Effects of sildenafil on isoniazid and streptomycin neurotoxicity in rats

Öz

Objectives: Neurotoxicity due to isoniazide (INH) and streptomycin has been reported. Experimental studies reported that sildenafil can reduce toxic effects of some drugs. The aim of this study was to investigate the pos­sible toxic effects of long-term streptomycin and INH use and probable protective effects of sildenafil on the rat brain and cerebellum. Materials and methods: In this study, 78 rats were di­vided into eight groups as follows; control group (n=10), INH group (n=10), streptomycin group (n=10), INH + streptomycin group (n=10), sildenafil group (n=10), INH+sildenafil group (n=10), streptomycin+sildenafil group (n=8) and INH+streptomycin + sildenafil group (n=10). At the end of 30 days of the treatment, the brain and cerebellar tissues of the rats were examined histo­pathologically. On the all tissues, inflammation, edema, congestion, degeneration and necrosis were investigated under a light microscope by the same pathologist blinded to the experimental groups. Results: Degeneration was significantly more prominent in the streptomycin group compared with the control group (respectively, p=0.002, p

Anahtar Kelimeler

• Isoniazid, streptomycin, sildenafil, neurotox­icity, histopathology

Sıçanlarda izoniazid ve streptomisin nörotoksisitesine sildenafil\'in etkileri

Öz

Amaç: İzoniazid (İNH) ve streptomisin (STR) kombinas­yonuna bağlı nörotoksisite bildirilmiştir. Sildenafil\'in (SLD) deneysel olarak bazı ilaç toksisitelerini azaltabildiği öne sürülmüştür. Çalışmada amacımız; uzun süreli İNH ve STR verilen sıçanların beyninde ve serebellumunda tok­sik etki olup olmadığı ve olası bu toksisite üzerine SLD\'nin etkisini araştırmaktır. Gereç ve yöntem: Bu çalışmada 78 sıçan; kontrol grubu (n= 10), İNH grubu (n= 10), STR grubu (n= 10), İNH + STR - (n= 10), SLD (n= 10), İNH + SLD (n= 10), STR + SLD (n= 8), İNH + STR + SLD (n= 10) grupları ola­rak sekiz gruba ayrıldı. İlaçlar 30 gün boyunca uygulan­dı. Sıçanların beyin ve serebellumu histopatolojik olarak incelendi. Beyin ve serebellum dokusunda; inflamasyon, ödem, konjesyon, dejenerasyon ve nekroz bulguları araş­tırıldı. Histopatolojik değerlendirme çalışma gruplarından habersiz tek bir patolog tarafından değerlendirildi. Bulgular: STR grubu sıçan beyninde ve serebellumunda kontrol grubuna göre istatistiksel olarak anlamlı yüksek dejenerasyon bulundu (sırayla, p=0.002, p

Anahtar Kelimeler

• İzoniazid, streptomisin, sildenafil, nö­rotoksisite, histopatoloji

Kaynakça

1. Lysov AV, Mordyk AV, Zatvornitskiĭ VA, Kondria AV. Ad- verse neurotoxic reactions of chemotherapy for tuber- culosis and their treatment. Probl Tuberk Bolezn Legk 2006;9(1):45-8.
2. Holdiness MR. Neurological manifestations and toxici- ties of the antituberculosis drugs. A review. Med Toxicol 1987;2(1):33-51.
3. Ramos A, Portero JL, Murillas J, Losada I, Martin H. Iso- niazid-induced toxic encephalopathy. Rev Neurol 1998; 26(2): 160-4.
4. Martinjak-Dvorsek I, Gorjup V, Horvat M, Noc M. Acute isoniazid neurotoxicity during preventive therapy. Crit Care Med 2000; 28(6): 567–8.
5. Kass JS, Shandera WX. Nervous system effects of antituber- culosis therapy. CNS Drugs 2010; 24(7): 655-67.
6. Brighi W. A case of encephalopathy caused by streptomycin. Clin Pediatr (Bologna) 1957; 39(3): 384-9.
7. Salom JB, Castelló-Ruiz M, Burguete MC, et al. Role of K+ and Ca2+ fluxes in the cerebroarterial vasoactive effects of sildenafil. Eur J Pharmacol 2008; 581(1-2): 138-47.
8. Yildirim A, Ersoy Y, Ercan F, et al. Phosphodiesterase-5 in- hibition by sildenafil citrate in a rat model of bleomycin- induced lung fibrosis. Pulm Pharmacol Ther 2010; 23 (3): 215-21.

9. Uçar E, Kiliç A, Ceyhan I, et al. Resistance rates to major an- ti-tuberculosis drugs in Mycobacterium tuberculosis strains isolated from seven different regions of Turkey in 2003- 2006 period. Mikrobiyol Bul 2010; 44 (1): 11-9.
10. Pappas G, Akritidis N, Christou L. Treatment of neurobru- cellosis: what is known and what remains to be answered. Expert Rev Anti Infect Ther 2007; 5 (6): 983-90.
11. Romero J, Kuczler F. Isoniazid overdose: recognition and management. Am Fam Physician 1998; 57(4):749–52.
12. Köse A, Zenginol M, Köse B, Günay N, Yıldırım C. Menin- goensafaliti taklit eden akut izoniazid zehirlenmesi: Olgu sunumu ve literatürün gözden geçirilmesi. Akademik Acil Tıp Dergisi doi: 10.4170/JAEM.2009.17363.
13. Kuruş M, Eşrefoğlu M, Otlu A. Siklosporine bağlı akciğer hasarında melatoninin histopatolojik etkileri üzerine deney- sel çalışma. Toraks Dergisi 2008; 9 (1): 1-6.
14. Tuç A, Tuğlu İ, Yavaşoğlu A, Varol T. Sıçanlarda kimyasal simpatektominin nörotoksik etkisi. Ege Tıp Dergisi 2006; 45(1): 25-30.
15. Rice DC, Barone S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animalmodels. Environ Health Perspect 2000; 108(Suppl 3): 511-33.
16. Kiliçkesmez K, Küçükoğlu MS. Phosphodiesterase type 5 inhibitors in the treatment of pulmonary arterial hyperten- sion. Anadolu Kardiyol Derg 2010;10 Suppl 2:16-8.
17. Zhang RL, Zhang Z, Zhang L, Wang Y, Zhang C, Chopp M. Delayed treatment with sildenafil enhances neurogenesis and improves functional recovery in aged rats after focal cerebral ischemia. J Neurosci Res 2006; 83(7); 1213–9.
18. Romanini CV, Schiavon AP, Ferreira ED, de Oliveira RM, Milani H. Sildenafil prevents mortality and reduces hip- pocampal damage after permanent, stepwise, 4-vessel oc- clusion in rats. Brain Res Bull 2010; 81(6): 631-40.
19. Inoha S, Inamura T, Ikezaki K, Nakamizo A, Amano T, Fu- kui M. Type V phosphodiesterase expression in cerebral ar- teries with vasospasm after subarachnoid hemorrhage in a canine model. Neurol Res 2002; 24(6): 607–12.
20. Ding G, Jiang Q, Li L, et al. Magnetic resonance imag- ing investigation of axonal remodeling and angiogenesis after embolic stroke in sildenafil-treated rats. J Cereb Blood Flow Metab 2008;28(8): 1440-8.
21. Lorberboym M, Mena I, Wainstein J, Boaz M, Lampl Y. The effect of sildenafil citrate (Viagra) on cerebral blood flow in patients with cerebrovascular risk factors. Acta Neurol Scand 2010;121(6):370-6.