Effects of Tacrolimus on Endothelin-1, Melatonin and Heat Shock Protein Levels in Experimental Brain Ischemia

Yıl 2019, Cilt: 14 Sayı: 2, 75 - 79, 15.07.2019

Özlem Güler , Mustafa Yıldız Mehmet Nuri Bozdemir , Ahmet Kavaklı Adile Ferda Dağlı Bilal Üstündağ

https://doi.org/10.17517/ksutfd.533419

Öz

Objective: We aimed to
investigate the effects of tacrolimus on plasma endothelin-1, melatonin and
brain Hsp-70 levels in experimental ischemic stroke in this study.

Material and Methods:
Twenty-one male Wistar-Albino rats randomly divided into three groups which
included seven rats. Animals in group 2 and group 3 were anesthetized and
bilateral common carotid arteries were clamped with aneurysm clips for 10
minutes. Animals in group 1 were not clamped and were not given any treatment.
Rats in group 2 were received 1 ml saline and in group 3 were received 1 mg/kg
tacrolimus intraperitoneally. Injections were applied 1st hour before ischemia
and at 6th, 24th, 48th and 72nd hours post ischemia. All the animals were
decapitated on the 4th day and plasmas were obtained and brains were excised.
Plasma endothelin-1 and melatonin levels were measured. Brain Hsp-70
immunostaining and neuron cell death were scored semiquantitatively.

Results: The plasma
endothelin-1 levels in group 3 were higher than group 2 and group 1, but were
similar in group 1 and group 2.  In group
1 plasma melatonin levels were lesser than group 2 and group 3. In group 2
plasma melatonin levels were higher than group 3. The mean neuron death in
group 3 was lesser than in group 2. The mean Hsp-70 immunostaining intensity in
group 2 was greater than group 3 and group 1. In group 1 the mean Hsp-70
immünostaining intensity was lesser than group 3.

Conclusions: Tacrolimus administration
in ischemic stroke reduces plasma melatonin and brain Hsp-70 levels and increases
plasma endothelin-1 levels and has neuroprotective effect.

Anahtar Kelimeler

Endothelin-1, Heat Shock Protein-70, ischemic stroke, melatonin, tacrolimus

Deneysel Beyin İskemisinde Tacrolimusun Endotelin-1, Melatonin ve Heat Shock Protein-70 Üzerine Etkileri

Öz

Amaç: Bu çalışmada deneysel
iskemik inmede tacrolimusun plazma endotelin-1, melatonin ve beyin Hsp-70
seviyeleri üzerine etkilerini araştırmayı amaçladık.

Gereç ve Yöntem: Yirmi bir
erkek Wistar-Albino rat her birinde yedi rat olan 3 grupa rasgele ayrıldı. Grup
2 ve grup 3'deki hayvanların ana karotis arterleri anestezi altında 10 dakika
süresince anevrizma klempleri ile bağlandı. Grup 1'deki hayvanlar bağlanmadı ve
herhangi bir tedavi almadı. Grup 2'deki ratlara 1 ml salin ve grup 3'dekilere 1
mg/kg tacrolimus intraperitonal olarak verildi. Enjeksiyonlar iskemiden 1 saat
önce ve iskemiden 6,24 ve 48 ve 72 saat sonra uygulandı. Tüm hayvanların 4.
günde kafaları kesildi, plazmaları ve beyinleri alındı. Plazma endotelin-1 ve
melatonin seviyeleri ölçüldü. Beyin Hsp-70 immünboyanması ve nöron hücre ölümü
yarı nicel olarak ölçüldü.

Bulgular: Plazma
endotelin-1 seviyeleri grup 3'de grup 2'den daha yüksekti, ancak grup 1 ve grup
2'de benzerdi. Grup 1 deki plazma melatonin seviyeleri grup 2 ve grup 3'den
daha düşüktü. Grup 2'deki melatonin seviyeleri grup 3'den daha yüksekti. Grup
3'deki hücre ölümü grup 2'den daha düşüktü. Grup 2'deki ortalama Hsp-70 immün
boyanma yoğunluğu grup 3 ve grup 1'den daha fazlaydı. Grup 1'deki ortalama
Hsp-70 immün boyanma yoğunluğu grup 3'den daha düşüktü.

Sonuç: İskemik inmede tacrolimus uygulanması
plazma melatonin ve beyin Hsp-70 seviyelerini azaltır, plazma endotelin-1
seviyelerini arttırır ve nöroprotektif etki gösterir.

