Yetişkin Sıçanlarda Testis Hücreleri ve Kalsinörin Immunopozitifliği Üzerine Ketaminin Etkileri: Bir Immunohistokimyasal ve Histopatolojik Çalışma

Year 2012, Volume: 7 Issue: 1, 7 - 17, 25.04.2012

Yıldıray Kalkan , Levent Tümkaya Habib Bostan Yakup Tomak Durdu Altuner Orhan Baş Orhan Ünal Zorba Hakkı Uzun

Abstract

Bu çalışmada, sıçanlara uygulanan uzun süreli ketaminin testis germ hücreleri ve kalsinörin immunopozitif hücreler
üzerine etkilerinin araştırılması amaçlandı. Otuz adet, yetişkin Sprague-Dawley erkek sıçan her grupta 6’şar adet olacak
şekilde 5 gruba ayrıldı. On dört gün süreyle ve günde iki defa olmak üzere, grup 1, 2, 3 ve 4’e sırasıyla 40, 60, 80 ve 100
mg/kg ketamin hidroklorid ve grup 5’e ise sadece % 0,9 NaCl intraperitonal (i.p.) olarak uygulandı. Bu çalışmada, ketamin
uygulanan gruplarda testis bağ dokusunda ödem ve germ hücrelerinde dejenerasyonlar gözlendi. Grup 3 ve 4’te, tubulus
seminiferus lumenlerinde sperm miktarındaki azalmanın grup 1 ve 2’ye göre daha fazla olduğu belirlendi. Uzun süreli ve
yüksek doz ketamin kullanımının bir sonucu olarak, spermatogenetik germ hücreleri ve Leydig hücreleri miktarında da
azalma olduğu tespit edildi. Ayrıca, immunhistokimyasal yöntemler ile boyanmış testis dokusu kesitlerinde, kalsinörin’in
değişik derecelerde, (+)’dan (+++)’a kadar, immunoreaktivite verdiği gözlendi. Sonuç olarak, uzun süreli ve yüksek doz
ketamin kullanımının testis intersitisyel dokularında, sperm yoğunluğunda ve germ hücre miktarlarında histopatolojik ve
immunohistokimyasal değişiklikler yapabileceği belirlenmiş oldu. Ayrıca, uzun süreli ketamin infüzyonunun erkek
infertilitesine neden olabileceği de düşünülmektedir.

