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Current Enzyme Inhibition

Editor-in-Chief

ISSN (Print): 1573-4080
ISSN (Online): 1875-6662

Research Article

Effect of Achyranthes Aspera Linn. Leaves Extract on Reactive Oxygen Species (ROS) in Diabetes-induced Rats by Flow cytometry and Possible Molecular Mechanism through Molecular Docking

Author(s): Trupti C. Deshpande and Hemant D. Une*

Volume 17 , Issue 1 , 2021

Published on: 28 December, 2020

Page: [71 - 81] Pages: 11

DOI: 10.2174/1573408016999201228193350

Price: $65

Abstract

Background: Oxidative stress is caused due to the overproduction of the reactive oxygen species (ROS) and the disturbance developed in the antioxidant potential of biochemical processes. ROS mostly form in the brain due to the high consumption of oxygen and the insufficiency of endogenous antioxidant resistance mechanisms. Cytochrome P450 2E1 has an excessive percentage of NADPH oxidase activity, which causes the production of ROS and increases oxidative stress.

Objectives: We have studied the effect of ethyl acetate extract of Achyranthes Aspera (EAAA) on ROS in the brain of diabetes-induced rats. We have also investigated the possible molecular mechanism of reduction in ROS through molecular docking.

Methods: To study the oxidative stress induced by ROS in diabetic rats, we estimated the ROS in rat brain through flow cytometry. The oral dose of EAAA 50mg/kg and 100 mg/kg was given to diabetesinduced rats. Results were articulated as mean ± standard deviation (SD). Data were analyzed using analysis of variance (ANOVA) followed by Bonferroni as a post hoc test. We performed molecular docking of flavonoids on CYP2E1 to study the inhibitory potential.

Results: The results have shown that EAAA reduces the generation of ROS in the diabetes-induced rat in a dose-dependent manner. The oral dose of EAAA 50mg/kg and 100 mg/kg was given to the rats and the ROS generation got affected accordingly. Luteolin, quercetin, and apigenin inhibited the CYP2E1 very effectively. Luteolin formed 4 hydrogen bonds with CYP2E1, which indicated its potential inhibition. Although, luteolin and apigenin showed a very good binding affinity with the enzyme.

Conclusion: From the present work, we have concluded that the ethyl acetate extract of achyrantesaspera can effectively inhibit the ROS generation in the diabetes-induced rats by inhibiting the activity of CYP2E1.

Keywords: Reactive Oxygen Species (ROS), Achyranthes Aspera, CYP2E1, flow cytometry, diabetes, rats.

