Protective Effect of Resveratrol and N-Acetylcysteine Combination Against Locomotor Hyperactivity Induced by MK-801

Abstract

N-Methyl-D-Aspartate (NMDA) receptors are one of the most important elements of the glutamatergic system. The hypofunction of this receptor causes locomotor hyperactivity. The chemical agent MK-801, which is an NMDA receptor antagonist, also causes locomotor hyperactivity in rodents. In the present study, it is aimed to find the lowest protective dose of neuroprotective resveratrol and N-acetyl-cysteine (NAC) combination on increased locomotor activity using MK-801 in mice. For this purpose, 84 female mice were used and 14 groups of equal number of mice were formed. Locomotor hyperactivity was created in two parts as acute (1 day drug administration) and sub-acute (4 days drug administration) phases. After drug administrations, animals were subjected to open field testing. According to the results, the drug combination was successful in reducing locomotor hyperactivity in the acute phase than in the sub-acute phase. It was observed that the intraperitoneal administration of both low doses of the combination, 40mg/kg resveratrol + 20mg/kg NAC and 20mg/kg resveratrol + 10mg/kg NAC, successfully prevented the locomotor hyperactivity in the acute phase. As a result, it was concluded that the combination of antioxidants has an effect on acutely formed locomotor hyperactivity.

Keywords

• MK-801
• N-acetylcysteine
• Antioxidant
• Locomotor Hyperactivity
• Resveratrol

Resveratrol ve N-Asetilsistein Kombinasyonunun MK-801’ le İndüklenen Lokomotor Hiperaktivite Karşısında Koruyucu Etkisi

Öz

N-Methyl-D-Aspartate reseptörleri glutamaterjik sistemin önemli bir öğesidir. Bu reseptörün hipofonksiyonu lokomotor hiperaktiviteye sebep olur. NMDA reseptörlerinin antagonisti olan MK-801 isimli kimyasal da lokomotor hiperaktiviteye sebep olmaktadır. Sunulan bu çalışmada nöroprotektif özellikleri olduğu bilinen resveratrol ve N-asetilsistein isimli iki antioksidan kombinasyonunun farelerde MK-801’le indüklenen lokomotor hiperaktivite üzerinde etkin olan en düşük dozu araştırılmıştır. Bu amaçla 84 dişi fare eşit olarak 14 gruba bölünmüştür. Lokomotor hiperaktivite akut (1 gün ilaç uygulanması) ve sub-akut (4 gün ilaç uygulanması) faz olmak üzere iki bölümde oluşturuldu. İlaç uygulamalarından sonra hayvanların katettikleri mesafe açık alan test düzeneğinde 10 dakika boyunca kaydedilmiştir. Ölçüm sonuçlarına göre antioksidan kombinasyonunun akut fazda sub-akut faza göre başarılı olduğu gözlenmiştir. Kombinasyonun her iki düşük dozu olan 40mg/kg resveratrol + 20mg/kg NAC ve 20mg/kg resveratrol + 10mg/kg NAC’ın intraperitoneal uygulamalarının akut fazda lokomotor hiperaktiviteyi başarıyla engellediği gözlendi. Sonuç olarak antioksidan kombinasyonunun akut oluşan lokomotor hiperaktivite karşısında etkisinin olduğu sonucuna varıldı.

