THE EFFECTS OF COMBINATION OF RADIOFREQUENCY AND PULSED MAGNETIC FIELD ON CAROTID ARTERIA ISCHEMIA AND REPERFUSION INDUCED BRAIN INJURY: A PRELIMINARY REPORT

Year 2023, Volume: 30 Issue: 4, 630 - 642, 30.12.2023

Rümeysa Taner , Halil Aşçı , Dinçer Uysal , Sanem Aşcı , Melike Doğan Ünlü , Ali Serdar Oğuzoğlu , Selçuk Çömlekçi , Özlem Özmen

https://doi.org/10.17343/sdutfd.1343406

Abstract

Objective
Cerebrovascular accident due to ischemia (IS)
mediated by atherosclerotic plaque in the brain
can trigger inflammation in the cerebral cortex,
hippocampus and cerebellum tissues. Radiofrequency
electromagnetic field (RF-EMF) and pulsed magnetic
field (PMF) applications can increase nitric oxide
formation from the vascular endothelial layer. The
aim of this preliminary study is to reduce the damage
caused by IS in different tissues of the brain by
magnetic field applications.
Material and Method
A total of 9 rats, one rat in each group; sham,
prophylactic RF, PMF, RF+PMF and therapeutic
RF-EMF, PMF, RF-EMF+PMF, prophylactic and
therapeutic RF-EMF+PMF and IS-only groups were
distinguished. In single or combined applications of
prophylactic/therapeutic RF-EMF and PMF groups,
rats were taken to the experimental unit for 30
minutes of magnetic field exposure before and after
30 minutes of carotid artery occlusion for IS purposes.
Histopathological hematoxylin-eosin staining in
brain tissue (cerebral cortex and hippocampus)
and cerebellum tissues taken after sacrification;
With immunohistochemical analysis, brain derived
neurotrophic factor (BDNF), tumor necrosis factoralpha
(TNF-α), mammalian target of rapamycin
(mTOR) and inducible nitric oxide synthase (iNOS)
expressions were examined.
Results
Histopathologically significant hyperemia, edema,
bleeding and neuronal degeneration were detected
in the IS group. Additionally, immunohistochemically,
an increase in TNF-α, mTOR, iNOS and a decrease
in BDNF staining were observed. Prophylactic and/or
therapeutic RF-EMF and/or PMF applications reversed
all these parameters. The greatest improvement
was observed in the Prophylactic+Therapeutic RFEMF+
PMF group.
Conclusion
As a result, the regression of IS-related inflammation in
both brain tissue parts and cerebellar tissues with RFEMF
and PMF is important in terms of the formation
of neurological deficits, the continuity of learning
and memory mechanisms, and the preservation of
balance functions.

Keywords

Cerebral ischemia, eNOS, iNOS, mTOR, Pulsed magnetic field, Radiofrequency electromagnetic field

Supporting Institution

Scientific Research Fund of Suleyman Demirel University

Project Number

TSG-2022-8783

RADYOFREKANS VE DARBELİ MANYETİK ALAN KOMBİNASYONUNUN KAROTİS ARTER İSKEMİ REPERFÜZYON KAYNAKLI BEYİN HASARI ÜZERİNDEKİ ETKİLERİ: BİR ÖN RAPOR

Abstract

Amaç
Beyindeki aterosklerotik plağın aracılık ettiği iskemi
(IS) nedeniyle serebrovasküler olay serebral korteks,
hipokampus ve serebellum dokularında inflamasyonu
tetikleyebilir. Radyofrekans elektromanyetik alan (RFEMF)
ve darbeli manyetik alan (PMF) uygulamaları
vasküler endotel tabakasından nitrik oksit oluşumunu
artırabilir. Bu ön çalışmanın amacı, iskemi nedeniyle
beynin farklı dokularında meydana gelen hasarı azaltmaktır.
Gereç ve Yöntem
Her bir grupta bir tane rat olacak şekilde toplamda 9
adet rat; sham, profilaktik RF, PMF, RF+PMF ve terapötik
RF-EMF, PMF, RF-EMF+PMF, profilaktik ve
terapötik RF-EMF+PMF ve yalnızca IS uygulanan
gruplara ayırt edilmiştir. Profilaktik/terapötik RF-EMF
ve PMF gruplarının tekli veya kombine uygulamalarında
ratlar IS amaçlı 30 dakikalık karotis arter oklüzyonu
öncesi ve sonrasında 30 dakikalık manyetik alan
maruziyetleri için deney ünitesine alındı. Sakrifikasyondan
sonra alınan beyin dokusu (serebral korteks
ve hipokampüs) ile beyincik dokularında, histopatolojik
olarak hematoksilin-eozin boyama; immünohistokimyasal
analizler ile de brain derivated neurotrophic
factor (BDNF), tumor necrosis factor-alpha (TNF-α),
mammalian target of rapamycin (mTOR) ve inducible
nitric oxide synthase (iNOS) ekspresyonlarına bakıldı.
Bulgular: IS grubunda histopatolojik olarak belirgin
hiperemi, ödem, kanama ve nöronal dejenerasyon
saptandı. Ayrıca immünohistokimyasal olarak TNF-α,
mTOR, iNOS artışı ve BDNF boyamasında azalma
gözlendi. Profilaktik ve/veya terapötik RF-EMF ve/
veya PMF uygulamaları tüm bu parametreleri tersine
çevirmiştir. En fazla düzelme Profilaktik+Terapötik
RF-EMF+PMF grubunda gözlendi.
Sonuç
Sonuç olarak RF-EMF ve PMF ile her iki beyin dokusu
kısımları ve beyincik dokularında IS’ye bağlı inflamasyon
tablosunun gerilemesi nörolojik defisitlerin oluşması,
öğrenme ve hafıza mekanizmalarının devamlılığı
ve denge fonksiyonlarının korunması açısından
önemlidir.