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[1]
Liguori, I.; Russo, G.; Curcio, F.; Bulli, G.; Aran, L.; Della-Morte, D.; Gargiulo, G.; Testa, G.; Cacciatore, F.; Bonaduce, D.; Abete, P. Oxidative stress, aging, and diseases. Clin. Interv. Aging, 2018, 13, 757-772.
[http://dx.doi.org/10.2147/CIA.S158513] [PMID: 29731617]
[2]
Ames, B.N.; Shigenaga, M.K.; Hagen, T.M. Oxidants, Antioxidants, and the Degenerative Diseases of Aging. PNAS, 1993, 90(17), 7915-7922.
[http://dx.doi.org/10.1073/pnas.90.17.7915]
[3]
Aschner, M.; Syversen, T.; Souza, D.O.; Rocha, J.B.T.; Farina, M. Involvement of glutamate and reactive oxygen species in methylmercury neurotoxicity. Braz. J. Med. Biol. Res., 2007, 40(3), 285-291.
[http://dx.doi.org/10.1590/S0100-879X2007000300001] [PMID: 17334523]
[4]
Reardon, A.M.; Bhat, H.K. Methylmercury neurotoxicity: role of oxidative stress. Toxicol. Environ. Chem., 2007, 3, 535-554.
[http://dx.doi.org/10.1080/02772240701201158]
[5]
Blesa, J.; Trigo-Damas, I.; Quiroga-Varela, A.; Jackson-Lewis, V.R. Oxidative stress and Parkinson’s disease. Front. Neuroanat., 2015, 9, 91.
[http://dx.doi.org/10.3389/fnana.2015.00091] [PMID: 26217195]
[6]
Drechsel, D.A.; Patel, M. Role of reactive oxygen species in the neurotoxicity of environmental agents implicated in Parkinson’s disease. Free Radic. Biol. Med., 2008, 44(11), 1873-1886.
[http://dx.doi.org/10.1016/j.freeradbiomed.2008.02.008] [PMID: 18342017]
[7]
Shibata, N.; Kobayashi, M. The role for oxidative stress in neurodegenerative diseases. Brain Nerve, 2008, 60(2), 157-170.
[PMID: 18306664]
[8]
Farina, M.; Aschner, M.; Rocha, J.B.T. Oxidative stress in MeHg-induced neurotoxicity. Toxicol. Appl. Pharmacol., 2011, 256(3), 405-417.
[http://dx.doi.org/10.1016/j.taap.2011.05.001] [PMID: 21601588]
[9]
Sayre, L.M.; Perry, G.; Smith, M.A. Oxidative stress and neurotoxicity. Chem. Res. Toxicol., 2008, 21(1), 172-188.
[http://dx.doi.org/10.1021/tx700210j] [PMID: 18052107]
[10]
Linhart, K.; Bartsch, H.; Seitz, H.K. The role of reactive oxygen species (ROS) and cytochrome P-450 2E1 in the generation of carcinogenic etheno-DNA adducts. Redox Biol., 2014, 3, 56-62.
[http://dx.doi.org/10.1016/j.redox.2014.08.009] [PMID: 25462066]
[11]
Veith, A.; Moorthy, B. Role of cytochrome P450s in the generation and metabolism of reactive oxygen species. Curr. Opin. Toxicol., 2018, 7, 44-51.
[http://dx.doi.org/10.1016/j.cotox.2017.10.003] [PMID: 29527583]
[12]
Seitz, H.K.; Mueller, S. Alcohol and cancer: An overview with special emphasis on the role of acetaldehyde and cytochrome P450 2E1. Adv. Exp. Med. Biol., 2015, 815, 59-70.
[http://dx.doi.org/10.1007/978-3-319-09614-8_4] [PMID: 25427901]
[13]
Mueller, S.; Peccerella, T.; Qin, H.; Glassen, K.; Waldherr, R.; Flechtenmacher, C.; Straub, B.K.; Millonig, G.; Stickel, F.; Bruckner, T.; Bartsch, H.; Seitz, H.K. Carcinogenic etheno DNA adducts in alcoholic liver disease: correlation with cytochrome P-4502E1 and fibrosis. Alcohol. Clin. Exp. Res., 2018, 42(2), 252-259.
[http://dx.doi.org/10.1111/acer.13546] [PMID: 29120493]
[14]
Sapone, A.; Gustavino, B.; Monfrinotti, M.; Canistro, D.; Broccoli, M.; Pozzetti, L.; Affatato, A.; Valgimigli, L.; Forti, G.C.; Pedulli, G.F.; Biagi, G.L.; Abdel-Rahman, S.Z.; Paolini, M. Perturbation of cytochrome P450, generation of oxidative stress and induction of DNA damage in Cyprinus carpio exposed in situ to potable surface water. Mutat. Res., 2007, 626(1-2), 143-154.
