Sildenafil alters biogenic amines and increases oxidative damage in brain regions of insulin-hypoglycemic rats


The aim of the present study was to determine the effect of sildenafil on dopamine, 5-hydroxyindol acetic acid (5-HIAA) and selected biomarkers of oxidative stress in the brain of hypoglycemic rats. The animals were treated intraperitoneally as follows: group 1 (control), saline solution; group 2, insulin (10 U per rat or 50 U kg−1); group 3, insulin + single dose of sildenafil (50 U kg−1 + 50 mg kg–1); group 4, insulin + three doses of sildenafil every 24 hours (50 U kg−1 + 50 mg kg−1). In groups 2, 3 and 4, insulin was administered every 24 hours for 10 days. Blood glucose was measured after the last treatment. On the last day of the treatment, the animals´ brains were extracted to measure the levels of oxidative stress markers [H2O2, Ca2+,Mg2+-ATPase, glutathione and lipid peroxidation (TBARS)], dopamine and 5-HIAA in the cortex, striatum and cerebellum/medulla oblongata by validated methods. The results suggest that administration of insulin in combination with sildenafil induces hypoglycemia and hypotension, enhances oxidative damage and provokes changes in the brain metabolism of biogenic amines. Administration of insulin and sildenafil promotes biometabolic responses in glucose control, namely, it induces hypoglycemia and hypotension. It also enhances oxidative damage and provokes changes in the brain metabolism of biogenic amines.

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  • 1. A. V. Raveendran, E. C. Chacko and J. M. Pappachan, Non-pharmacological treatment options in the management of diabetes mellitus, Eur. Endocrinol.14 (2018) 31–39;

  • 2. A. Hussain, O. B. Latiwesh, F. Ali, M. Y. G. Younis and J. A. Alammari, Effects of body mass index, glycemic control, and hypoglycemic drugs on serum uric acid levels in type 2 diabetic patients, Cureus10 (2018) e3158;

  • 3. G. T. Chen, B. B. Yang, J. H. Chen, Z. Zhang, L. L. Zhu, H. S. Jiang, W. Yu, Y. Chen and Y. T. Dai, Pancreatic kininogenase improves erectile function in streptozotocin-induced type 2 diabetic rats with erectile dysfunction, Asian J. Androl.20 (2018) 448–453;

  • 4. L. Chen, S. E. Staubli, M. P. Schneider, A. G. Kessels, S. Ivic, L. M. Bachmann and T. M. Kessler, Phosphodiesterase 5 inhibitors for the treatment of erectile dysfunction: a trade-off network meta-analysis, Eur. Urol.68 (2015) 674–680;

  • 5. R. S. Calabrò, G. Polimeni and P. Bramanti, Current and future therapies of erectile dysfunction in neurological disorders, Rec. Pat. CNS Drug Discov.6 (2011) 48–64.

  • 6. S. J. Flora, Role of free radicals and antioxidants in health and disease, Cell. Mol. Biol.53 (2007) 1–2.

  • 7. J. T. Coyle and P. Puttfarcken, Oxidative stress, glutamate, and neurodegenerative disorders, Science262 (1993) 689–695.

  • 8. M. C. Vogt and J. C. Brüning, CNS insulin signaling in the control of energy homeostasis and glucose metabolism – from embryo to old age, Trends Endocrinol. Metab. 24 (2013) 76–84;

  • 9. G. D. Calderon, N. Osnaya Brizuela, M. Ortiz Herrera, O. H. Juarez, A. Valenzuela Peraza and G. Barragan Mejía, Effect of an antiviral and vitamins A, C, D on dopamine and some oxidative stress markers in rat brain exposed to ozone, Arch. Biol. Sci. Belgrade65 (2013) 1371–1379;

  • 10. D. Calderón Guzmán, N. Osnaya Brizuela, M. Ortíz Herrera, E. Hernandez Garcia, G. Barragan Mejía, H. Juarez Olguín, A. Valenzuela Peraza, J. Attilus and N. Labra Ruiz, Effect of cerebrolysin on dopaminergic neurodegeneration of rat with oxidative stress induced by 3-nitropropionic acid, Acta Pharm. 66 (2016) 443–448;

  • 11. F. Bilotta and G. Rosa, Optimal glycemic control in neurocritical care patients, Crit. Care16 (2012) 163–165;

  • 12. S. Ammon-Treiber, D. Stolze, H. Schroder, H. Loh and V. Hollt, Effects of opioid antagonists and morphine in a hippocampal hypoxia/hypoglycemia model, Neuropharmacology49 (2005) 1160–1169;

  • 13. J. H. Jhamandas, K. H. Harris, T. Petrov and K. H. Jhamandas, Activation of nitric oxide-synthesizing neurons during precipitated morphine withdrawal, Neuroreport7 (1996) 2843–2846.

  • 14. G. D. Calderón, G. E. Hernández, M. G. Barragán, O. H. Juárez, G. J. Saldivar and R. N. Labra, Effect of morphine and lacosamide on levels of dopamine and 5-HIAA in brain regions of rats with induced hypoglycemia, Pak. J. Biol. Sci. 17 (2014) 292–296.

  • 15. S. P. Filippov, ATPase activity of rat brain microsomal and synaptosomal fractions in insulin hypoglycemia and its treatment with glucose, Probl. Endokrinol. (Moskow) 37 (1991) 52–54;

  • 16. E. Mandosi, E. Giannetta, T. Filardi, M. Lococo, C. Bertolini, M. FAllarino, D. Gianfrilli, M. A. Venneri, L. Lenti, S. Morano and A. Lenzi, Endothelial dysfuntion markers as a therapeutic target for sildenafil treatment and effects on metabolic control in type 2 diabetes, Expert Opin. Ther. Target. 19 (2015) 1617–1622;

  • 17. C. E. Ramirez, H. Nian, Y. Chang, L. J. Gamboa, J. M. Luther, N. J. Brown and C. A. Shibao, Treatment with sildenafil improves insulin sensitivity in prediabetes: a randomized, controlled trial, JCEM100 (2015) 4533–4540;

  • 18. F. G. Al-Amran, A. A. Zwain, N. R. Hadi and A. M. Al-Mudhaffer, Autonomic cerebral vascular response to sildenafil in diabetic patient, Diabetol. Metab. Syndr.4 (2012) 2–8;


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