Keywords

Serebral iskemi, eNOS, iNOS, mTOR, Darbeli manyetik alan, Radyofrekans elektromanyetik alan

Project Number

TSG-2022-8783

References

• 1. Sarıbaş O, Topçuoğlu MA, Arsava EM. Akut İskemik İnmelerde Tedavi Yaklaşımları. In: Balkan S (edt). Serebrovasküler Hastalıklar. Antalya, Güneş Kitapevi: 2005;289-311.
• 2. Kutluk K. İskemik inme. In: Kutluk K. Epidemiyoloji. İstanbul, Nobel Tıp Kitapevi: 2004;1-4.
• 3. Kutluk K. İskemik inme. In: Kutluk K. Patogenez. İstanbul, Nobel Tıp Kitapevi: 2004;19-35.
• 4. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; Jan;24(1):35-41. doi: 10.1161/01.str.24.1.35.
• 5. Şahan M, Satar S, Koç AF, Sebe A. İskemik İnme ve Akut Faz Reaktanları. aktd 2010; 19(2): 85-140.
• 6. Utku U, Çelik Y. Strokta Etyoloji, Sınıflandırma ve Risk Faktörleri. In: Serebrovasküler Hastalıklar, Edt. Balkan S. Antalya, Güneş Kitapevi: 2005; 57-71.
• 7. Incalza MA, D'Oria R, Natalicchio A, Perrini S, Laviola L, Giorgino F. Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases. Vascul Pharmacol. 2018;100:1-19. doi:10.1016/j. vph.2017.05.005
• 8. Zhai Y, Petrowsky H, Hong JC, et al. Ischaemia-reperfusion injury in liver transplantation—From bench to bedside. Nat Rev Gastroenterol Hepatol 2013; 10:79–89
• 9. Lowenstein CJ, Dinerman JL, Snyder SH. Nitric oxide: a physiologic messenger. Annals of internal medicine 1994; 120(3): 227–237. doi: 10.7326/0003-4819-120-3-199402010-00009.
• 10. Lucas KA, Pitari GM, Kazerounian S, Ruiz-Stewart I, Park J. Schulz S, et al. Guanylyl cyclases and signaling by cyclic GMP. Pharmacological reviews 2000; 52(3): 375–414. PMID: 10977868.
• 11. Marín J, Rodríguez-Martínez MA. Role of vascular nitric oxide in physiological and pathological conditions. Pharmacology & therapeutics 1997;75(2):111–134. doi:10.1016/s0163- 7258(97)00051-x.
• 12. Wang XL, Wang J. Endothelial nitric oxide synthase gene sequence variations and vascular disease. Molecular genetics and metabolism 2000; 70(4): 241–251. doi: 10.1006/ mgme.2000.3033.
• 13. Watanabe A, Sasaki T, Yukami T, Kanki H, Sakaguchi M, Takemori H, et al. Serine racemase inhibition induces nitric oxide- mediated neurovascular protection during cerebral ischemia. Neuroscience 2016; Dec 17;339:139-149. doi: 10.1016/j. neuroscience.2016.09.036.
• 14. Miura, M, Takayama, K, Okada, J. Increase in nitric oxide and cyclic GMP of rat cerebellum by radio frequency burst-type electromagnetic field radiation. The Journal of Physiology 1993;461:513-24. doi: 10.1113/jphysiol.1993.sp019526 86.
• 15. Miura M, Okada J. Non-thermal vasodilatation by radio frequency burst-type electromagnetic field radiation in the frog. J Physiol. 1991; 435:257–273. 87. doi: 10.1113/jphysiol.1991. sp018509.
• 16. Oladnabi M, Bagheri A, Rezaei Kanavi M, Azadmehr A, Kianmehr A. Extremely low frequency-pulsed electromagnetic fields affect proangiogenic-related gene expression in retinal pigment epithelial cells. Iranian journal of basic medical sciences 2019;22(2):128–133. doi: 10.22038/ijbms.2018.25023.6214.
• 17. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265-75.
