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Roles of Simvastatin and Sildenafil in Modulation of Cranial Irradiation-Induced Bystander Multiple Organs Injury in Rats

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Abstract—

In radiobiology and radiation oncology fields, the observation of a phenomenon called radiation-induced bystander effect (RIBE) has introduced the prospect of remotely located tissues’ affection. This phenomenon has been broadly developed to involve the concept of RIBE, which are relevant to the radiation-induced response of a distant tissue other than the irradiated one. The current study aimed at investigating each of the RIBE of cranial irradiation on oxidative and inflammatory status in different organs such as liver, kidney, heart, lung, and spleen. Being a vital target of the cholinergic anti-inflammatory response to an inflammatory stimulus, the splenic α-7-nicotinic acetylcholine receptor (α-7nAchR) was evaluated and the hepatic contents of thioredoxin, peroxisome proliferator-activated receptor-alpha and paraoxinase-1 (Trx/PPAR-α/PON) were also assessed as indicators for the liver oxidative stress and inflammatory responses. Being reported to act as antioxidant and anti-inflammatory agents, simvastatin (SV) and/or sildenafil (SD) were investigated for their effects against RIBE on these organs. These objectives were achieved via the biochemical assessments and the histopathological tissues examinations. Five experimental groups, one sham irradiated and four irradiated groups, were exposed to cranial irradiation at dose level of 25 Gy using an experimental irradiator with a Cobalt (Co60) source, RIBE, RIBE + SV (20 mg.(kg.bw)‐1 day‐1), RIBE + SD (75 mg.(kg.bw)‐1 day‐1), and RIBE + SV + SD. Cranial irradiation induced structural, biochemical, and functional dys-regulations in non-targeted organs. RIBE-induced organs’ injuries have been significantly corrected by the administration of SV and/or SD. Our results suggest the possibility of a potentiated interaction between SV and SD in the modulation of the RIBE associated with head and neck radiotherapy.

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References

  1. Najafi, M., R. Fardid, G. Hadadi, and M. Fardid. 2014. The mechanisms of radiation-induced bystander effect. Journal of biomedical physics and engineering 4: 163–172.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. ASCO American Society of Clinical Oncology. 2017. Understanding and managing radiation-induced bystander effect. https://ascopost.com/News/57853.

  3. CCS: Canadian Cancer Society. 2021. Side effects of radiation therapy.https://www.cancer.ca/en/cancer-information/diagnosis-and-treatment/radiation-therapy/side-effects-of-radiation-therapy/region=on.

  4. Mohye El-Din, A.A., A.B. Abdelrazzak, M.T. Ahmed, and M.A. El-Missiry. 2017. Radiation induced bystander effects in the spleen of cranially-irradiated rats. British Journal of Radiology 90: 20170278.

    Article  Google Scholar 

  5. Kirolikar, S., P. Prasannan, G.V. Raghuram, N. Pancholi, T. Saha, P. Tidke, P. Chaudhari, A. Shaikh, B. Rane, R. Pandey, H. Wani, N. Khare, S. Siddiqui, and D’souza, J., Prasad, R., Shinde, S., Parab, S., Nair, N., Pal, K., and I. Mittra. 2018. Prevention of radiation-induced bystander effects by agents that inactivate cell-free chromatin released from irradiated dying cells. Cell Death & Disease 9: 1142.

    Article  Google Scholar 

  6. Marín, A., M. Martín, O. Liñán, F. Alvarenga, M. López, L. Fernández, and L. Cerezo. 2014. Bystander effects and radiotherapy. Reports of practical oncology and radiotherapy 20: 12–21.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Neumann, S., N.J. Shields, T. Balle, M. Chebib, and A.N. Clarkson. 2015. Innate immunity and inflammation post-stroke: An α7-nicotinic agonist perspective. International Journal of Molecular Sciences 16: 29029–29046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fujii, T., M. Mashimo, Y. Moriwaki, H. Misawa, S. Ono, K. Horiguchi, and K. Kawashima. 2017. Expression and function of the cholinergic system in immune cells. Frontiers in Immunology 8: 1085.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Krishnaswamy, G., J. Kelley, L. Yerra, J.K. Smith, and D.S. Chi. 1999. Human endothelium as a source of multifunctional cytokines: Molecular regulation and possible role in human disease. Journal of Interferon & Cytokine Research 19: 91–104.