[http://dx.doi.org/10.1016/j.mrgentox.2006.09.010] [PMID: 17141554]
[15]
Nuran Ercal, B.S.P.; Hande Gurer-Orhan, B.S.P.; Nukhet Aykin-Burns, B.S.P. Toxic metals and oxidative stress Part I: Mechanisms involved in Me-Tal induced oxidative damage. Curr. Top. Med. Chem., 2005, 1(6), 529-539.
[http://dx.doi.org/10.2174/1568026013394831] [PMID: 16022675]
[16]
Dixon, S.J.; Stockwell, B.R. The role of iron and reactive oxygen species in cell death. Nat. Chem. Biol., 2014, 10(1), 9-17.
[http://dx.doi.org/10.1038/nchembio.1416] [PMID: 24346035]
[17]
Harrison, D.; Griendling, K.K.; Landmesser, U.; Hornig, B.; Drexler, H. Role of oxidative stress in atherosclerosis. Am. J. Cardiol., 2003, 91(3A), 7A-11A.
[http://dx.doi.org/10.1016/S0002-9149(02)03144-2] [PMID: 12645638]
[18]
Waris, G.; Ahsan, H. Reactive oxygen species: role in the development of cancer and various chronic conditions. J. Carcinog., 2006, 5, 14.
[http://dx.doi.org/10.1186/1477-3163-5-14] [PMID: 16689993]
[19]
Volpe, C.M.O.; Villar-Delfino, P.H.; Dos Anjos, P.M.F.; Nogueira-Machado, J.A. Cellular death, reactive oxygen species (ROS) and diabetic complications. Cell Death Dis., 2018, 9(2), 119.
[http://dx.doi.org/10.1038/s41419-017-0135-z] [PMID: 29371661]
[20]
Houstis, N.; Rosen, E.D.; Lander, E.S. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature, 2006, 440(7086), 944-948.
[http://dx.doi.org/10.1038/nature04634] [PMID: 16612386]
[21]
Sung, J.Y.; Hong, J.H.; Kang, H.S.; Choi, I.; Lim, S.D.; Lee, J.K.; Seok, J.H.; Lee, J.H.; Hur, G.M. Methotrexate suppresses the interleukin-6 induced generation of reactive oxygen species in the synoviocytes of rheumatoid arthritis. Immunopharmacology, 2000, 47(1), 35-44.
[http://dx.doi.org/10.1016/S0162-3109(99)00185-X] [PMID: 10708808]
[22]
Christophe, M.; Nicolas, S. Mitochondria: a target for neuroprotective interventions in cerebral ischemia-reperfusion. Curr. Pharm. Des., 2006, 12(6), 739-757.
[http://dx.doi.org/10.2174/138161206775474242] [PMID: 16472163]
[23]
Kalogeris, T.; Bao, Y.; Korthuis, R.J. Mitochondrial reactive oxygen species: a double edged sword in ischemia/reperfusion vs preconditioning. Redox Biol., 2014, 2, 702-714.
[http://dx.doi.org/10.1016/j.redox.2014.05.006] [PMID: 24944913]
[24]
Shah, M.S.; Brownlee, M. Molecular and cellular mechanisms of cardiovascular disorders in diabetes. Circ. Res., 2016, 118(11), 1808-1829.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.306923] [PMID: 27230643]
[25]
Misra, M.K.; Sarwat, M.; Bhakuni, P.; Tuteja, R.; Tuteja, N. Oxidative stress and ischemic myocardial syndromes. Med. Sci. Monit., 2009, 15(10), RA209-RA219.
[PMID: 19789524]
[26]
Willcox, J.K.; Ash, S.L.; Catignani, G.L. Antioxidants and prevention of chronic disease. Crit. Rev. Food Sci. Nutr., 2004, 44(4), 275-295.
[http://dx.doi.org/10.1080/10408690490468489] [PMID: 15462130]
[27]
Cadenas, E.; Davies, K.J.A. Mitochondrial free radical generation, oxidative stress, and aging. Free Radic. Biol. Med., 2000, 29(3-4), 222-230.
[http://dx.doi.org/10.1016/S0891-5849(00)00317-8] [PMID: 11035250]
[28]
Poli, G.; Leonarduzzi, G.; Biasi, F.; Chiarpotto, E. Oxidative stress and cell signalling. Curr. Med. Chem., 2004, 11(9), 1163-1182.
[http://dx.doi.org/10.2174/0929867043365323] [PMID: 15134513]
[29]
