SİSPLATİN'İN NÖROTOKSİK ETKİSİNE BAĞLI GELİŞEN HİPOKAMPAL NÖRON HASARINA KARŞI MELATONİN NÖROPROTEKTİF ETKİNLİĞİNİN ARAŞTIRILMASI

Yıl 2021, Cilt: 4 Sayı: 1, 87 - 93, 30.05.2021

Ümit Ali Malçok , Başak Büyük

https://doi.org/10.52538/iduhes.926453

Cited By: 2

Öz

Sisplatin yaygın kullanılan ancak yaşam kalitesini düşüren etkileri olan bir antineoplastiktir. Özellikle nörotoksik etkileri, hastaların %70’inde tedavi esnasında veya sonrasında bilişsel bozulmalara yol açmaktadır. Bu çalışmada melatoninin siplatin toksistesini azaltıcı etkinliği araştırıldı. Denek olarak 24 yetişkin erkek Wistar Albino ırkı sıçan kullanılarak 4 grup oluşturuldu. Sıçanlara 1. 5. 9. ve 13. günlerde ve 4 mg/kg dozunda intraperitoneal (ip) sisplatin verilerek nörotoksisite oluşturuldu. Tedavi grubuna ise 13 gün 10 mg/kg/gün dozunda ip melatonin uygulanarak gruplar karşılaştırıldı. 14. günde yapılan sakrifikasyon sonrası hipokampus dokuları alındı. Piknozis ve ödem skorları hesaplanarak sisplatin toksisitesi ve melatoninin etkinliği analiz edildi. Sham grubu ile Mel ve Cisp+Mel grupları arasında piknosis açısından anlamlı fark olmadığı ancak sisplatin verilen grupta belirgin düzeyde piknotik nöron artışı olduğu görüldü (p<0.01). Sisplatin verilen ratlarda hipokampus dokusundaki ödemin belirgin düzeyde arttığı buna karşın melatonin verildiğinde ödem skorlarının istatistiksel olarak anlamlı seviyede düştüğü izlendi (p<0.01). Sisplatin ve melatonin benzer oksidatif ve apoptotik süreçleri zıt yönlerde etkilemektedir. Biz de çalışmamızda melatoninin sisplatin toksisitesi üzerine olan etkilerini inceledik ve melatoninin sisplatinin nörotoksik etkilerine karşı koruyucu etki gösterdiği sonucuna ulaştık. Ulaştığımız bu sonuç yaygın kullanılan bir kemoteropatik olan sisplatin, melatonin ile kombine edilerek kullanıldığında kanser hastalarının daha az nörotoksik yan etkilere maruz kalmasını sağlayacaktır.

Anahtar Kelimeler

Sisplatin, melatonin, nörotoksisite, hipokampüs

INVESTIGATION OF THE NEUROPROTECTIVE EFFECT OF MELATONIN ON HIPPOCAMPAL NEURON INJURY DEVELOPING DUE TO THE NEUROTOXIC EFFECT OF CISPLATIN

Öz

Cisplatin is a widely used antineoplastic agent, but it has side effects that decrease quality of life. Its neurotoxic effects lead to cognitive disorders during or after treatment in 70% of the patients. In this study, the efficiency of melatonin to reduce cisplatin-induced toxicity was investigated. Four subject groups were established using 24 adult male Wistar Albino rats. Neurotoxicity was produced by administering intraperitoneal (ip) cisplatin on the 1st, 5th, 9th and 13th day at a dose of 4 mg/kg. Intraperitoneal melatonin was applied to the treatment group for 13 days at a dose of 10 mg/kg/day and the groups were compared. Following sacrification on the 14th day, hippocampal tissues were excised. Cisplatin toxicity and melatonin efficiency were analyzed by calculating pyknosis and edema scores. It was observed that there was no significant difference between the Sham, Mel and Cisp+Mel groups in terms of pyknosis, but a marked increase in pyknotic neurons occurred in the group which was given cisplatin (p<0.01). It was found that edema in the hippocampal tissue increased markedly in the rats which were given cisplatin, but edema scores statistically significantly decreased when melatonin was given (p<0.01). Cisplatin and melatonin influence the same oxidative and apoptotic processes in opposite directions. In our study, we examined the effects of melatonin on cisplatin-induced toxicity and concluded that melatonin showed protective action against cisplatin-induced neurotoxic effects. Our conclusion indicated that cancer patients would be exposed to fewer neurotoxic side effects when cisplatin, a widely used chemotherapeutic drug, is used in combination with melatonin.