    Article  CAS  Google Scholar 

  10. Zhang, J.M., and J. An. 2007. Cytokines, inflammation, and pain. International anesthesiology clinics 45: 27–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Turner, M.D., B. Nedjai, T. Hurst, and D.J. Pennington. 2014. Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease. Biochimica et Biophysica Acta 1843: 2563–2582.

    Article  CAS  PubMed  Google Scholar 

  12. Ren, C., Y.L. Tong, J.C. Li, Z.Q. Lu, and Y.M. Yao. 2017. The protective effect of alpha 7 nicotinic acetylcholine receptor activation on critical illness and its mechanism. International Journal of Biological Sciences 13: 46–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kinsey, G.R. 2017. The spleen as a bidirectional signal transducer in acute kidney injury. Kidney International 91: 1001–1003.

    Article  CAS  PubMed  Google Scholar 

  14. Minemura, M., K. Tajiri, and Y. Shimizu. 2009. Systemic abnormalities in liver disease. World Journal of Gastroenterology 15: 2960–2974.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Robinson, M.W., C. Harmon, and C. O’Farrelly. 2016. Liver immunology and its role in inflammation and homeostasis. Cellular & Molecular Immunology 13: 267–276.

    Article  CAS  Google Scholar 

  16. Burri, L., G.H. Thoresen, and R.K. Berge. 2010. The role of PPARα activation in liver and muscle. PPAR Research 2010: 542359.

  17. Wang, Y., T. Nakajima, F.J. Gonzalez, and N. Tanaka. 2020. PPARs as metabolic regulators in the liver: Lessons from liver-specific PPAR-null mice. International Journal of Molecular Sciences 21: E2061.

    Article  PubMed  Google Scholar 

  18. Kumar, A. 2010. Effect of simvastatin on paraoxonase 1 (PON1) activity and oxidative stress. Asian Pacific Journal of Tropical Medicine 3: 310–314.

    Article  CAS  Google Scholar 

  19. Yorulmaz, H., E. Ozkok, E. Kaptan, G. Ates, and S. Tamer. 2018. Therapeutic effects of simvastatin on Galectin-3 and oxidative stress parameters in endotoxemic lung tissue. Bioscience Reports 38: BSR20180308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Semen, K., O. Yelisyeyeva, I. Jarocka-Karpowicz, D. Kaminskyy, L. Solovey, E. Skrzydlewska, and O. Yavorskyi. 2016. Sildenafil reduces signs of oxidative stress in pulmonary arterial hypertension: Evaluation by fatty acid composition, level of hydroxynonenal and heart rate variability. Redox biology 7: 48–57.

    Article  CAS  PubMed  Google Scholar 

  21. Buell, M.G., and R.K. Harhing. 1989. Proinflammatory effects of local abdominal irradiation on rat gastrointestinal tract. Digestive Diseases and Sciences 34: 390–399.

    Article  CAS  PubMed  Google Scholar 

  22. ISO/ASTM E 51026. 2015. Practice for using the Frick dosimetry system, ASTM international, west Conshohocken, PA.

  23. Moravan, M.J., J.A. Olschowka, J.P. Williams, and M.K. O’Banion. 2011. Cranial irradiation leads to acute and persistent neuroinflammation with delayed increases in T cell infiltration and CD11c expression in C57BL/6 mouse brain. Radiation Research 176: 459–473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Nezić, L., R. Skrbić, S. Dobrić, M.P. Stojiljković, V. Jaćević, S.S. Satara, Z.A. Milovanović, and N. Stojaković. 2009. Simvastatin and indomethacin have similar anti-inflammatory activity in a rat model of acute local inflammation. Basic & Clinical Pharmacology & Toxicology 104: 185–191.

    Article  Google Scholar 

  25. Zhao, L., A. Sebkhi, O. Ali, B. Wojciak-Stothard, L. Mamanova, Q. Yang, J. Wharton, and M.R. Wilkins. 2009. Simvastatin and sildenafil combine to attenuate pulmonary hypertension. European Respiratory Journal 34: 948–957.

    Article  CAS  Google Scholar 

  26. Alves-Filho, J.C., F. Sônego, F.O. Souto, A. Freitas, W.A. Verri Jr., M. Auxiliadora-Martins, A. Basile-Filho, A.N. McKenzie, D. Xu, F.Q. Cunha, and F.Y. Liew. 2010. Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection. Nature Medicine 16: 708–712.