• 18. Özden ES, Aşcı H, Büyükbayram Hİ, Sevük MA, İmeci OB, Doğan HK, et al. Dexpanthenol protects against lipopolysaccharide- induced acute kidney injury by restoring aquaporin-2 levels via regulation of the silent information regulator 1 signaling pathway. Korean J Anesthesiol. 2023; Oct;76(5):501-509. doi: 10.4097/kja.23207.
• 19. Meng LB, Shan MJ, Yu ZM, Lv J, Qi RM, Guo P, et al. Chronic stress: a crucial promoter of cell apoptosis in atherosclerosis. J Int Med Res. 2020;Jan;48(1):300060518814606. Doi: 10.1177/0300060518814606.
• 20. Gao Z, Xu X, Li Y, Sun K, Yang M, Zhang Q, et al. Mechanistic Insight into PPARγ and Tregs in Atherosclerotic Immune Inflammation. Front Pharmacol. 2021; Sep 29;12:750078. doi: 10.3389/fphar.2021.750078.
• 21. Hermus L, van Dam GM, Zeebregts CJ. Advanced carotid plaque imaging. Eur J Vasc Endovasc Surg. 2010; Feb 39(2):125-33. doi: 10.1016/j.ejvs.2009.11.020.
• 22. Wang X, Cui L, Ji X. Cognitive impairment caused by hypoxia: from clinical evidences to molecular mechanisms. Metab Brain Dis. 2022; Jan 37(1):51-66. doi: 10.1007/s11011-021-00796-3.
• 23. Lee D, Choi JI. Hydrogen-Rich Water Improves Cognitive Ability and Induces Antioxidative, Antiapoptotic, and Anti-Inflammatory Effects in an Acute Ischemia-Reperfusion Injury Mouse Model. Biomed Res Int. 2021; Oct 27;2021:9956938. doi: 10.1155/2021/9956938.
• 24. Erfani S, Valadbeigi T, Aboutaleb N, Karimi N, Moghimi A, Khaksari M. Usnic acid improves memory impairment after cerebral ischemia/reperfusion injuries by anti-neuroinflammatory, anti-oxidant, and anti-apoptotic properties. Iran J Basic Med Sci. 2020; Sep;23(9):1225-1231. doi: 10.22038/ijbms. 2020.43280.10165.
• 25. Voronkov AV, Mamleev AV. Endothelial dysfunction and Protein kinase C activity development interrelation at ischemic injury of a brain. Patol Fiziol Eksp Ter. 2016;60(4):134-42. PMID: 29244935.
• 26. Lapi D, Stornaiuolo M, Sabatino L, Sommella E, Tenore G, Daglia M, et al.The Pomace Extract Taurisolo Protects Rat Brain From Ischemia-Reperfusion Injury. Front Cell Neurosci. 2020; Jan 28;14:3. doi: 10.3389/fncel.2020.00003.
• 27. Han L, Su L, Chen D, Zhang S, Zhang Y, Zhao B, et al. ZnS nanoarchitectures induced dysfunction of vascular endothelial cells in vitro and in vivo. Environ Toxicol. 2015; Jul 30(7):755- 68. doi: 10.1002/tox.21955.
• 28. Bhanu C, Nimmons D, Petersen I, Orlu M, Davis D, Hussain H, et al. Drug-induced orthostatic hypotension: A systematic review and meta-analysis of randomised controlled trials. PLoS Med. 2021;18(11):e1003821. doi: 10.1371/journal.pmed.1003821.
• 29. Andrew PJ, Mayer B. Enzymatic function of nitric oxide synthases. Cardiovascular research. 1999; 43(3):521–531. https:// doi.org/10.1016/s0008-6363(99)00115-7
• 30. Barbato JE, Tzeng E. Nitric oxide and arterial disease. Journal of vascular surgery. 2004; 40(1): 187–193. doi: 10.1016/j. jvs.2004.03.043. PMID: 15218485.
• 31. Davis CM, Ammi AY, Zhu W, Methner C, Cao Z, Giraud D, et al. Low-Intensity Ultrasound Reduces Brain Infarct Size by Upregulating Phosphorylated Endothelial Nitric Oxide in Mouse Model of Middle Cerebral Artery Occlusion. Ultrasound Med Biol. 2023; May 49(5):1091-1101. doi: 10.1016/j.ultrasmedbio. 2022.12.008.