Keywords

İmmunohistokimya, Kalsinörin, Ketamin, Sıçan, Testis

References

• Arras M., Autenried P., Rettich A., Spaeni D., Rülicke T., 2001. Optimization of intraperitoneal injection anes- thesia in mice: drugs, dosages, adverse effects, and anesthesia depth. Comp. Med., 51, 443-56.
• Bannai H., Levi S., Schweizer C., Inoue T., Launey T., Racine V., Sibarita JB, Mikoshiba K., Triller A., 2009. Activ- ity-dependent tuning of inhibitory neurotransmis- sion based on GABAAR diffusion dynamics. Neuron, 62, 670–682.
• Beal MW., Brown DC., Shofer FS., 2000. The effects of perioperative hypothermia and the duration of an- esthesia on postoperative wound infection rate in clean wounds: a retrospective study. Vet. Surg., 29, 123-127.
• Berridge MJ., Bootman MD., Lipp P., 1998. Calcium--a life and death signal. Nature. 395, 645-648.
• Caneguim BH., Cerri PS., Spolidório LC., Miraglia SM., Sasso-Cerri E., 2009. Structural alterations in the seminiferous tubules of rats treated with immuno- suppressor tacrolimus. Reprod. Biol. Endocrinol., 25, 7-19.
• Chen JT., Chen RM., 2010. Mechanisms of ketamine- involved regulation of cytochrome P450 gene ex- pression. Expert. Opin. Drug Metab. Toxicol., 6, 273- 281.
• Craven R., 2007. Ketamine. Anaesthesia, 62, 48–53.
• Dahan A., Olofsen E., Sigtermans M., Noppers I., Niesters M., Aarts L., Bauer M., Sarton E., 2011. Population pharmacokinetic-pharmacodynamic modeling of ketamine-induced pain relief of chronic pain. Eur. J. Pain., 15, 258-267.
• De Cesaris P, Filippini A, Cervelli C, Riccioli A, Muci S, Starace G, Stefanini M, Ziparo E., 1992. Immuno- suppressive molecules produced by Sertoli cells cul- tured in vitro: biological effects on lymphocytes. Biochem. Biophys. Res. Commun., 186, 1639-1646.
• Farber JL., 1981. The role of calcium in cell death. Life Sci., 29, 1289-1295.
• Goldberg ME., Domsky R., Scaringe D., Hirsh R., Dotson J., Sharaf I., Torjman MC., Schwartzman RJ., 2005. Multi-day low dose ketamine infusion for the treat- ment of complex regional pain syndrome. Pain Phy- sician, 8, 175-179.
• Heys SD., Norton AC., Dundas CR., Eremin O., Ferguson K., Garlick PJ., 1989. Anaesthetic agents and their effect on tissue protein synthesis in the rat. Clin. Sci. (Lond)., 77, 651-655.
• Huang R-Q., and Dıllon GH., 1998. Maintenance of recombinant type A g-aminobutyric acid receptor function: role of protein tyrosine phosphorylation and calcineurin. J. Pharmacol. Exp. Ther., 286, 243– 255,
• Johnsen SG., 1970. Testicular biopsy score count--a method for registration of spermatogenesis in hu- man testes: normal values and results in 335 hypo- gonadal males. Hormones, 1, 2-25.
• Johnson-Delaney C., 1996. Exotic Animal Companion Medicine Handbook for Veterinarians, Lake Worth, FL: Zoological Education Network.
• Krupitsky EM., Grinenko AY., 1997. Ketamine psychedelic therapy (KPT): a review of the results of ten years of research. J. Psychoactive Drugs., 29, 165-183.
• Krystal JH., Madonick S., Perry E., Gueorguieva R., Brush L., Wray Y., Belger A., D'Souza DC., 2006. Potentia- tion of low dose ketamine effects by naltrexone: potential implications for the pharmacotherapy of alcoholism. Neuropsychopharmacology, 31, 1793- 1800.
• Li M., Kondo T., Zhao QL., Li FJ., Tanabe K., Arai Y., Zhou ZC., Kasuya M., 2000. Apoptosis induced by cad- mium in human lymphoma U937 cells through Ca2+- calpain and caspase-mitochondria- dependent pathways. J. Biol. Chem., 275, 39702-39709.
• Loh C., Carew JA., Kim J., Hogan PG., Rao A., 1996. T-cell receptor stimulation elicits an early phase of activa- tion and a later phase of deactivation of the tran- scription factor NFAT1. Mol. Cell Biol., 16, 3945– 3954.
• Loh C., Shaw KT., Carew J., Viola JP., Luo C., Perrino BA., Rao A., 1996. Calcineurin binds the transcription factor NFAT1 and reversibly regulates its activity. J. Biol. Chem., 271, 10884–10891.
• McConkey DJ., Orrenius S., 1997. The role of calcium in the regulation of apoptosis. Biochem. Biophys. Res. Commun., 239, 357-366.
