Protective Effect of N-Acetylcysteine on The Kidney and Liver Pathology Induced by NMDA Receptor Antagonist Mk-801 in Mice

Yıl 2019, , 258 - 263, 30.09.2019

Murat Sırrı Akosman , Hasan Hüseyin Demirel Ruhi Türkmen

https://doi.org/10.30607/kvj.571397

Öz

The glutamatergic system and its receptor
N-methyl-D-aspartate (NMDA) is an important synapse mechanism in the nervous
system. The MK-801 is the blocker of this receptor and according to the
literature, the sub-chronic administration of 1mg/kg MK-801 resulted in
schizophrenia-like symptoms and degeneration in the mice brain. The aim of the
present study was to observe whether this dose of MK-801 has any pathological
effect on the liver and kidney tissues and whether N-acetylcysteine (NAC) was a
protective effect. For this purpose, the 24 Balb/C male mice were divided into
4 groups, equally. The first group was the control and 0.9% saline (10mg/kg)
was intraperitoneally (i.p.) injected. The 1mg/kg MK-801 was i.p. administered
to the second group. The third group was i.p. received 1mg/kg MK-801, 100 mg/kg
NAC and finally the 100mg/kg NAC i.p. injected to the fourth group. The drug
administration was ended on the 14^th day. The kidney and the liver
of the sacrificed mice were collected and routine histology procedure was
applied. The histopathological changes in the organs and NAC’s mostly
protective effect were noticed after the observations. In conclusion, NAC has a
partially but significantly protective effect against the MK-801 dependent
histopathological changes on the kidney and liver tissues.

Anahtar Kelimeler

Histopathology, Kidney, Liver, Mice, MK-801, N-acetylcysteine

Destekleyen Kurum

Afyon Kocatepe University Scientific Research Project Coordination Unit

Proje Numarası

17.Kariyer.45

Farelerde NMDA Reseptör Antagonisti Mk-801 ile Böbrek ve Karaciğerde Oluşan Patolojik Değişikliklere Karşı N-Asetilsisteinin Koruyucu Etkisi

Öz

Glutamaterjik sistem sinir sisteminde önemli bir sinaps mekanizmasıdır.
N-metil-D-aspartat (NMDA) reseptörleri bu sistemin önemli bir parçasıdır. NMDA
reseptörlerinin  hipofonksiyonu farelerde
kognitif ve motorik sorunlara sebep olmaktadır. MK-801 bu reseptörün oldukça
önemli bir blokörüdür. 1mg/kg MK-801’in sub-kronik uygulanması farelerde
şizofreni benzeri semptomlara ve beyinde dejenerasyona sebep olmaktadır.
Sunulan bu çalışmada MK-801’in 1mg/kg’lık sub-kronik uygulamasının farelerin
böbrek ve karaciğerlerinde patolojik etkileri olup olmadığı ve N-asetilsisteinin’in
(NAS) bu etkiler karşısında koruyucu etkisinin olup olmadığı araştırıldı. Bu
amaçla 24 adet erkek Balb/C faresi alınarak dört eşit gruba bölündü. İlk grup
kontrollerden oluştu ve bu gruba %0,9 fizyolojik tuzlu su (10mg/kg)
intraperitoneal (i.p.) yolla, ikinci gruba 1mg/kg dozunda MK-801 i.p., üçüncü
gruba 1mg/kg MK-801 ile 100mg/kg NAS birlikte i.p ve dördüncü gruba da 100mg/kg
NAS i.p. yolla verildi. İlaç uygulamaları 14 gün boyunca sürdü. Sakrifiye
edilen farelerin karaciğer ve böbrekleri alınarak bunlara rutin histoloji
prosedürü uygulandı. İncelemelerden sonra organlarda histopatolojik
değişkilikler ve NAS’ın genelde koruyucu etkisinin olduğu gözlendi. Sonuç
olarak NAS’ın böbrek ve karaciğer üzerinde MK-801’le indüklenen histopatolojik
değişikliklere karşı önemli bir koruyucu etkisinin olduğu ortaya kondu. 