Casetta, I.; Govoni, V.; Granieri, E. Oxidative stress, antioxidants and neurodegenerative diseases. Curr. Pharm. Des., 2005, 11(16), 2033-2052.
[http://dx.doi.org/10.2174/1381612054065729] [PMID: 15974957]
[30]
Okayama, Y. Oxidative stress in allergic and inflammatory skin diseases. Curr. Drug Targets Inflamm. Allergy, 2005, 4(4), 517-519.
[http://dx.doi.org/10.2174/1568010054526386] [PMID: 16127829]
[31]
Smith, A.R.; Shenvi, S.V.; Widlansky, M.; Suh, J.H.; Hagen, T.M. Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress. Curr. Med. Chem., 2004, 11(9), 1135-1146.
[http://dx.doi.org/10.2174/0929867043365387] [PMID: 15134511]
[32]
Ma, Q. Advances in mechanisms of anti-oxidation. Discov. Med., 2014, 17(93), 121-130.
[PMID: 24641954]
[33]
Virdis, A.; Duranti, E.; Taddei, S. Oxidative stress and vascular damage in hypertension: role of angiotensin II. Int. J. Hypertens., 2011, 2011, 916310.
[http://dx.doi.org/10.4061/2011/916310] [PMID: 21747985]
[34]
Schmitt, F.J.; Renger, G.; Friedrich, T.; Kreslavski, V.D.; Zharmukhamedov, S.K.; Los, D.A.; Kuznetsov, V.V.; Allakhverdiev, S.I. Reactive oxygen species: re-evaluation of generation, monitoring and role in stress-signaling in phototrophic organisms. Biochim. Biophys. Acta, 2014, 1837(6), 835-848.
[http://dx.doi.org/10.1016/j.bbabio.2014.02.005] [PMID: 24530357]
[35]
Fakhruddin, S.; Alanazi, W.; Jackson, K.E. Diabetes-induced reactive oxygen species: mechanism of their generation and role in renal injury. J. Diabetes Res., 2017, 2017, 8379327.
[http://dx.doi.org/10.1155/2017/8379327] [PMID: 28164134]
[36]
Kaneto, H.; Katakami, N.; Matsuhisa, M.; Matsuoka, T.A. Role of reactive oxygen species in the progression of type 2 diabetes and atherosclerosis. Mediators Inflamm., 2010, 2010453892
[http://dx.doi.org/10.1155/2010/453892] [PMID: 20182627]
[37]
Bhosale, U.A.; Yegnanarayan, R.; Pophale, P.; Somani, R. Effect of aqueous extracts of Achyranthes aspera Linn. on experimental animal model for inflammation. Anc. Sci. Life, 2012, 31(4), 202-206.
[http://dx.doi.org/10.4103/0257-7941.107362] [PMID: 23661870]
[38]
Lakshmi, V.; Mahdi, A.; Sharma, D.; Agarwal, S. An Overview of Achyranthes Aspera Linn. J. Sci. Innov. Res., 2018, 7(1), 27-29.
[39]
Srivastav, S.; Singh, P.; Mishra, G.; Jha, K.K.; Khosa, R.L. Achyranthes aspera-an important medicinal plant : a review. J. Nat. Prod. Plant Resour., 2011, 1(1), 1-14.
[40]
Elumalai, E.K.; Chandrasekaran, N.; Thirumalai, T.; Sivakumar, C.; Therasa, S.V.; David, E. Achyranthes aspera leaf extracts inhibited fungal growth. Int. J. Pharm. Tech. Res., 2009, 1(4), 1576-1579.
[41]
Rani, N.; Sharma, S.K.; Vasudeva, N. Assessment of Antiobesity Potential of Achyranthes aspera Linn. Seed. Evid. Based Complement. Alternat. Med., 2012, 2012, 715912.
[http://dx.doi.org/10.1155/2012/715912] [PMID: 22919417]
[42]
Barua, C.C.; Talukdar, A.; Begum, S.A.; Pathak, D.C.; Sarma, D.K.; Borah, R.S.; Gupta, A. In vivo wound-healing efficacy and antioxidant activity of Achyranthes aspera in experimental burns. Pharm. Biol., 2012, 50(7), 892-899.
[http://dx.doi.org/10.3109/13880209.2011.642885] [PMID: 22480137]
[43]
Vijaya Kumar, S.; Sankar, P.; Varatharajan, R. Anti-Inflammatory activity of roots of Achyranthes aspera. Pharm. Biol., 2009, 47(10), 973-975.
[http://dx.doi.org/10.1080/13880200902967979]
[44]