• McKinsey TA., Zhang CL., Olson EN., 2002. MEF2: a calcium-dependent regulator of cell division, differ- entiation and death. Trends Biochem. Sci., 27, 40-7.
• Melis MR., Argiolas A., 1995. Dopamine and sexual behavior. Neurosci. Biobehav. Rev. Spring., 19, 19- 38.
• Miyamoto K., Matsui H., Tomizawa K., Kuwata Y., Itano T., Tokuda M., and Hatase O., 1994. In situ localization of rat testis-specific calcineurin B subunit isoform b1 in the developing rat testis. Biochem. Biophys. Res. Commun., 203, 1275–1283.
• Moia LJ., Matsui H., de Barros GA., Tomizawa K., Miyamoto K., Kuwata Y., Tokuda M., Itano T., Hatase O., 1994. Immunosuppressants and calcineurin in- hibitors, cyclosporin A and FK506, reversibly inhibit epileptogenesis in amygdaloid kindled rat. Brain Res., 648, 337-341.
• Moriya M., Fujinaga K., Yazawa M., and Katagiri C., 1995. Immunohistochemical localization of the cal- cium/calmodulin-dependent protein phosphatase calcineurin, in the mouse testis: its unique accumu- lation in spermatid nuclei. Cell Tissue Res., 281, 273–281.
• Mulero MC., Aubareda A., Orzaez M., Messeguer J., Serrano-Candelas E., Martinez-Hoyer S., Messeguer A., Perez-Payá E., Pérez-Riba M., 2009. Inhibiting the calcineurin-NFAT (nuclear factor of activated T cells) signaling pathway with a regulator of calcineurin- derived peptide without affecting general cal- cineurin phosphatase activity. J. Biol. Chem., 284, 9394-9401.
• Nishio H., Matsui K., Tsuji H., Tamura A., Suzuki K., 2000. Immunolocalization of calcineurin and FKBP12, the FK506-binding protein, in Hassall's corpuscles of human thymus and epidermis. Histochem. Cell Biol., 114, 9-14.
• Reich DL., Silvay G., 1989. Ketamine: an update on the first twenty-five years of clinical experience. Can. J. Anaesth., 36, 186-197.
• Ritta MN., Calamera JC., Bas DE,. 1998. Occurrence of GABA and GABA receptors in human spermatozoa. Mol. Hum. Reprod., 4, 769-773.
• Rusnak F., Mertz P., 2000. Calcineurin: form and function. Physiol. Rev., 80, 1483-1521.
• Salo M., 1992. Effects of anaesthesia and surgery on the immune response. Acta Anaesthesiol. Scand., 36, 201-220.
• Shibasaki F., Hallin U., Uchino H., 2002. Calcineurin as a multifunctional regulator. J. Biochem., 131, 1-15.
• Smith KM., Larive LL., Romanelli F., 2002. Club drugs: methylenedioxymethamphetamine, flunitrazepam, ketamine hydrochloride, and gammahydroxybu- tyrate. Am. J. Health Syst. Pharm., 59, 1067-1076.
• Sorensen AG., Barnung S., Rasmussen LS., 2011. Ketamine is used and abused in new ways. Ugeskr Laeger. 173, 2123-2126.
• Su Q., Zhao M., Weber E., Eugster HP., Ryffel B., 1995. Distribution and activity of calcineurin in rat tissues, Evidence for post-transcriptional regulation of tes- tis-specific calcineurin. B. Eur. J. Biochem., 230, 469- 474.
• Sugiura R., Sio SO., Shuntoh H., Kuno T., 2002. Calcineurin phosphatase in signal transduction: lessons from fission yeast. Genes Cells., 7, 619-627.
• Sugiura R., 2002. Functional analysis of calcineurin- mediated signalling pathway using fission yeast as a model system. Nihon Yakurigaku Zasshi., 119, 155- 161.
• Takadera T., Ishida A., Ohyashiki T., 2006. Ketamine- induced apoptosis in cultured rat cortical neurons. Toxicol. Appl. Pharmacol., 210, 100-107.
• Tash JS., Krınks M., Patel J., Means RL., Klee CB., and Means AR., 1988. Identification, characterization, and functional correlation of calmodulin- dependent protein phosphatase in sperm. J. Cell Biol., 106, 1625–1633.
• White JM., Ryan CF., 1996. Pharmacological properties of ketamine. Drug Alc. Review, 15, 145-155.
• Wilson RD., Priano LL., Traber D., et al., 1971. An investigation of possible immunosuppression from ketamine and 100% oxygen in normal human chil- dren. Anesth & Analg., 50, 464-470.
• Yamashita M., Katsumata M., Iwashima M., Kimura M., Shimizu C., Kamata T., Shin T., Seki N., Suzuki S., Ta- niguchi M., Nakayama T., 2000. T cell receptor- induced calcineurin activation regulates T helper type 2 cell development by modifying the inter- leukin 4 receptor signaling complex. J. Exp. Med., 191, 1869–1879.