Sildenafilin Depresyon Benzeri Etkisinin Farelerde Zorunlu Yüzdürme Testi İle Değerlendirilmesi

Abstract

The Depressant-Like Effect of Sildenafil in The Forced Swimming Test in Mice Phosphodiesterease type 5 (PDE5), nitric oxide synthase (NOS) and guanilate cyclase have shown high activity in areas responsible to behaviours in brain. It is alleged that PDE5 inhibitor sildenafil which is used in erectile disfunction passes blood brain barrier and can cause adverse effects related to behaviours. The aim of this study, to investigate the effect of sildenanil in depression by forced swimming test in mice. We administered sildenafil (1, 5, 10, 15, 20, 30 mg/kg), sertraline (20 mg/kg) and imipramine (30 mg/kg) with intraperitoneal (ip) injection. All drugs were injected 15 min. before testing. Sertraline and imipramine given alone and in combination with sildenafil. When combination with sildenafil and other drugs were employed, other drugs were administered 10 min. before sildenafil. The activity of each mice was recorded for 5 min. in an activity cage (Ugo Basile, 7430-Varese, Italy). Then immobility was measured during the last 4 min. of the 6 min. swim test. Increase immobility time in a swim test has been found to represent "depression-like" behaviour. Sildenafil at a dose of 10mg/kg increased the immobility time without affecting locomotor activity (p<0.05). İmipramine and sertraline significantly decreased the immobility time (p<0.05). The depressant-like effect of sildenafil (10 mg/kg) was prevented by pretreatment with both sertraline and imipramine (p<0.05). These findings suggest that, sildenafil has a depressant-like effect on the forced swimming test and NO-cGMP pathway may play a role in depression. Fosfodiesteraz tip 5 (PDE5), nitrik oksit sentaz (NOS) ve guanilat siklazın beyinde davranışlardan sorumlu alanlarda yüksek aktivite gösterdiği bildirilmektedir. Erektil disfonksiyon tedavisinde kullanılan PDE5 inhibitörü sildenafilin kan beyin bariyerini geçtiği ve davranışla ilgili bazı yan etkilere neden olabileceği ileri sürülmektedir. Bu çalışmanın amacı, sildenafilin depresyon üzerine etkisini farelerde, zorunlu yüzdürme testi ile araştırmaktır. Sildenafil (1, 5, 10, 15, 20, 30 mg/kg), sertralin (20 mg/kg) ve imipramin (30 mg/kg) intraperitoneal (ip) olarak verildi. Tüm ilaçlar testlerden 15 dakika önce uygulandı. Sertralin ve imipramin hem tek başlarına hem de sildenafil ile kombine edilerek kullanıldı. Kombinasyon uygulamalarında diğer ilaçlar sildenafilden 10 dakika önce verildi. Lokomotor aktivite ölçüm cihazında (Ugo Basile,7430-Varese, İtalya) her bir farenin lokomotor aktivitesi kaydedildi. Ardından, 6 dakikalık yüzme testinin son 4 dakikasında immobilite süreleri ölçüldü. İmmobi-lite süresinin uzaması depresyon benzeri etki olarak değerlendirildi. Sildenafil yalnızca 10 mg/kg dozda lokomotor aktiviteyi değiştirmeden immobilite süresini artırdı (p<0.05). İmipramin ve sertralin immobilite süresini anlamlı olarak azalttı (p<0.05). Sildenafilin (10 mg/kg) depresan benzeri etkisi sertralin ve imipramin ile kombine edildiğinde önlendi (p<0.05). Bu bulgular, sildenafilin zorunlu yüzdürme testinde depresan benzeri etkisinin olduğunu ve NO-cGMP yolağının depresyonda önemli rolünün olabileceğini düşündürmektedir.

Keywords

• -

References

1. Manganiello V.Cyclic nucleotide phosphodiesterase 5 and sildenafil: promises realized. Mol Pharmacol. 2003; 63: 1209–1211.
2. Kukreja RC, Salloum F, Das A, et al. Pharmacological preconditioning with sildenafil: Basic mechanisms and clinical implications. Vascul Pharmacol. 2005; 42: 219–232.
3. Hotchkiss AK, Pyter LM, Gatien ML, et al. Aggressive behavior increases after termination of chronic silde- nafil treatment in mice. Physiol Behav. 2005; 83: 683–688.
4. Canteros G, Rettori V, Genaro A, et al. Nitric oxide synthase content of hypothalamic explants: increase by norepinephrine and inactivated by NO and cGMP. Proc Natl Acad Sci. 1996; 93: 4246–4250.
5. Yanık M, Vural H, Tutkun H, ve ark. The role of the arginine-nitric oxide pathway in the pathogenesis of bipolar affective disorder. Eur Arch Psychiatry Clin Neurosci. 2004; 254: 43–47.
6. Moncada S, Palmer RM, Higgs EA. Nitric oxide: phys- iology,
7. Pharmacol Rev. 1991; 43: 109–142. and
8. pharmacology. 7. Yıldız F, Erden BF, Ulak G, ve ark. Antidepressant- like effect of 7-nitroindazole in the forced swimming test in rats. Psychopharmacology. 2000; 149: 41–44. 8. Eroğlu L, Cağlayan B. Anxiolytic and antidepressant properties of methylene blue in animal models. Pharmacol Res. 1997; 36: 381–385.

