failure: a hypothesis. Europace.

;11(8):995-1000. doi: 10.1093/europace/eup127. PMID: 19493912.

Bhargava U, Westfall B. The mechanism of blood pressure depression by ellagic acid. Proc Soc Exp Biol Med.

; 132 (2): 754-6. PMID: 4187712.

Ishiwata S, Nishiyama S, Nakanishi S, Nishimura S, Yanagishita Y, Kato K, et al. [Natural history of 82

patients with hypertrophic cardiomyopathy: follow-up for over ten years]. J Cardiol. 1991; 21(1):61-73. PMID:

Ito Y, Ohkubo T, Asano Y, Hattori K, Shimazu T, Yamazato M, et al. Nitric oxide production during cerebral

ischemia and reperfusion in eNOS- and nNOS-knockout mice. Curr Neurovasc Res. 2010; 7 (1): 23-31. doi:

2174/156720210790820190. PMID: 20158465.

Shinde R, Shinde S, Makhale C, Grant P, Sathe S, Durairaj M, et al. Occurrence of "J waves" in 12-lead ECG as

a marker of acute ischemia and their cellular basis. Pacing Clin Electrophysiol. 2007; 30 (6): 817-9. doi:

1111/j.1540-8159.2007.00760.x. PMID: 17547622, PMCID: PMC 1989774.

Perlaki G, Orsi G, Schwarcz A, Bodi P, Plozer E, Biczo K,et al. Pain-related autonomic response is modulated

by the medial prefrontal cortex: An ECG-fMRI study in men. J Neurol Sci. 2015; 349 (1-2): 202-8. doi:

http://dx.doi.org/10.1016/j.jns.2015.01.019.

Mari Kannan M, Darlin Quine S. Pharmacodynamics of ellagic acid on cardiac troponin-T, lyosomal enzymes

and membrane bound ATPases: mechanistic clues from biochemical, cytokine and in vitro studies. Chem Biol

Interact. 2011; 193(2):154-61. doi: 10.1016/j.cbi.2011.06.005. PMID: 21762681.

Schmidt J, Crimmins M, Lantigua H, Fernandez A, Zammit C, Falo C, Agarwal S, Claassen J, Mayer SA.

Prolonged elevated heart rate is a risk factor for adverse cardiac events and poor outcome after subarachnoid

hemorrhage. Neurocrit Care. 2014; 20(3):390-8. doi: 10.1007/s12028-013-9909-z. PMID: 24043479, PMCID:

PMC4437199.

Liang G, Shi B, Luo W, Yang J. The protective effect of caffeic acid on global cerebral ischemia-reperfusion

injury in rats. Behav Brain Funct. 2015; 11: 18. doi: 10.1186/s12993-015-0064-x. PMID: 25907417, PMCID:

PMC4407787.

Published

2022-03-08

Issue

Section

Articles