    Article  CAS  PubMed  Google Scholar 

  27. Beutler, E., O. Duron, and B.M. Kelly. 1963. Improved method for the determination of blood glutathione. Journal of Laboratory and Clinical Medicine 61: 882–888.

    CAS  Google Scholar 

  28. Gross, R.T., R. Bracci, N. Rudolph, E. Schroeder, and J.A. Kochen. 1967. Hydrogen peroxide toxicity and detoxification in the erythrocytes of newborn infants. Blood 29: 481–493.

    Article  CAS  PubMed  Google Scholar 

  29. Mihara, M., and M. Uchiyama. 1978. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Analytical Biochemistry 86: 271–278.

    Article  CAS  PubMed  Google Scholar 

  30. Lowry, O.H., N.J. Rosenbrough, A.L. Farr, and R.J. Randall. 1951. Protein measurement with Folin phenol reagent. Journal of Biological Chemistry 193: 265–275.

    Article  CAS  Google Scholar 

  31. Reitman, S., and S. Frankel. 1957. A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. American Journal of clinical Pathology 28: 56–63.

    Article  CAS  PubMed  Google Scholar 

  32. Fawcett, J.K., and J.E. Soctt. 1960. A rapid and precise method for the determination of urea. Journal of Clinical Pathology 13: 156–159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bartles, H., M. Bohmer, and C. Heirli. 1972. Serum creatinine determination without protein precipitation. Clinica Chimica Acta 37: 193–197.

    Google Scholar 

  34. Trinder, P. 1969. Determination of Glucose in Blood using Glucose Oxidase with an alternative oxygen acceptor. Annals of Clinical Biochemistry: International Journal of Laboratory Medicine 6: 24–27.

    Article  CAS  Google Scholar 

  35. Omar, H.A., A.M. Sargeant, J.R. Weng, D. Wang, S.K. Kulp, T. Patel, and C.S. Chen. 2009. Targeting of the Akt-nuclear factor-kappa B signaling network by [1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol (OSU-A9), a novel indole-3-carbinol derivative, in a mouse model of hepatocellular carcinoma. Molecular Pharmacology 76: 957–968.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mingone, C.J., S.A. Gupte, S. Quan, N.G. Abraham, and M.S. Wolin. 2003. Influence of heme and heme oxygense-1 transfection of pulmonary microvascular endothelium on oxidant generation and cGMP. Experimental Biology and Medicine (Maywood). 228: 535–539.

    Article  CAS  PubMed  Google Scholar 

  37. Bancroft, J.D., A. Stevans, and D.R. Turner. 1996. In Theory and practice of histological techniques, 4th ed. Edinburgh, London, Melbourne, New York: Churchill Livingstone.

    Google Scholar 

  38. Plaza, G.L., and M. Charbonneau. 1994. Detection and evaluation of chemically induced liver injury. In Principles and methods of toxicology, 3rd ed., ed. A.W. Hayes. New York: Raven press.

  39. Zhang, J., R.P. Brown, M. Shaw, V.S. Vaidya, Y. Zhou, P. Espandiari, N. Sadrieh, M. Stratmeyer, J. Keenan, C.G. Kilty, J.V. Bonventre, and P.L. Goering. 2008. Immunolocalization of Kim-1, RPA-1, and RPA-2 in kidney of gentamicin-, mercury-, or chromium-treated rats: Relationship to renal distributions of iNOS and nitrotyrosine. Toxicologic Pathology 36: 397–409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Acikel, M., M.E. Buyukokuroglu, F. Erdogan, H. Aksoy, E. Bozkurt, and H. Senocak. 2005. Protective effects of dantrolene against myocardial injury induced by isoproterenol in rats: Biochemical and histological findings. International Journal of Cardiology 98: 389–394.

    Article  PubMed  Google Scholar 

  41. Braganza, M.Z., C.M. Kitahara, B.A. de González, P.D. Inskip, K.J. Johnson, and P. Rajaraman. 2012. Ionizing radiation and the risk of brain and central nervous system tumors: A systematic review. Neuro-Oncology 14: 1316–1324.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Hladik, D., and S. Tapio. 2016. Effects of ionizing radiation on the mammalian brain. Mutation Research 770: 219–230.