Anahtar Kelimeler

• Antioksidan
• Lokomotor Hiperaktivite
• MK-801
• N-asetilsistein
• Resveratrol

Kaynakça

1. Adair JC, Knoefel JE, Morgan N. Controlled trial of N-acetylcysteine for patients with probable Alzheimer’s disease. Neurology. 2001; 57 (8): 1515-1517.
2. Akillioglu K, Babar Melik E, Melik E, Kocahan S. The investigation of neonatal MK-801 administration and physical environmental enrichment on emotional and cognitive functions in adult Balb/c mice. Pharmacology Biochemistry and Behavior. 2012; 102 (3): 407-414.
3. Al-Amin HA, Weinberger DR, Lipska BK. Exaggerated MK-801-induced motor hyperactivity in rats with the neonatal lesion of the ventral hippocampus. Behavioural Pharmacology. 2000; 11 (3-4): 269-278.
4. Atalay T, Gulsen I, Colcimen N, Alp HH, Sosuncu E, Alaca I, Ak H, Ragbetli MC. Resveratrol treatment prevents hippocampal neurodegeneration in a rodent model of traumatic brain injury. Turkish Neurosurgery. 2017; 27 (6): 924-930.
5. Bastianetto S, Ménard C, Quirion R. Neuroprotective action of resveratrol. Biochimica et Biophysica Acta - Molecular Basis of Disease. 2015; 852 (6): 1195-1201.
6. Bulut M, Savas HA, Altindag A, Virit O, Dalkilic A. Beneficial effects of N-acetylcysteine in treatment resistant schizophrenia. The World Journal of Biological Psychiatry. 2009; 10 (4–2): 626-628.
7. De Oliveira RV, Dall’Igna OP, Tort ABL, Schuh JF, Neto PF, Santos Gomes MW, Souza DO, Lara DR. Effect of subchronic caffeine treatment on MK-801-induced changes in locomotion, cognition and ataxia in mice. Behavioural Pharmacology. 2005; 16 (2): 79-84.
8. Dean O, Giorlando F, Berk M. N-acetylcysteine in psychiatry: Current therapeutic evidence and potential mechanisms of action. Journal of Psychiatry and Neuroscience. 2011; 36 (2): 78-86.

