ISSN 1214-0287 (on-line)
ISSN 1214-021X (printed)

Volume 6 (2008), No 3, p 153-163

Calcium channel blockade alleviates brain injury induced by long term exposureto an electromagnetic field

Sahar El-Swefy, Hala Soliman, Magdy Huessein

Address: Sahar El-Swefy, Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt

Received 3rd May 2008.
Revised 25th August 2008.
Published online 16th September 2008.

Full text article (pdf)

This study aimed to examine the effects of short and long term exposures to 81 mG EMF intensity. It focused on the roles ofROS, Ca2+ and calcium channel blocker (CCB) on the rat brain. Rats were exposed to 81 mG EMF intensity at the mobile phone base station for one and four weeks (2 hr/day, EMF exposed group). Another group of rats was pretreated with CCB (amlodipine 20 mg/ kg) for four weeks and similarly exposed to EMF (EMF + amlodipine group). Sham exposed and amlodipinecontrol groups were used. At the end of the study, Ca2+ as well as pro-inflammatory and oxidative stress markers were measured. Immunohistochemical staining for Bax in brain samples was carried out. Short term exposure evoked a cellular adaptation response. This was evident by a transient increase in brain levels of Ca2+, glutathione (GSH) and serum tumor necrosis factor alpha (TNFalpha). Long term exposure to EMF was lethal; progressive oxidative damage, and a prolonged increase in the Ca2+ levelaccompanied by a marked pro-inflammatory reaction (TNFalpha and CRP) were demonstrated. These alterations were ameliorated by pre- and con-comitant treatment with amlodipine. Furthermore, it restored the EMF induced apoptosis in brain tonear normal. In conclusion, EMF is a stressor agent that induces an imbalance between ROS generation and antioxidant defense response. Calcium ions may play a pivotal role in enhancing oxidative stress, pro-inflammatory reactions and apoptosis associated with EMF exposure. Therefore calcium channel blockade seems to play a role in brain protection.

electromagnetic field; calcium; oxidative stress; apoptosis; amlodipine; rats

Ahmed AE, Hussein GI, Loh JP, Abdel-Rahman SZ: Studies on the mechanism of haloacetonitrile-induced gastrointestinal toxicity - interaction of dibromoacetonitrile with glutathione and glutathione -S-transferase in rats. J Biochem Toxicol 6:115-121, 1991.

Annuziato L, Amoroso S, Pannaccione A, Cataldi M, Pignataro G, D'Alessio A, Sirabella R, Secondo A, Sibaud L, Di Renzo GF: Apotosis induced in neuronal. cells by oxidative stress: role played by caspases and intracellular calcium ions. Toxicol Lett 139:125-133, 2003.

Bancroft D, Steven A: Theory and Practice of Histological Techniques. 4th ed. Churchill Livingstone. New York, London and Tokyo, 1996, pp. 435-465.

Berridge MJ, Bootman MD, Lipp P: Calcium a life and death signal. Nature 395:645-648, 1998.

Brown DM, Donaldson K, Borm PJ, Schins RP, Dehnhardt M, Gilmour P, Jimenez LA, Stone V: Calcium and ROS-mediated activation of transcription factors and TNF-cytokine gene expression in macrophages exposed to ultrafine particles. Am J Physiol Lung Cell Mol Physiol 286:L344-L353, 2004.

Buge JA, Aust SD: Microsomal lipid peroxidation. Methods Enzymol 52:302-310, 1978.

Campillo N, Vinas P, Garcia L, Cordoba H: Selenium determination in biological fluids using Zeeman background correction electrothermal atomic absorption spectrometry. Anal Biochem 280:195-200, 2000.

Bediz CS, Baltaci AK, Mogulkoc R, Oztekin E: Zinc supplementation ameliorates electromagnetic field- induced lipid peroxidation in the rat brain. J Exp Med 208:133-140, 2006.

Chromy V, Fischer J: Photometric determination of total protein in lipemic sera. Clin Chem 23:754-756, 1977.

Drury RA, Wallington EA: Histological techniques. 5th edn. Oxford university press, Oxford, 1980, pp. 27-29.

Ermak G, Davies KJ: Calcium and oxidative stress: from cell signaling to cell death. Mol Immunol 38:713-721, 2002.

Frumkin H, Jacobson A, Gansler T, Thun MJ: Cellular phones and risk of brain tumors. CA Cancer J Clin 51:137-141, 2001.

Fukuo K, Yang J, Yasuda O: Nifedipine indirectly up regulates superoxide dismutase expression in endothelial cells via vascular smooth muscle cell-dependent pathways. Circulation 106:356-361, 2002.

Hassoun EA, Stohs SJ: Cadmium-induced production of superoxide anion oxide, DNA single strand breaks and lactate dehydrogenase leakage in J774A.1 cell cultures Toxicol 112:219-226, 1996.