    Article  CAS  PubMed  Google Scholar 

  43. Fong, C.W. 2014. Statins in therapy: Understanding their hydrophilicity, lipophilicity, binding to 3-hydroxy-3-methylglutaryl-CoA reductase, ability to cross the blood brain barrier and metabolic stability based on electrostatic molecular orbital studies. European Journal of Medicinal Chemistry 85: 661–674.

    Article  CAS  PubMed  Google Scholar 

  44. Gómez-Vallejo, V., A. Ugarte, C. García-Barroso, M. Cuadrado-Tejedor, B. Szczupak, I.G. Dopeso-Reyes, J.L. Lanciego, A. García-Osta, J. Llop, J. Oyarzabal, and R. Franco. 2016. Pharmacokinetic investigation of sildenafil using positron emission tomography and determination of its effect on cerebrospinal fluid cGMP levels. Journal of Neurochemistry 136: 403–415.

    Article  PubMed  Google Scholar 

  45. Widel, M. 2016. Radiation induced bystander effect: From in vitro studies to clinical application. International Journal of Medical Physics, Clinical Engineering and Radiation Oncology 5: 1–17.

    Article  Google Scholar 

  46. Siva, S., M.P. MacManus, R.F. Martin, and O.A. Martin. 2015. Abscopal effects of radiation therapy: A clinical review for the radiobiologist. Cancer Letters 356: 82–90.

    Article  CAS  PubMed  Google Scholar 

  47. Najafi, M., E. Motevaseli, A. Shirazi, G. Geraily, A. Rezaeyan, F. Norouzi, S. Rezapoor, and H. Abdollahi. 2018. Mechanisms of inflammatory responses to radiation and normal tissues toxicity: Clinical implications. International Journal of Radiation Biology 94: 335–356.

    Article  CAS  PubMed  Google Scholar 

  48. Stone, H.B., C.N. Coleman, M.S. Anscher, and W.H. McBride. 2003. Effects of radiation on normal tissue: Consequences and mechanisms. Lancet Oncology 4: 529–536.

    Article  CAS  PubMed  Google Scholar 

  49. Brush, J., S.L. Lipnick, T. Phillips, J. Sitko, J.T. McDonald, and W.H. McBride. 2007. Molecular mechanisms of late normal tissue injury. Seminars in Radiation Oncology 17: 121–130.

    Article  PubMed  Google Scholar 

  50. Verma, V., and S.H. Lin. 2016. Implications of the bystander and abscopal effects of radiation. Therapy Clin Cancer Research 22: 4763–4765.

    Article  CAS  Google Scholar 

  51. Narendran, N., L. Luzhna, and O. Kovalchuk. 2019. Sex difference of radiation response occupational and accidental exposure. Frontiers in Genetics 10: 260–271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhang, J., D. Yao, Y. Song, Y. Pan, L. Zhu, Y. Bai, Y. Xu, J. Zhang, and C. Shao. 2019. Fractionated irradiation of right thorax induces abscopal damage on testes leading to decline in fertility. Scientific Reports 9: 15221.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Leigh, T., R.G. Scalia, and M.V. Autieri. 2020. Resolution of inflammation in immune and nonimmune cells by interleukin-19. American Journal of Physiology Cell Physiology 319: C457–C464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. McKelvey, K.J., A.L. Hudson, M. Back, T. Eade, and C.I. Diakos. 2018. Radiation, inflammation and the immune response in cancer. Mammalian Genome 29: 843–865.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Holley, A.K., L. Miao, D.K. St Clair, and W.H. St Clair. 2014. Redox-modulated phenomena and radiation therapy: The central role of superoxide dismutases. Antioxidant & Redox Signaling 20: 1567–1589.

    Article  CAS  Google Scholar 

  56. Moustafa, E.M., and N.M. Thabet. 2017. Beta-sitosterol upregulated paraoxonase-1 via peroxisome proliferator-activated receptor-γ in irradiated rats. Canadian Journal of Physiology and Pharmacology 95: 661–666.

    Article  CAS  PubMed  Google Scholar 

  57. Galal, S.M., M.K. Abdel-Rafei, and H.F. Hasan. 2018. Cholinergic and cytoprotective signaling cascades mediate the mitigative effect of erythropoietin on acute radiation syndrome. Canadian Journal of Physiology and Pharmacology 96: 442–458.