9. Heiberg IL, Wegener G, Rosenberg R. Reduction of cGMP and nitric oxide has antidepressant-like effects in the forced swimming test in rats. Behav Brain Res. 2002; 134: 479–484.
10. Suzuki E, Yagi G, Nakaki T, et al. Elevated plasma nitrate levels in depressive states. J Affect Disord. 2001; 63: 221–224.
11. Chrapko WE, Jurasz P, Radomski MW, et al. Decreased platelet nitric oxide synthase activity and plasma nitric oxide metabolites in major depressive disorder. Biol Psychiatry. 2004; 56: 129–134.
12. Bernstein HG, Stanarius A, Baumann B, et al. Nitric oxide synthase-containing neurons in the human hypothalamus: reduced number of immunoreactive cells in the paraventricular nucleus of depressive patients and schizophrenics. Neuroscience. 1998; 83: 867–875.
13. Karolewicz B, Szebeni K, Stockmeier CA, et al. Low nNOS protein in the locus coeruleus in major depres- sion. J Neurochem. 2004; 91: 1057–1066.
14. Porsolt RD, Le Pichon M., Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature. 1977; 266: 730–32.
15. Bourin M, Mocaer E, Porsolt R. Antidepressant-like activity of S 20098 (agomelatine) in the forced swim- ming test in rodents: involvement of melatonin and serotonin receptors. J Psychiatry Neurosci. 2004; 29: 126–133.
16. Schultheiss D, Muller SV, Nager W, et al. Central effects of sildenafil (Viagra) on auditory selective attention and verbal recognition memory in humans: a study with event-related brain potentials. World J Urol. 2001; 19: 46–50.
17. Zhang R, Wang Y, Zhang L, et al. Sildenafil (Viagra) induces neurogenesis and promotes functional recov- ery after stroke in rats. Stroke. 2002; 33: 2675–2680. 18. Rutten K, Vente JD, Sik A, et al. The selective PDE5 inhibitor, sildenafil, improves object memory in Swiss mice and increases cGMP levels in hippocampal slices. Behav Brain Res. 2005; 164: 11–16.
18. Heiberg IL, Wegener G, Rosenberg R. Reduction of cGMP and nitric oxide has antidepressant-like effects in the forced swimming test in rats. Behav Brain Res. 2002; 134: 479–484.
19. Garthwaite J, Boulton CL. Nitric oxide signaling in the central nervous system. Annu Rev Physiol. 1995; 57: 683–706.
20. Molina JA, Jimenez-Jimenez FJ, Orti-Pareja M, et al. The role of nitric oxide in neurodegeneration. Potential for pharmacological intervention. Drugs Aging. 1998; 12: 251–259.
21. Simpson KL, Waterhouse BD, Lin RC. Differential expression of nitric oxide in serotonergic projection neurons: neurochemical identification of dorsal raphe inputs to rodent trigeminal somatosensory targets. J Comp Neurol. 2003 ;466: 495–512.
22. Ramos AJ, Tagliaferro P, Lopez-Costa JJ, et al. Neuronal and inducible nitric oxide synthase immunoreactivity following serotonin depletion. Brain Res. 2002; 958: 112–121.
23. Prasad HC, Zhu CB, McCauley JL, et al. Human sero- tonin transporter variants display altered sensitivity to protein kinase G and p38 mitogen-activated protein kinase. Proc Natl Acad Sci. 2005; 102: 11545–11550. 25. Zhu CB, Hewlett WA, Francis SH, et al. Stimulation of serotonin transport by the cyclic GMP phosphodi- esterase-5 inhibitor sildenafil. Eur J Pharmacol. 2004; 504: 1–6.
24. Kiss JP. Role of nitric oxide in the regulation of monoaminergic neurotransmission. Brain Res Bull. 2000; 52: 459–466.
25. Kaehler ST, Singewald N, Sinner C, et al. Nitric oxide modulates the release of serotonin in the rat hypo- thalamus. Brain Res. 1999; 835: 346–349.
26. Wegener G, Volke V, Rosenberg R. Endogenous nitric oxide decreases hippocampal levels of serotonin and dopamine in vivo. Br J Pharmacol. 2000; 130: 575–580.
27. Harkin A, Connor TJ, Burns MP, et al. Nitric oxide synthase inhibitors augment the effects of serotonin re-uptake inhibitors in the forced swimming test. Eur Neuropsychopharmacol. 2004; 14: 274–281.
28. Joca SR, Guimaraes FS. Inhibition of neuronal nitric oxide synthase in the rat hippocampus induces anti- depressant-like effects. Psychopharmacology. 2006; 185: 298–305.
29. Wegener G, Volke V, Harvey BH, et al. Local, but not systemic, administration of serotonergic antidepres- sants decreases hippocampal nitric oxide synthase activity. Brain Res. 2003; 959: 128–134.