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CNS & Neurological Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Research Article

Neuroprotective Efficacy of Edaravone against Arsenic-Induced Behavioral and Neurochemical Deficits in Rats: Amelioration of Cholinergic and Mitochondrial Functions

Author(s): Mandeep K. Arora*, Deepika Singh, Ritu Tomar and Ashok Jangra*

Volume 22, Issue 1, 2023

Published on: 01 April, 2022

Page: [125 - 136] Pages: 12

DOI: 10.2174/1871527321666220225112241

open access plus

Abstract

Background: A substantial amount of evidence indicates that long-term arsenic exposure leads to various types of pathological complications, especially cognitive dysfunction.

Objective: The present study was designed to assess the neuroprotective potential of edaravone (a potent free radical scavenger) against arsenic-induced neurotoxicity in Wistar rats.

Methods: Adult male Wistar rats were randomly divided into five groups. Arsenic (20 mg/kg/day; p.o.) and Edaravone (5 and 10 mg/kg/day; i.p.) were administered in different experimental groups for 28 days.

Results: The results of various behavioral test paradigms revealed that arsenic caused significant learning and memory deficits, along with anxiety-like behavior. In biochemical analysis, we found marked elevations of oxidative-nitrosative stress (indicated by augmentation of lipid peroxidation and nitrite) and a reduction of glutathione levels in the hippocampus and frontal cortex region of arsenictreated rats. Moreover, arsenic administration caused mitochondrial complexes impairment and reduction of acetylcholinesterase level. On the other hand, chronic treatment with edaravone (10 mg/kg) significantly ameliorated the arsenic-induced behavioral deficits and neurochemical anomalies.

Conclusion: This study suggests that edaravone confers neuroprotection against arsenic-induced memory impairment and anxiety-like behavior, which may be attributed to the inhibition of oxidativenitrosative stress and amelioration of cholinergic and mitochondrial functions.

Keywords: Arsenic, edaravone, oxidative-nitrosative stress, neurotoxicity, cognitive deficits, hippocampus.