    Article  CAS  PubMed  Google Scholar 

  58. Sawal, H.A., K. Asghar, M. Bureik, and N. Jalal. 2017. Bystander signaling via oxidative metabolism. Onco Targets Therapeutics 10: 3925–3940.

    Article  Google Scholar 

  59. Xu, H., Q. Shi, Y. Mo, L. Wu, J. Gu, and Y. Xu. 2019. Downregulation of α7 nicotinic acetylcholine receptors in peripheral blood monocytes is associated with enhanced inflammation in preeclampsia. BMC Pregnancy and Childbirth 19: 188.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Subramanian, V., I. Seemann, J. Merl-Pham, S.M. Hauck, F.A. Stewart, M.J. Atkinson, S. Tapio, and O. Azimzadeh. 2017. Role of TGF beta and PPAR alpha signaling pathways in radiation response of locally exposed heart: Integrated global transcriptomics and proteomics analysis. Journal of Proteome Research 16: 307–318.

    Article  CAS  PubMed  Google Scholar 

  61. Cabrero, A., M. Alegret, R.M. Sanchez, T. Adzet, J.C. Laguna, and M.V. Carrera. 2002. Increased reactive oxygen species production down-regulates peroxisome proliferator-activated α pathway in C2C12 skeletal muscle cells. Journal of Biological Chemistry 277: 10100–10107.

    Article  CAS  Google Scholar 

  62. Jekell, A., A. Hossain, U. Alehagen, U. Dahlström, and A. Rosén. 2004. Elevated circulating levels of thioredoxin and stress in chronic heart failure. European Journal of Heart Failure 6: 883–890.

    Article  CAS  PubMed  Google Scholar 

  63. Liu, G.H., J. Qu, and X. Shen. 2006. Thioredoxin-mediated negative autoregulation of peroxisome proliferator-activated receptor alpha transcriptional activity. Molecular Biology of the Cell 17: 1822–1833.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Camps, J., A. García-Heredia, A. Rull, C. Alonso-Villaverde, G. Aragonès, R. Beltrán-Debón, E. Rodríguez-Gallego, and J. Joven. 2012. PPARs in regulation of paraoxonases: control of oxidative stress and inflammation pathways. PPAR Research 2012: 616371.

  65. Moore, R.E., M. Navab, J.S. Millar, F. Zimetti, S. Hama, G.H. Rothblat, and D.J. Rader. 2005. Increased atherosclerosis in mice lacking apolipoprotein A-I attributable to both impaired reverse cholesterol transport and increased inflammation. Circulation Research 97: 763–771.

    Article  CAS  PubMed  Google Scholar 

  66. Yanai, H., and H. Yoshida. 2019. Beneficial effects of adiponectin on glucose and lipid metabolism and atherosclerotic progression: Mechanisms and perspectives. International Journal of Molecular Sciences 20: 1190.

    Article  CAS  PubMed Central  Google Scholar 

  67. Chen, S.J., C.H. Huang, Y.C. Lee, S. Hsia, and P.T. Lin. 2012. Relationships between inflammation, adiponectin, and oxidative stress in metabolic syndrome. PLoS One 7: e45693.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Suman, S., B.V. Kallakury, A.J. Fornace Jr., and K. Datta. 2015. Protracted upregulation of leptin and IGF1 is associated with activation of PI3K/Akt and JAK2 pathway in mouse intestine after ionizing radiation exposure. International Journal of Biological Sciences 11: 274–283.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Suman, S., S. Kumar, A.J. Fornace, and K. Datta. 2016. Space radiation exposure persistently increased leptin and IGF1 in serum and activated leptin-IGF1 signaling axis in mouse intestine. Scientific Reports 6: 31853.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Barale, C., C. Frascaroli, R. Senkeev, F. Cavalot, and I. Russo. 2018. Simvastatin effects on inflammation and platelet activation markers in hypercholesterolemia. BioMed Research International 2018: Article ID 6508709 (11 pages).

  71. Işeri, S., F. Ercan, N. Gedik, M. Yüksel, and I. Alican. 2007. Simvastatin attenuates cisplatin-induced kidney and liver damage in rats. Toxicology 230: 256–264.

    Article  PubMed  Google Scholar 

  72. Mohamadin, A.M., A.A. Elberry, H.S. Abdel Gawad, G.M. Morsy, and F.A. Al-Abbasi. 2011. Protective effects of simvastatin, a lipid lowering agent, against oxidative damage in experimental diabetic rats. Journal of Lipids 2011: 167958.