Anahtar Kelimeler

Böbrek, Fare, Histopatoloji, Karaciğer, MK-801, N-asetilsistein

Proje Numarası

17.Kariyer.45

Kaynakça

• Cauli O, Rodrigo R, Boix J, Piedrafita B, Agusti A, Felipo V. Acute liver failure-induced death of rats is delayed or prevented by blocking NMDA receptors in brain. Am J Physiol Gastrointest Liver Physiol. 2008;295(3):G503-11.
• Deepmala J, Slattery N, Kumar L, Delhey M, Berk O, Dean C, Spielholz RF. Clinical trials of N-acetylcysteine in psychiatry and neurology: a systematic review. Neurosci. Biobehav. Rev. 2015;55:294-321.
• Deng A, Valdivielso JM, Munger KA, Blantz RC, Thomson SC. Vasodilatory N-methyl-D-aspartate receptors are constitutively expressed in rat kidney. J Am Soc Nephrol. 2002;13(5):1381-4.
• Deng A, Thomson SC. Renal NMDA receptors independently stimulate proximal reabsorption and glomerular filtration. Am J Physiol Renal Physiol. 2009;296(5):F976-82.
• Dryer SE. Glutamate receptors in the kidney. Nephrology Dialysis Transplantation, 2015;30(10):1630–1638.
• Fix AS, Stitzel SR, Ridder GM, Switzer RC. MK-801 neurotoxicity in cupric silver-stained sections: lesion reconstruction by 3-dimensional computer image analysis. Toxicol Pathol. 2000;28(1):84-90.
• Giardino L, Armelloni S, Corbelli A, Mattinzoli D, Zennaro C, Guerrot D, Tourrel F, Ikehata M, Li M, Berra S, Carraro M, Messa P, Rastaldi MP. Podocyte glutamatergic signaling contributes to the function of the glomerular filtration barrier. J Am Soc Nephrol. 2009;20(9):1929-40. Gibson-Corley KN, Olivier AK, Meyerholz DK. Principles for valid histopathological scoring in research. Vet Pathol. 2013;50(6):1007-15.
• Hashimoto K: The NMDA receptors. Humana Press. pp. 62-64, 2017.
• Hu JH, Yang N, Ma YH, Jiang J, Zhang JF, Fei J, Guo LH. Identification of glutamate transporters and receptors in mouse testis. Acta Pharmacol Sin. 2004;25:366-371.
• IOM (Institute of Medicine). Glutamate-related biomarkers in drug development for disorders of the nervous system: A workshop summary. Washington, DC: The National Academies Press. pp: 5-8. 2011.
• Javitt DC. Glutamate and schizophrenia: phencyclidine, N-methyl-D-aspartate receptors, and dopamine-glutamate interactions. Int Rev Neurobiol. 2007;78:69-108.
• Khoshbaten M1, Aliasgarzadeh A, Masnadi K, Tarzamani MK, Farhang S, Babaei H, Kiani J, Zaare M, Najafipoor F. N-acetylcysteine improves liver function in patients with non-alcoholic Fatty liver disease. Hepat Mon. 2010;10(1):12-6.
• Kruk-Slomka M, Budzynska B, Slomka T, Banaszkiewicz I, Biala G. The influence of the CB1 receptor ligands on the schizophrenia-like effects in mice induced by MK-801. Neurotox Res. 2016;30:658-676.
• Leung JC, Marphis T, Craver RD, Silverstein DM. Altered NMDA receptor expression in renal toxicity: Protection with a receptor antagonist. Kidney Int. 2004;66(1):167-176.
• Leung JC, Ragland N, Marphis T, Silverstein DM. NMDA agonists and antagonists induce renal culture cell toxicity. Med Chem. 2008;4(6):565-571.
• Lin CS, Hung SF, Huang HS, Ma MC. Blockade of the N-Methyl-D-Aspartate Glutamate Receptor Ameliorates Lipopolysaccharide- Induced Renal Insufficiency. PLoS ONE. 2015;10(7):1-18.
• Nitescu N, Ricksten SE, Marcussen N, Haraldsson B, Nilsson U, Basu S, Guron G. N-acetylcysteine attenuates kidney injury in rats subjected to renal ischaemia-reperfusion. Nephrol Dial Transplant. 2006;21:1240–1247.
• Ozyurt H, Ozyurt B, Sarsilmaz M, Kus I, Songur A, Akyol O. Potential role of some oxidant/antioxidant status parameters in prefrontal cortex of rat brain in an experimental psychosis model and the protective effects of melatonin. Eur Rev Med Pharmacol Sci. 2014;18(15):2137-2144.
• Rodrigo R, Cauli O, Boix J, ElMlili N, Agusti A, Felipo V. Role of NMDA receptors in acute liver failure and ammonia toxicity: therapeutical implications. Neurochem Int. 2009;55(1-3):113-8.
• Roshanravan H, Kim EY, Dryer SE. NMDA Receptors as Potential Therapeutic Targets in Diabetic Nephropathy: Increased Renal NMDA Receptor Subunit Expression in Akita Mice and Reduced Nephropathy Following Sustained Treatment With Memantine or MK-801. Diabetes. 2016;65(10):3139-50.
• Sekita-Krzak J, Visconti J, Wójtowicz Z, Zebrowska-Lupina I, Ossowska G, Klenk-Majewska B. Histological examination of the kidney after experimental administration of MK-801 and dexamethasone. Ann Univ Mariae Curie Sklodowska Med. 2004;59(2):70-4.
• Vandongen MA. Biology of the NMDA receptor. CRC Press Taylor and Francis Group. USA. pp:1-8. 2009.
• Xiu Y, Kong XR, Zhang L, Qiu X, Chao FL, Peng C, Gao Y, Huang CX, Wang SR, Tang Y. White matter injuries induced by MK-801 in a mouse model of schizophrenia based on NMDA antagonism. Anat Rec (Hoboken). 2014;297(8):1498-507.
• Xiu Y, Kong XR, Zhang L, Qiu X, Gao Y, Huang CX, Chao FL, Wang SR, Tang Y. The Myelinated Fiber Loss in the Corpus Callosum of Mouse Model of Schizophrenia Induced by MK-801. J Psychiatr Res. 2015;63:132-40.