Anahtar Kelimeler

ischemic stroke, melatonin, tacrolimus, Endothelin-1, Heat Shock Protein-70, tacrolimus

Kaynakça

• 1. Ginsberg MD. Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology 2008; 55: 363-89.
• 2. Shuaib A, Hussain MS. The past and future of neuroprotection in cerebral ischaemic stroke. Eur Neurol 2008; 59: 4-14.
• 3. Patury S, Miyata Y, Gestwicki JE. Pharmacological targeting of the Hsp70 chaperone. Curr Top Med Chem 2009; 9: 1337-51.
• 4. Abraham D, Dashwood M. Endothelin--role in vascular disease. Rheumatology (Oxford) 2008; 47: v23-24.
• 5. Esposito E, Cuzzocrea S. Antiinflammatory activity of melatonin in central nervous system. Curr Neuropharmacol 2010; 8: 228-42.
• 6. Reiter RJ. Oxidative damage in the central nervous system: protection by melatonin. Prog Neurobiol 1998; 56: 359-84.
• 7. Almawi WY, Melemedjian OK. Clinical and mechanistic differences between FK506 (tacrolimus) and cyclosporin A. Nephrol Dial Transplant 2000; 15: 1916-18.
• 8. Sharkey J, Crawford JH, Butcher SP, Marston HM. Tacrolimus (FK506) ameliorates skilled motor deficits produced by middle cerebral artery occlusion in rats. Stroke 1996;27:2282-6.
• 9. Zawadzka M, Kaminska B. A novel mechanism of FK506-mediated neuroprotection: downregulation of cytokine expression in glial cells. Glia 2005; 49: 36-51.
• 10. Cho S, Liu D, Gonzales C, Zaleska MM, Wood A. Temporal assessment of caspase activation in experimental models of focal and global ischemia. Brain Res 2003; 982: 146-55.
• 11. Sun XC, Xian XH, Li WB, Li L, Yan CZ, Li QJ, et al. Activation of p38 MAPK participates in brain ischemic tolerance induced by limb ischemic preconditioning by up-regulating HSP 70. Exp Neurol 2010; 224: 347-55.
• 12. Zararsiz I, Kus I, Ogeturk M, Akpolat N, Kose E, Meydan S, et al. Melatonin prevents formaldehyde-induced neurotoxicity in prefrontal cortex of rats: an immunohistochemical and biochemical study. Cell Biochem Funct 2007; 25: 413-18.
• 13. Aghdasi B, Ye K, Resnick A, Huang A, Ha HC, Guo X, et al. FKBP12, the 12-kDa FK506-binding protein, is a physiologic regulator of the cell cycle. Proc Natl Acad Sci USA 2001; 98: 2425-30.
• 14.Giffard RG, Yenari MA. Many mechanisms for hsp70 protection from cerebral ischemia. J Neurosurg Anesthesiol 2004;16: 53-61.
• 15. Yenari MA, Liu J, Zheng Z, Vexler ZS, Lee JE, Giffard RG. Antiapoptotic and anti-inflammatory mechanisms of heat-shock protein protection. Ann N Y Acad Sci 2005;1053:74-83.
• 16. Guzmán-Lenis MS, Vallejo C, Navarro X, Casas C. Analysis of FK506-mediated protection in an organotypic model of spinal cord damage: heat shock protein 70 levels are modulated in microglial cells. Neuroscience 2008;155:104-13.
• 17. McCarron RM, Chen Y, Tomori T, Strasser A, Mechoulam R, Shohami E, et al. Endothelial-mediated regulation of cerebral microcirculation. J Physiol Pharmacol 2006; 57: 133-44.
• 18. Franceschini R, Gandolfo C, Cataldi A, Del Sette M, Rolandi A, Corsini G, et al. Twenty-four-hour endothelin-1 secretory pattern in stroke patients. Biomed Pharmacother 2001; 55: 272-6.
• 19. Brondani R, Rieder CR, Valente D, Araújo LF, Clausell N. Levels of vascular cell adhesion molecule-1 and endothelin-1 in ischemic stroke: a longitudinal prospective study. Clin Biochem 2007;40:282-4.
• 20. Alioglu Z, Orem A, Bülbül I, Boz C, Ozmenoğlu M, Vanizor B. Evaluation of plasma endothelin-1 levels in patients with cerebral infarction. Angiology 2002;53:77-82.
• 21. Trapp A, Weis M. The impact of immunosuppression on endothelial function. J Cardiovasc Pharmacol 2005;45:81-7.
• 22. Narayanan U, Weiss HR, Liu X, Chi OZ. Exogenous endothelin-1 improves microvascular oxygen balance during focal cerebral ischemia in the rat. Regul Pept 2002;105:1-7.
• 23. Dashwood MR, Loesch A. Endothelin-1 as a neuropeptide: neurotransmitter or neurovascular effects? J Cell Commun Signal 2010;4:51-62.
• 24. Lin HW, Lee EJ. Effects of melatonin in experimental stroke models in acute, sub-acute, and chronic stages. Neuropsychiatr Dis Treat 2009; 5:1571-62.
• 25. Beloosesky Y, Grinblat J, Laudon M, Grosman B, Streifler JY, Zisapel N. Melatonin rhythms in stroke patients. Neurosci Lett 2002; 319:103-6.