Highton J, Hessian P: A solid-phase enzyme immunoassay for C-reactive protein: clinical value and the effect of rheumatoid factor. J Immunol Methods 68:185-192, 1984.

Huang BS, Leenen FH: Sympatho-inhibitory and depressor effects of amlodipine in spontaneously hypertensive rats. J Cardiovasc Pharmacol 42:153-160, 2003.

Hwang S, Kim GH: Biomarkers for oxidative stress status of DNA, lipids, and proteins in vitro and in vivo cancer research. Toxicol 229:1-10, 2007.

Hyland G : Physics and biology of mobile telephony. Lancet 356:1833-1836, 2000.

Julius S, Kieldsen SE, Weber M: Outcome in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the value randomized trial. Lancet 363:2022-2031, 2004.

Kataoka C, Egashira K, Ishibashi M, Inoue S, Ni W, Hiasa K, Kitamoto S, Usui M, Takeshita A: Novel anti-inflammatory actions of amlodipine in a rat model of arteriosclerosis induced by long-term inhibition of nitric oxide synthesis. Am J Physiol Heart Circ Physiol 286:H768-74, 2004.

Kaune WT, Dovan T, Kavet RI, Savitz DA, Neutra RR: Study of high and low current configuration homes from the 1988 Denver childhood cancer study. Bioelectromagnetics 23:177-188, 2002.

Kim S, Rome D, Yoo Y, Park K: Transforming growth factor beta expression in normal and pathological condition. Horm Res 42:5-8, 1994.

Krjukow AA, Semenkova GN, Cherenkevich SN, Gerein V: Activation of redox-systems of monocytes by hydrogen proxide. Biofactors 26:283-292, 2006.

Kwee S, Raskmark P, Velizarov S: Changes in cellular proteins due to environmental non-ionizing radiation and heat shock proteins. Electro Mangetobiol 20:165-176, 2001.

Lai H, Singh NP: Magnetic field induced DNA strand breaks in brain cells of the rat. Environ. Health perspect 112:687-694, 2004.

Lantow M, Scheudere J, Hartwig C, Simko M: Free radical release and HSP70 expression in two human immune-relevant cell lines after exposure to 1800 MHz radiofrequency radiation. Radiat Res 165:88-94, 2006.

Leszczynski D, Joenvaara S, Reivinen J, Kuokka R: Non-thermal activation of the hsp27/p38 MAPK stress pathway by mobile phone radiation in human endothelial cells: molecular mechanism for cancer and blood brain barrier related effects. Differentiation 70:120-129, 2002.

Mak IT, Zhang J, Welgicki WB : Productive effects of dihydropyridine Ca-blockers against endothelial cell oxidative injury due to combined nitric oxide and superoxide. Pharmacol Res 45:27-33, 2002.

Minelli TA, Balduzzo M, Milone FF, Nofrate V:Modleing cell dynamics under mobile phone radiation. Nonlinear Dynamics Psychol Lif Sci 11:197-218, 2007.

Moshage H, Hok B, Huizenga JB, Jansen PLM: (1995) Nitrite and nitrate determinations in plasma: a critical evaluation. Clin Chem 41:892-896, 1995.

Mostafa YM, Moustafa RM, Belac, A, Abou-El-Ela SH, Ali FM: Effects of acute exposure to the radiofrequency fields of cellular phones on plasma lipid peroxide and anti-oxidative activities in human erythrocytes. J Pharm Biomed Anal 26:605-608, 2001.

Muth JN, Varadi G, Schwartz A : Use of transgenic mice to study voltage-dependent Ca2+ channels. Trends pharmacol Sci 22:526-532, 2001.

Oelze M, Warnholt, A, Faulhaber J, Wenzel P, Kleschyov AL, Coldewey M, Hink U, Pongs O, Fleming, I, Wassmann S, Meinertz T, Ehmke H, Daiber A, Munzel T: NADPH oxidase accounts for enhanced superoxide production and impaired endothelium-dependent smooth muscle relaxation in BKbeta1-/-mice. Arterioscler Thromb Vasc Biol 26:1753-1759, 2006.

Orendacova J, Orendac M, Racekova E, Marsala J: Neurological effects of microwave exposure: a review focused on morphological findings in experimental animals. Arch Ital Biol 145:1-12, 2007.

Ozguner F, Bardak Y, Comlecki S: Protective effects of melatonin and caffeic acid phenylethyl ester against retinal oxidative stress in long-term use of mobile phone: a comparative study. Mol Cell Biochem 282:83-88, 2006.

Qiu C, Fratiglioni L, Karp A, Winblad B, Bellander T: Occupational exposure to electromagnetic fields and risk of Alzheimer's disease. Epidemiology 15:687-694, 2004.

Quinn SJ, Kifor O, Kifor I, Butters RB, Brown EM: Role of the cytoskeleton in extracellular calcium-regulated OTH release. Biochem Biophys Res Commun 354:8-13, 2006.