Gawande, D.Y.; Druzhilovsky, D.; Gupta, R.C.; Poroikov, V.; Goel, R.K. Anticonvulsant activity and acute neurotoxic profile of Achyranthes aspera Linn. J. Ethnopharmacol., 2017, 202, 97-102.
[http://dx.doi.org/10.1016/j.jep.2017.03.018] [PMID: 28315457]
[45]
Das, A.K.; Bigoniya, P.; Verma, N.K.; Rana, A.C. Gastroprotective effect of Achyranthes aspera Linn. leaf on rats. Asian Pac. J. Trop. Med., 2012, 5(3), 197-201.
[http://dx.doi.org/10.1016/S1995-7645(12)60024-8] [PMID: 22305784]
[46]
Vasudeva, N.; Sharma, S.K. Post-coital antifertility activity of Achyranthes aspera Linn. root. J. Ethnopharmacol., 2006, 107(2), 179-181.
[http://dx.doi.org/10.1016/j.jep.2006.03.009] [PMID: 16725289]
[47]
Srivastav, S.; Plants, A.; Singh, P.; Mishra, G.; Srivastava, S.; Studies, M. Diuretic activity of whole plant extract of Achyranthus aspera Linn. Eur. J. Exp. Biol., 2011, 1, 97-102.
[48]
Khan, N.; Akhtar, M.S.; Khan, B.A. Braga, Vde.A.; Reich, A. Antiobesity, hypolipidemic, antioxidant and hepatoprotective effects of Achyranthes aspera seed saponins in high cholesterol fed albino rats. Arch. Med. Sci., 2015, 11(6), 1261-1271.
[http://dx.doi.org/10.5114/aoms.2015.56353] [PMID: 26788089]
[49]
Priya, C.L.; Kumar, G.; Karthik, L.; Rao, K.V.B. Antioxidant activity of Achyranthes aspera Linn stem extracts. Pharmacologyonline, 2010, 2, 228-237.
[50]
Khan, M.T.J.; Ahmad, K.; Alvi, M.N. Noor-Ul-Amin; Mansoor, B.; Asif Saeed, M.; Khan, F. Z.; Jamshaid, M. Antibacterial and irritant activities of organic solvent extracts of Agave americana linn., Albizzia lebbek benth. Achyranthes aspera linn, and Abutilon indicum linn - a preliminary investigation. Pak. J. Zool., 2010, 42(1), 93-97.
[51]
Talreja, T.; Kumar, M.; Goswami, A.; Gahlot, G. HPLC analysis of saponins in Achyranthes aspera and cissus quadrangularis. J. Pharmacogn. Phytochem., 2017, 6(1), 89-92.
[52]
Cotelle, N. Role of flavonoids in oxidative stress. Curr. Top. Med. Chem., 2001, 1(6), 569-590.
[http://dx.doi.org/10.2174/1568026013394750] [PMID: 11895132]
[53]
de Andrade Teles, R.B.; Diniz, T.C.; Costa Pinto, T.C.; de Oliveira Júnior, R.G.; Gama, E. Silva, M.; de Lavor, É.M.; Fernandes, A.W.C.; de Oliveira, A.P.; de Almeida Ribeiro, F.P.R.; da Silva, A.A.M.; Cavalcante, T.C.F.; Quintans Júnior, L.J.; da Silva Almeida, J.R.G. Flavonoids as therapeutic agents in alzheimer’s and parkinson’s diseases: a systematic review of preclinical evidences. Oxid. Med. Cell. Longev., 2018, 2018, 7043213.
[http://dx.doi.org/10.1155/2018/7043213] [PMID: 29861833]
[54]
Vidhya, R.; Rajiv Gandhi, G.; Jothi, G.; Radhika, J.; Brindha, P. Evaluation of antidiabetic potential of achyranthes aspera linn. on alloxan induced diabetic animals. Int. J. Pharm. Pharm. Sci., 2012, 4(Suppl. 5), 577-580.
[55]
Firdaus, F.; Zafeer, M.F.; Anis, E.; Ahmad, M.; Afzal, M. Ellagic acid attenuates arsenic induced neuro-inflammation and mitochondrial dysfunction associated apoptosis. Toxicol. Rep., 2018, 5, 411-417.
[http://dx.doi.org/10.1016/j.toxrep.2018.02.017] [PMID: 29854611]
[56]
Huxtable, R.J. Handbook of Experimental Pharmacology Volume 93: Pharmacology of Antihypertensive Therapeutics;, 1990, 11
[57]
Freedman, A.D. Handbook of Experimental Pharmacology Vol 14. Arch. Intern. Med., 1972, 130(2), 302.
[http://dx.doi.org/10.1001/archinte.1972.03650020118031]
[58]
Kandhare, A.D.; Raygude, K.S.; Ghosh, P.; Ghule, A.E.; Bodhankar, S.L. Neuroprotective effect of naringin by modulation of endogenous biomarkers in streptozotocin induced painful diabetic neuropathy. Fitoterapia, 2012, 83(4), 650-659.