• 32. Palomares SM, Cipolla MJ. Vascular Protection Following Cerebral Ischemia and Reperfusion. J Neurol Neurophysiol. 2011; Sep 20;2011:S1- 004. doi: 10.4172/2155-9562.s1-004.
• 33. Liu J, Wang Y, Akamatsu Y, Lee CC, Stetler RA, Lawton MT, et al. Vascular remodeling after ischemic stroke: mechanisms and therapeutic potentials. Prog Neurobiol. 2014; Apr 115:138-56. doi: 10.1016/j.pneurobio.2013.11.004.
• 34. Liu J, Huang X, Zhou J, Li L, Xiao H, Qu M, et al. Pulsed electromagnetic field alleviates synovitis and inhibits the NLRP3/ Caspase-1/GSDMD signaling pathway in osteoarthritis rats. Electromagn Biol Med. 2022; Jan 2;41(1):101-107. doi: 10.1080/15368378.2021.2021933.
• 35. Huegel J, Chan PYW, Weiss SN, Nuss CA, Raja H, Waldorff EI, et al. Pulsed electromagnetic field therapy alters early healing in a rat model of rotator cuff injury and repair: Potential mechanisms. J Orthop Res. 2022; Jul;40(7):1593-1603. doi: 10.1002/ jor.25185.
• 36. Bragin DE, Statom GL, Hagberg S, Nemoto EM. Increases in microvascular perfusion and tissue oxygenation via pulsed electromagnetic fields in the healthy rat brain. J Neurosurg. 2015; May 122(5):1239-47. doi: 10.3171/2014.8.JNS132083.
• 37. Hao X, Wang D, Yan Z, Ding Y, Zhang J, Liu J, et al. Bone Deterioration in Response to Chronic High-Altitude Hypoxia Is Attenuated by a Pulsed Electromagnetic Field Via the Primary Cilium/HIF-1α Axis. J Bone Miner Res. 2023; Jan 21. Doi: 10.1002/jbmr.4772.
• 38. Luo L, Zang G, Liu B, Qin X, Zhang Y, Chen Y, et al. Bioengineering CXCR4-overexpressing cell membrane functionalized ROS-responsive nanotherapeutics for targeting cerebral ischemia- reperfusion injury. Theranostics 2021; Jul 6;11(16):8043- 8056. doi: 10.7150/thno.60785.
• 39. Lund MC, Clausen BH, Brambilla R, Lambertsen KL. The Role of Tumor Necrosis Factor Following Spinal Cord Injury: A Systematic Review. Cell Mol Neurobiol. 2023; Apr;43(3):925-950. doi: 10.1007/s10571-022-01229-0.
• 40. Bragin DE, Bragina OA, Hagberg S, Nemoto EM. Pulsed Electromagnetic Field (PEMF) Mitigates High Intracranial Pressure (ICP) Induced Microvascular Shunting (MVS) in Rats. Acta Neurochir Suppl. 2018;126:93-95. doi: 10.1007/978-3-319- 65798-1_20.
• 41. Lu DN, Xie Q, Xu Z, Yuan JM, Ma R, Wang J. Protective effects of three kinds of borneol on different brain regions in acute cerebral ischemia/reperfusion model rats. Zhongguo Zhong Yao Za Zhi. 2023; Mar 48(5):1289-1299. doi: 10.19540/j.cnki. cjcmm.20221025.406.
• 42. Maiese K, Chong ZZ, Shang YC, Wang S. Targeting disease through novel pathways of apoptosis and autophagy. Expert Opin Ther Targets. 2012; Dec 16(12):1203-14. doi: 10.1517/14728222.2012.719499.
• 43. Han JH, Park J, Kang TB, Lee KH. Regulation of Caspase-8 Activity at the Crossroads of Pro-Inflammation and Anti-Inflammation. Int J Mol Sci. 2021; Mar 24;22(7):3318. doi: 10.3390/ ijms22073318.
• 44. Korley FK, Diaz-Arrastia R, Wu AH, Yue JK, Manley GT, Sair HI, et al. Circulating Brain-Derived Neurotrophic Factor Has Diagnostic and Prognostic Value in Traumatic Brain Injury. J Neurotrauma. 2016; Jan 15;33(2):215-25. doi: 10.1089/ neu.2015.3949.
• 45. Cunha C, Brambilla R, Thomas KL. A simple role for BDNF in learning and memory? Front Mol Neurosci. 2010; Feb 9;3:1. doi: 10.3389/neuro.02.001.2010.