Rollwiz J, Lupke M, Simko M: Fifty-hertz magnetic fields induce free radical formation in mouse bone marrow-derived monocytes and macrophages. Biochim Biophys Acta 1974:231-238, 2004.

Ronit L, Asher S, Harry F, Vladimir S, Ophra R, Maor E, Doron K, Rachel L: Low energy visible light induces reactive oxygen species generation and stimulates an increase of intracellular calcium concentration in cardiac cells. J Biological Chem 278:40917-40922, 2003.

Roy-Byrine PP: The GABA-benzodiazepine receptor complex: structure, function, and role in anxiety. J Clin Psychiatry 66 (Suppl 2):14-20, 2005.

Salford LG, Brun AE, Eberhardt JL, Malmgren L, Bertil R : Nerve cell damage in mammalian brain after exposure to microwaves from GSM mobile phones, Environmental Health Prespectives V 111:881-883, 2003.

Sasaki H, Watanabe F, Murano T, Moyashita Y, Shirai K: Vascualr smooth muscle cell apoptosis induced by 7-ketocholesterol was mediated via Ca2+ and inhibited by the calcium channel blocker nifedipine. Metabolism 56:357-362, 2007.

Shibko P, Koivistoenen C, Tratnyet A, Newhall C, Friendman L: A method for sequential quantitative separation and determination of protein, RNA, DNA, lipid, and glycogen from a single rat liver homogenate or from a subcellular fraction. Anal Biochem 19:514-528, 1967.

Simko M, Hartwig C, Lantow M, Lupke M, Mattsson MO, Rahman Q, Rollwitz J: HSP 70 expression and free radical release after exposure to non-thermal radio-frequency electromagnetic fields and ultrafine particles in human Mono Mac 6 cells. Toxicol Lett 161:73-82, 2006.

Snedecor GW, Cochran WG: Statistical methods 7th ed Iowa Uni Press Ames Iowa USA, 1981, pp: 175-191.

Sun LX, Yao K, Jiang H, He JL, Lu DQ, Wang KJ, Li HW: DNA damage and repair induced by acute exposure of microwave from mobile phone on cultured human lens epithelial cells. Zhonghua Yan Ke ZA Zhi 42:1084-1088, 2006.

Toba H, Nakagawa Y, Miki S, Shimizu T, Yoshimura A, Inoue R, Asayama J, Kobara M, Nakata T: Calcium channel blockades exhibit anti-inflammatory and antioxidative effects by augmentation of endothelial nitric oxide synthetase and the inhibition of angiotensin converting enzyme in the N(G)-nitro-L-arginine methyl ester-induced hypertensive rat aorta: vasoprotective effects beyond the blood pressure-lowering effects of amlodipine and manidipine. Hypertens Res 28:689-700, 2005.

Uccelletti D, Farina F, Inton P, Goffrini P, Mancini P, Talora C, Rizzuto R, Palleschi C: The Golgi Ca2+ ATPase function is required for oxidative stress response by controlling the expression of the heat-shock element HSP60 in Kluyveromuyces lactiss. Mo Biol. Cell 16:4636-4647, 2005.

Yeniterzi M, Avunduk MC, Baltaci AK, Aribas OK, Gormus N, Tosun E: The histopathological changes in the rats caused by magnetic field of 50Hz frequency. Selcuk J Med 19:39-51, 2002.

Yokus B, Cakir DU, Akdag MZ, Sert C, Mete N: Oxidative DNA damage in rats exposed to extremely low frequency electromagnetic fields. Free Radic Res. 39:317-323, 2005.

Yoshii T, Iwa M, Li Z, Chen R, Ide A, Fukunaga S, Oshita A, Mogi M, Higaki J, Horiuchi M: Regression of atherosclerosis by amlodipine via anti-oxidative stress actions. Hypertens Res 29:457-466, 2006.

Yoshikawa T, Tanigawa M, Imai A, Hongo H, Kondo M: Enhancement of nitric oxide generation by low frequency electromagnetic field. Pathophysiology 7:131-135, 2000.

Yoshitaka H, Yoshikuni K, Masatsugu N, Yoji S, Koji I, Kenji S: Amoldipine-induced reduction of oxidative stress in the brain is associated with sympatho-inhibitory effects in stroke-prone spontaneously hypertensive rats. Hypertens Res 29:49-56, 2006.

Zhou X, Yang W, Li J: Ca2+ and protein kinase C-dependent signaling pathway for nuclear factor-kappaB activation, inducible nitric-oxide synthetase expression, and tumor necrosis factor-alpha production in lipopolysaccharide-stimulated rat peritoneal macrophages. J Biol Chem 281:31337-31347, 2006.


Kovacic P, Somanathan R. Electromagnetic fields: mechanism, cell signaling, other bioprocesses, toxicity, radicals, antioxidants and beneficial effects. J Recept Signal Transduction. 30: 214-226, 2010.