[http://dx.doi.org/10.1016/j.fitote.2012.01.010] [PMID: 22343014]
[59]
Dureshahwar, K.; Mubashir, M.; Une, H.D. Quantification of quercetin obtained from Allium cepa lam. leaves and its effects on streptozotocin-induced diabetic neuropathy. Pharmacognosy Res., 2017, 9(3), 287-293.
[http://dx.doi.org/10.4103/pr.pr_147_16] [PMID: 28827972]
[60]
Ravi, K.; Ramachandran, B.; Subramanian, S. Protective effect of Eugenia jambolana seed kernel on tissue antioxidants in streptozotocin-induced diabetic rats. Biol. Pharm. Bull., 2004, 27(8), 1212-1217.
[http://dx.doi.org/10.1248/bpb.27.1212] [PMID: 15305024]
[61]
Akbarzadeh, A.; Norouzian, D.; Farhangi, A.; Mehrabi, M.R.; Jamshidi, S.; Zare, D.; Shafiei, M. Isolation and purification of rat islet cells by flow cytometry. Indian J. Clin. Biochem., 2008, 23(1), 57-61.
[http://dx.doi.org/10.1007/s12291-008-0014-6] [PMID: 23105722]
[62]
Eruslanov, E.; Kusmartsev, S. Identification of ROS using oxidized DCFDA and flow-cytometry. Methods Mol. Biol., 2010, 594, 57-72.
[http://dx.doi.org/10.1007/978-1-60761-411-1_4] [PMID: 20072909]
[63]
Kauffman, M.E.; Kauffman, M.K.; Traore, K.; Zhu, H.; Trush, M.A.; Jia, Z.; Li, Y.R. MitoSOX-Based flow cytometry for detecting mitochondrial ROS. React. Oxyg. Species (Apex), 2016, 2(5), 361-370.
[http://dx.doi.org/10.20455/ros.2016.865] [PMID: 29721549]
[64]
Woolley, J.F.; Stanicka, J.; Cotter, T.G. Recent advances in reactive oxygen species measurement in biological systems. Trends Biochem. Sci., 2013, 38(11), 556-565.
[http://dx.doi.org/10.1016/j.tibs.2013.08.009] [PMID: 24120034]
[65]
Dallakyan, S.; Olson, A.J. Small-molecule library screening by docking with PyRx. Methods Mol. Biol., 2015, 1263, 243-250.
[http://dx.doi.org/10.1007/978-1-4939-2269-7_19] [PMID: 25618350]
[66]
Miyata, T. Discovery studio modeling environment. Ensemble, 2015, 17(2), 98-104.
[67]
Rappé, A.K.; Casewit, C.J.; Colwell, K.S.; Goddard, W.A.; Skiff, W.M. UFF, A full periodic table force field for molecular mechanics and molecular dynamics simulations. J. Am. Chem. Soc., 1992, 114(25), 10024-10035.
[http://dx.doi.org/10.1021/ja00051a040]
[68]
Porubsky, P.R.; Battaile, K.P.; Scott, E.E. Human cytochrome P450 2E1 structures with fatty acid analogs reveal a previously unobserved binding mode. J. Biol. Chem., 2010, 285(29), 22282-22290.
[http://dx.doi.org/10.1074/jbc.M110.109017] [PMID: 20463018]
[69]
Khan, S.L.; Siddiqui, F.A.; Jain, S.P.; Sonwane, G.M. Discovery of Potential Inhibitors of SARS-CoV-2 (COVID-19) Main Protease (Mpro) from Nigella Sativa (Black Seed) by Molecular Docking Study; Coronaviruses, 2020, p. 1.
[http://dx.doi.org/10.2174/2666796701999200921094103]
[70]
Brunetti, C.; Di Ferdinando, M.; Fini, A.; Pollastri, S.; Tattini, M. Flavonoids as antioxidants and developmental regulators: relative significance in plants and humans. Int. J. Mol. Sci., 2013, 14(2), 3540-3555.
[http://dx.doi.org/10.3390/ijms14023540] [PMID: 23434657]
[71]
Baydas, G.; Sonkaya, E.; Tuzcu, M.; Yasar, A.; Donder, E. Novel role for gabapentin in neuroprotection of central nervous system in streptozotocine-induced diabetic rats. Acta Pharmacol. Sin., 2005, 26(4), 417-422.
[http://dx.doi.org/10.1111/j.1745-7254.2005.00072.x] [PMID: 15780189]

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