  73. Tripathi, D.M., M. Vilaseca, E. Lafoz, H. Garcia-Calderó, G. Viegas Haute, A. Fernández-Iglesias, J. Rodrigues de Oliveira, J.C. García-Pagán, J. Bosch, and J. Gracia-Sancho. 2018. Simvastatin prevents progression of acute on chronic liver failure in rats with cirrhosis and portal hypertension. Gastroenterology 155: 1564–1577.

    Article  CAS  PubMed  Google Scholar 

  74. Ashrafi, M., B. Karimi, M. Sabahi, and T. Shomali. 2018. Hepatoprotective effect of simvastatin in mice with DMBA-induced breast cancer: Histopathological, biochemical and antioxidant status evaluation. Biomedical Research and Therapy 5: 2064–2077.

    Article  Google Scholar 

  75. Karimi, B., M. Ashrafi, T. Shomali, and A. Yektaseresht. 2019. Therapeutic effect of simvastatin on DMBA-induced breast cancer in mice. Fundamental & Clinical Pharmacology 33: 84–93.

    Article  CAS  Google Scholar 

  76. Li, J., Y.M. Sun, L.F. Wang, Z.Q. Li, W. Pan, and H.Y. Cao. 2010. Comparison of effects of simvastatin versus atorvastatin on oxidative stress in patients with coronary heart disease. Clinical Cardiology 33: 222–227.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Haendeler, J., J. Hoffmann, A.M. Zeiher, and S. Dimmeler. 2004. Antioxidant effects of statins via S-nitrosylation and activation of thioredoxin in endothelial cells: A novel vasculoprotective function of statins. Circulation 110: 856–861.

    Article  CAS  PubMed  Google Scholar 

  78. Roensch, J., M. Crisby, A. Nordberg, Y. Xiao, L.J. Zhang, and Z.Z. Guan. 2007. Effects of statins on alpha7 nicotinic receptor, cholinesterase and alpha-form of secreted amyloid precursor peptide in SH-SY5Y cells. Neurochemistry International 50: 800–806.

    Article  CAS  PubMed  Google Scholar 

  79. Fujii, T., Y. Takada-Takatori, and K. Kawashima. 2008. Basic and clinical aspects of non-neuronal acetylcholine: Expression of an independent, non-neuronal cholinergic system in lymphocytes and its clinical significance in immunotherapy. Journal of Pharmacological Sciences 106: 186–192.

    Article  CAS  PubMed  Google Scholar 

  80. Jackson, A., D. Bagdas, P.P. Muldoon, A.H. Lichtman, F.I. Carroll, M. Greenwald, M.F. Miles, and M.I. Damaj. 2017. In vivo interactions between α7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-α: Implication for nicotine dependence. Neuropharmacology 118: 38–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Paumelle, R., C. Blanquart, O. Briand, O. Barbier, C. Duhem, G. Woerly, F. Percevault, J.C. Fruchart, D. Dombrowicz, C. Glineur, and B. Staels. 2006. Acute antiinflammatory properties of statins involve peroxisome proliferator-activated receptor-alpha via inhibition of the protein kinase C signaling pathway. Circulation Research 98: 361–369.

    Article  CAS  PubMed  Google Scholar 

  82. Esposito, E., B. Rinaldi, E. Mazzon, M. Donniacuo, D. Impellizzeri, I. Paterniti, A. Capuano, P. Bramanti, and S. Cuzzocrea. 2012. Anti-inflammatory effect of simvastatin in an experimental model of spinal cord trauma: Involvement of PPAR-α. Journal of Neuroinflammation 9: 81–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Katsiki, N., and C.S. Mantzoros. 2016. Statins in relation to adiponectin: A significant association with clinical implications. Atherosclerosis 253: 270–272.

    Article  CAS  PubMed  Google Scholar 

  84. Singh, P., Y. Zhang, P. Sharma, N. Covassin, F. Soucek, P.A. Friedman, and V.K. Somers. 2018. Statins decrease leptin expression in human white adipocytes. Physiological Reports 6: e13566.