9. Dean O, van den Buuse M, Copolov D, Berk M, Bush A. N-acetyl-cysteine treatment inhibits depletion of brain glutathione levels in rats: implications for schizophrenia. International Journal of Neuropsychopharmacology. 2004; 7 (Suppl. 2): 262.
10. Farr SA, Poon HF, Dogrukol-Ak D, Drake J, Banks WA, Eyerman E, Butterfield DA, Morley JE. The antioxidants α-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. Journal of Neurochemistry. 2003; 84 (5): 1173-1183.
11. Fukami G, Hashimoto K, Koike K, Okamura N, Shimizu E, Iyo M. Effect of antioxidant N-acetyl-L-cysteine on behavioral changes and neurotoxicity in rats after administration of methamphetamine. Brain Research. 2004; 1016 (1): 90-95.
12. Furuie H, Yamada K, Ichitani Y. MK-801-induced and scopolamine-induced hyperactivity in rats neonatally treated chronically with MK-801. Behavioural Pharmacology. 2013; 24 (8): 678-683.
13. García-Alcántara F, Murillo-Cuesta S, Pulido S, Bermúdez-Muñoz JM, Martínez-Vega R, Milo M, Varela-Nieto I, Rivera T. The expression of oxidative stress response genes is modulated by a combination of resveratrol and N-acetylcysteine to ameliorate ototoxicity in the rat cochlea. Hearing Research. 2018; 358: 10-21.
14. Gattaz, WF, Schummer B, Behrens S. Effects of zotepine, haloperidol and clozapine on MK-801-induced stereotypy and locomotion in rats. J Neural Transm Gen Sect. 1994; 96 (3): 227-232.
15. Genius J, Geiger J, Dölzer AL, Benninghoff J, Giegling I, Hartmann AM, Möller HJ, Rujescu D. Glutamatergic dysbalance and oxidative stress in in vivo and in vitro models of psychosis based on chronic nmda receptor antagonism. PLoS One. 2013; 8 (7): e59395.
16. Gerszon J, Rodacka A, Puchała M. Antioxidant properties of resveratrol and its protective effects in neurodegenerative diseases. Advances in Cell Biology. 2014; 2: 97-117.
17. Giovinazzo G, Grieco F. Functional properties of grape and wine polyphenols. Plant Foods for Human Nutrition. 2015; 70 (4): 454-462.
18. Gupta RC. Nutraceuticals : Efficacy, safety and toxicity. UK, Academic Press-Elsevier. 2016.
19. Gururajan A, Taylor DA, Malone DT. Cannabidiol and clozapine reverse MK-801-induced deficits in social interaction and hyperactivity in Sprague–Dawley rats. Journal of Psychopharmacology. 2012; 26 (10): 1317-1332.
20. Himi T, Ikeda M, Yasuhara T, Murota SI. Oxidative neuronal death caused by glutamate uptake inhibition in cultured hippocampal neurons. J Neurosci Res. 2003; 71 (5): 679-688.
21. Janáky R, Dohovics R, Saransaari P, Oja SS. Modulation of [3H] dopamine release by glutathione in mouse striatal slices. Neurochem Res. 2007; 32 (8): 1357-1364.
22. Jeon BT, Jeong EA, Shin HJ, Lee Y, Lee DH, Kim HJ, Kang SS, Cho GJ, Choi WS, Roh GS. Resveratrol attenuates obesity-associated peripheral and central inflammation and improves memory deficit in mice fed a high-fat diet. Diabetes. 2012; 61 (6): 1444-1454.
23. Kim TW, Kang HS, Park JK, Lee SJ, Baek SB, Kim CJ. Voluntary wheel running ameliorates symptoms of MK-801-induced schizophrenia in mice. Molecular Medicine Reports. 2014; 10 (6): 2924-2930.
24. Kocahan S, Babar E, Melik E, Akillioglu K. The effect of the interaction between N-methyl-D-aspartate receptor blockade and growth environment during the last maturation period of the nervous system on anxiety-related behaviour in adulthood in the rat. Neurochemical Journal. 2012; 6 (3): 194-201.
25. 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. Neurotoxicity Research. 2016; 30 (4): 658-676.
26. Lin CH, Lane HY. Early identification and intervention of schizophrenia: Insight from hypotheses of glutamate dysfunction and oxidative stress. Frontiers in Psychiatry. 2019; 10: 1-9.
27. Miller DK, Oelrichs CE, Sage AS, Sun GY, Simonyi A. Repeated resveratrol treatment attenuates methamphetamine-induced hyperactivity and [3H]dopamine overflow in rodents. Neuroscience Letters. 2013; 554: 53-58.
28. Monserrat Hernández-Hernández E, Serrano-García C, Antonio Vázquez-Roque R, Díaz A, Monroy E, Rodriguez-Moreno A, Florán B, Flores G. Chronic administration of resveratrol prevents morphological changes in prefrontal cortex and hippocampus of aged rats. Synapse. 2016; 70 (5): 206-217.
29. Ozyurt B, Ozyurt H, Akpolat N, Erdogan H, Sarsilmaz M. Oxidative stress in prefrontal cortex of rat exposed to MK-801 and protective effects of CAPE. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2007; 31 (4): 832-838.
30. 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. European Review for Medical and Pharmacological Sciences. 2014; 18 (15): 2137-2144.
31. Pasinetti GM, Wang J, Ho L, Zhao W, Dubner L. Roles of resveratrol and other grape-derived polyphenols in Alzheimer’s disease prevention and treatment. Biochimica et Biophysica Acta - Molecular Basis of Disease. 2014; 1852 (6): 1202-1208.
32. Pietraszek M, Michaluk J, Romańska I, Wa̧sik A, Golembiowska K, Antkiewicz-Michaluk L. 1-Methyl-1,2,3,4-tetrahydroisoquinoline antagonizes a rise in brain dopamine metabolism, glutamate release in frontal cortex and locomotor hyperactivity produced by MK-801 but not the disruptions of prepulse inhibition, and impairment of working memory in rat. Neurotoxicity Research. 2009; 16 (4): 390-407.
33. Pinar N, Akillioglu K, Sefil F, Alp H, Sagir M, Acet A. Effect of clozapine on locomotor activity and anxiety-related behavior in the neonatal mice administered MK-801. Bosnian Journal of Basic Medical Sciences. 2015; 15 (3): 74-79.
34. Rege SD, Kumar S, Wilson DN, Tamura L, Geetha T, Mathews ST, Huggins KW, Broderick TL, Babu JR. Resveratrol protects the brain of obese mice from oxidative damage. Oxidative Medicine and Cellular Longevity. 2013; 419092: 2013.
35. Tardiolo G, Bramanti P, Mazzon E. Overview on the effects of N-acetylcysteine in neurodegenerative diseases. Molecules. 2018; 23 (12): 3305.
36. Varga V, Jenaei Z, Janáky R, Saransaari P, Oja SS. Glutathione is an endogenous ligand of rat brain N-methyl-D-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors. Neurochem Res. 1997; 22 (9): 1165-1171.
37. Venturini CD, Merlo S, Souto AA, Fernandes MDC, Gomez R, Rhoden CR. Resveratrol and red wine function as antioxidants in the central nervous system without cellular proliferative effects during experimental diabetes. Oxidative Medicine and Cellular Longevity. 2010; 3 (6): 434-441.
38. Xiu Y, Kong X, 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. Journal of Psychiatric Research. 2015; 63: 132-140.
39. 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. Anatomical Record. 2014; 297 (8): 1498-1507.
40. Yu J, Qi D, Xing M, Li R, Jiang K, Peng Y, Cui D. MK-801 induces schizophrenic behaviors through downregulating Wnt signaling pathways in male mice. Brain Research. 2011; 1385: 281-292.