Anahtar Kelimeler

Cisplatin, melatonin, neurotoxicity, hippocampus

Kaynakça

• Ali T., Kim MO. (2015). Melatonin ameliorates amyloid beta-induced memory deficits, tau hyperphosphorylation and neurodegeneration via PI3/Akt/GSk3beta pathway in the mouse hippocampus. J Pineal Res, 59, 47‐59.
• Amidi A., Hosseini SMH., Leemans A., Kesler SR., Agerbæk M., Wu LM., et al. (2017). Changes in Brain Structural Networks and Cognitive Functions in Testicular Cancer Patients Receiving Cisplatin-Based Chemotherapy. J Natl Cancer Inst, 109(12), 1-7. doi: 10.1093/jnci/djx085
• Cankara FN., Günaydın C., Çelik ZB., Şahin Y., Pekgöz Ş., Erzurumlu Y., et al. (2021). Agomelatine confers neuroprotection against cisplatin-induced hippocampal neurotoxicity. Metab Brain Dis 36(2), 339-349. doi: 10.1007/s11011-020-00634-y
• Ding K., Wang H., Xu J., Li T., Zhang L., Ding Y., et al. (2014). Melatonin stimulates antioxidant enzymes and reduces oxidative stress in experimental traumatic brain injury: the Nrf2-ARE signaling pathway as a potential mechanism. Free Radic Biol Med, 73, 1-11. doi: 10.1016/j.freeradbiomed.2014.04.031
• Dong Y., Fan C., Hu W., Jiang S., Ma Z., Yan X., et al. (2016). Melatonin attenuated early brain injury induced by subarachnoid hemorrhage via regulating NLRP3 inflammasome and apoptosis signaling. J Pineal Res, 60, 253‐262.
• Feng D., Wang B., Wang L., Abraham N., Tao K., Huang L., et al. (2017). Pre- ischemia melatonin treatment alleviated acute neuronal injury after ischemic stroke by inhibiting endoplasmic reticulum stress-dependent autophagy via PERK and IRE1 signalings. J Pineal Res, 62(3), 1-13. doi: 10.1111/jpi.12395
• Fernández A., Ordóñez R., Reiter RJ., González-Gallego J., Mauriz JL. (2015). Melatonin and endoplasmic reticulum stress: relation to autophagy and apoptosis. J Pineal Res, 59, 292‐307.
• Kazak F., Akalın PP., Yarım GF., Başpınar N., Özdemir Ö., Ateş MB., et al. (2021). Protective effects of nobiletin on cisplatin induced neurotoxicity in rats. Int J Neurosci, 8, 1-7. doi: 10.1080/00207454.2021.1896507
• Krarup-Hansen A., Helweg-Larsen S., Schmalbruch H., Rørth M., Krarup C. (2007). Neuronal involvement in cisplatin neuropathy: prospective clinical and neurophysiological studies. Brain, 130, 1076–1088. https://doi.org/10.1093/brain/awl356
• Liu Y., Hamaue N., Endo T., Hirafuji M., Minami M. (2003). 5-hydroxytryptamine (5-HT) concentrations in the hippocampus, the hypothalamus and the medulla oblongata related to cisplatin-induced pica of rats. Res Commun Mol Pathol Pharmacol, 113-114, 97-113.
• Lomeli N., Di K., Czerniawski J., Guzowski JF., Bota DA. (2017). Cisplatin-induced mitochondrial dysfunction is associated with impaired cognitive function in rats. Free Radic Biol Med, 102, 274-286. doi: 10.1016/j.freeradbiomed.2016.11.046
• Lopez-Gonzalez MA., Guerrero JM., Rojas F., Delgado F. (2000). Ototoxicity caused by cisplatin is ameliorated by melatonin and other antioxidants. J Pineal Res, 28(2), 73-80. doi: 10.1034/j.1600-079x.2001.280202.x
• Luo Y., Peng M., Wei H. (2017). Melatonin Promotes Brain-Derived Neurotrophic Factor (BDNF) Expression and Anti-Apoptotic Effects in Neonatal Hemolytic Hyperbilirubinemia via a Phospholipase (PLC)-Mediated Mechanism. Med Sci Monit 23, 5951-5959. doi: 10.12659/msm.907592
• Manohar S., Jamesdaniel S., Salvi R. (2014). Cisplatin inhibits hippocampal cell proliferation and alters the expression of apoptotic genes. Neurotox Res, 25(4), 369-80. doi: 10.1007/s12640-013-9443-y
• Namikawa K., Asakura M., Minami T., Okazaki Y., Kadota E., Hashimoto S. (2000). Toxicity of cisplatin to the central nervous system of male rabbits. Biol Trace Elem Res 74(3), 223-35. doi: 10.1385/BTER:74:3:223
• Pazar A., Kolgazi M., Memisoglu A., Bahadir E., Sirvanci S., Yaman A., et al. (2016). The neuroprotective and anti-apoptotic effects of melatonin on hemolytic hyperbilirubinemia-induced oxidative brain damage. J Pineal Res 60(1), 74-83. doi: 10.1111/jpi.12292
• Troy L., McFarland K., Littman-Power S., Kelly BJ., Walpole ET., Wyld D., et al. (2000). Cisplatin-based therapy: a neurological and neuropsychological review. Psychooncology, 9(1), 29-39. doi: 10.1002/(sici)1099-1611(200001/02)9:1<29::aid-pon428>3.0.co;2-z
• Zandbergen N., de Rooij BH., Vos MC., Pijnenborg JMA., Boll D., Kruitwagen RFPM., et al. (2019). Changes in health-related quality of life among gynecologic cancer survivors during the two years after initial treatment: a longitudinal analysis. Acta Oncol, 58(5), 790-800. doi: 10.1080/0284186X.2018.1560498