    Article  PubMed Central  Google Scholar 

  85. Wortel, R.C., A. Mizrachi, H. Li, E. Markovsky, B. Enyedi, J. Jacobi, O. Brodsky, J. Cao, A.R. Lippert, L. Incrocci, J.P. Mulhall, and A. Haimovitz-Friedman. 2019. Sildenafil protects endothelial cells from radiation-induced oxidative stress. The Journal of Sexual Medicine 16: 1721–1733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Ali, F.E.M., A.A. Azouz, A.G. Bakr, A.M. Abo-Youssef, and R.A.M. Hemeida. 2018. Hepatoprotective effects of diosmin and/or sildenafil against cholestatic liver cirrhosis: The role of Keap-1/Nrf-2 and P38-MAPK/NF-κB/iNOS signaling pathway. Food and Chemical Toxicology 120: 294–304.

    Article  CAS  PubMed  Google Scholar 

  87. Zaobornyj, T., T. Mazo, V. Perez, A. Gomez, M. Contin, V. Tripodi, V. D’Annunzio, and R.J. Gelpi. 2019. Thioredoxin-1 is required for the cardioprotecive effect of sildenafil against ischaemia/reperfusion injury and mitochondrial dysfunction in mice. Free Radical Research 53: 993–1004.

    Article  CAS  PubMed  Google Scholar 

  88. Raposo, C., A.K. Nunes, R.L. Luna, S.M. Araújo, M.A. da Cruz-Höfling, and C.A. Peixoto. 2013. Sildenafil (Viagra) protective effects on neuroinflammation: The role of iNOS/NO system in an inflammatory demyelination model. Mediators of Inflammation 2013: 321460.

  89. Zhao, S., L. Zhang, G. Lian, X. Wang, H. Zhang, X. Yao, J. Yang, and C. Wu. 2011. Sildenafil attenuates LPS-induced pro-inflammatory responses through down-regulation of intracellular ROS-related MAPK/NF-κB signaling pathways in N9 microglia. International Immunopharmacology 11: 468–474.

    Article  CAS  PubMed  Google Scholar 

  90. Nunes, A.K., C. Rapôso, S.W. Rocha, K.P. Barbosa, R.L. Luna, M.A. da Cruz-Höfling, and C.A. Peixoto. 2015. Involvement of AMPK, IKβα- NFκB and eNOS in the sildenafil anti-inflammatory mechanism in a demyelination model. Brain Research 1627: 119–133.

    Article  CAS  PubMed  Google Scholar 

  91. Berthoud, H.-R., and W.L. Neuhuber. 2019. Vagal mechanisms as neuromodulatory targets for the treatment of metabolic disease. Annals of the New York Academy of Sciences 1454: 42–55.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Cano, G., A.F. Sved, L. Rinaman, B.S. Rabin, and J.P. Card. 2001. Characterization of the central nervous system innervation of the rat spleen using viral transneuronal tracing. The Journal of Comparative Neurology 439: 1–18.

    Article  CAS  PubMed  Google Scholar 

  93. Cano, G., J.P. Card, and A.F. Sved. 2004. Dual viral transneuronal tracing of central autonomic circuits involved in the innervation of the two kidneys in rat. The Journal of Comparative Neurology 471: 462–481.

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors acknowledge Professor of Histopathology, Dr. Ahmed Osman in Faculty of Veterinary Medicine-Cairo University for his efforts in the histopathological tissue examination in the current work.

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Engy Refaat Rashed and Mohamed Khairy Abdel-Rafei conceived the idea. Engy Refaat Rashed and Noura Magdy Thabet performed the experiments and analysed data. Mohamed Khairy Abdel-Rafei, Noura Magdy Thabet, and Engy Refaat Rashed wrote and edited the manuscript. All authors approved the final manuscript.

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Correspondence to Mohamed Khairy Abdel-Rafei.

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Animal experiments were conducted in accordance the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health (NIH no. 85:23, revised 1996), in compliance to the regulations of Ethical Committee of NCRRT, Egyptian Atomic Energy Authority, Cairo, Egypt (Approval NO: 29A/20).

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Rashed, E.R., Abdel-Rafei, M.K. & Thabet, N.M. Roles of Simvastatin and Sildenafil in Modulation of Cranial Irradiation-Induced Bystander Multiple Organs Injury in Rats. Inflammation 44, 2554–2579 (2021). https://doi.org/10.1007/s10753-021-01524-w

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  • DOI: https://doi.org/10.1007/s10753-021-01524-w

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