[1]
Yadav RS, Shukla RK, Sankhwar ML, et al. Neuroprotective effect of curcumin in arsenic-induced neurotoxicity in rats. Neurotoxicology 2010; 31(5): 533-9.
[http://dx.doi.org/10.1016/j.neuro.2010.05.001] [PMID: 20466022]
[2]
Vahidnia A, Romijn F, van der Voet GB, de Wolff FA. Arsenic-induced neurotoxicity in relation to toxicokinetics: Effects on sciatic nerve proteins. Chem Biol Interact 2008; 176(2-3): 188-95.
[http://dx.doi.org/10.1016/j.cbi.2008.07.001] [PMID: 18674524]
[3]
Manna P, Sinha M, Sil PC. Arsenic-induced oxidative myocardial injury: Protective role of arjunolic acid. Arch Toxicol 2008; 82(3): 137-49.
[http://dx.doi.org/10.1007/s00204-007-0272-8] [PMID: 18197399]
[4]
Soni M, Prakash C, Dabur R, Kumar V. Protective effect of hydroxytyrosol against oxidative stress mediated by arsenic-induced neurotoxicity in rats. Appl Biochem Biotechnol 2018; 186(1): 27-39.
[http://dx.doi.org/10.1007/s12010-018-2723-5] [PMID: 29497947]
[5]
Nelson-Mora J, Escobar ML, Rodríguez-Durán L, et al. Gestational exposure to inorganic arsenic (iAs3+) alters glutamate disposition in the mouse hippocampus and ionotropic glutamate receptor expression leading to memory impairment. Arch Toxicol 2018; 92(3): 1037-48.
[http://dx.doi.org/10.1007/s00204-017-2111-x] [PMID: 29204679]
[6]
Singh AP, Goel RK, Kaur T. Mechanisms pertaining to arsenic toxicity. Toxicol Int 2011; 18(2): 87-93.
[http://dx.doi.org/10.4103/0971-6580.84258] [PMID: 21976811]
[7]
Chandravanshi LP, Gupta R, Shukla RK. Developmental neurotoxicity of arsenic: Involvement of oxidative stress and mitochondrial functions. Biol Trace Elem Res 2018; 186(1): 185-98.
[http://dx.doi.org/10.1007/s12011-018-1286-1] [PMID: 29502250]
[8]
Jangra A, Kwatra M, Singh T, et al. Edaravone alleviates cisplatin-induced neurobehavioral deficits via modulation of oxidative stress and inflammatory mediators in the rat hippocampus. Eur J Pharmacol 2016; 791(791): 51-61.
[http://dx.doi.org/10.1016/j.ejphar.2016.08.003] [PMID: 27492363]
[9]
Liu Z, Yang C, Meng X, Li Z, Lv C, Cao P. Neuroprotection of edaravone on the hippocampus of kainate-induced epilepsy rats through Nrf2/HO-1 pathway. Neurochem Int 2018; 112: 159-65.
[http://dx.doi.org/10.1016/j.neuint.2017.07.001] [PMID: 28697972]
[10]
Ren Y, Wei B, Song X, et al. Edaravone’s free radical scavenging mechanisms of neuroprotection against cerebral ischemia: Review of the literature. Int J Neurosci 2015; 125(8): 555-65.
[http://dx.doi.org/10.3109/00207454.2014.959121] [PMID: 25171224]
[11]
Takei K, Watanabe K, Yuki S, Akimoto M, Sakata T, Palumbo J. Edaravone and its clinical development for amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 2017; 18 (Suppl. 1): 5-10.
[http://dx.doi.org/10.1080/21678421.2017.1353101] [PMID: 28872907]
[12]
Zheng J, Chen X. Edaravone offers neuroprotection for acute diabetic stroke patients. Ir J Med Sci 2016; 185(4): 819-24.
[http://dx.doi.org/10.1007/s11845-015-1371-9] [PMID: 26597952]
[13]
Sriram CS, Jangra A, Gurjar SS, Mohan P, Bezbaruah BK. Edaravone abrogates LPS-induced behavioral anomalies, neuroinflammation and PARP-1. Physiol Behav 2016; 154: 135-44.
[http://dx.doi.org/10.1016/j.physbeh.2015.10.029] [PMID: 26522738]
[14]
Datusalia AK, Sharma SS. Amelioration of diabetes-induced cognitive deficits by GSK-3β inhibition is attributed to modulation of neurotransmitters and neuroinflammation. Mol Neurobiol 2014; 50(2): 390-405.
[http://dx.doi.org/10.1007/s12035-014-8632-x] [PMID: 24420785]
[15]
Vorhees CV, Williams MT. Morris water maze: Procedures for assessing spatial and related forms of learning and memory. Nat Protoc 2006; 1(2): 848-58.
[http://dx.doi.org/10.1038/nprot.2006.116] [PMID: 17406317]
[16]
Rajput P, Jangra A, Kwatra M, Mishra A, Lahkar M. Alcohol aggravates stress-induced cognitive deficits and hippocampal neurotoxicity: Protective effect of melatonin. Biomed Pharmacother 2017; 91: 457-66.
[http://dx.doi.org/10.1016/j.biopha.2017.04.077] [PMID: 28477462]
[17]
Jangra A, Sriram CS, Lahkar M. Lipopolysaccharide-induced behavioral alterations are alleviated by sodium phenylbutyrate via attenuation of oxidative stress and neuroinflammatory cascade. Inflammation 2016; 39(4): 1441-52.
[http://dx.doi.org/10.1007/s10753-016-0376-5] [PMID: 27192986]
[18]
Walf AA, Frye CA. The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2007; 2(2): 322-8.
[http://dx.doi.org/10.1038/nprot.2007.44] [PMID: 17406592]
[19]
Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95(2): 351-8.
[http://dx.doi.org/10.1016/0003-2697(79)90738-3] [PMID: 36810]
[20]
Ellman GL, Courtney KD, Andres V Jr, Feather-Stone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 1961; 7(2): 88-95.
[http://dx.doi.org/10.1016/0006-2952(61)90145-9] [PMID: 13726518]
[21]
Swamy M, Suhaili D, Sirajudeen KN, Mustapha Z, Govindasamy C. Propolis ameliorates tumor nerosis factor-α nitric oxide levels, caspase-3 and nitric oxide synthase activities in kainic acid mediated excitotoxicity in rat brain. Afr J Tradit Complement Altern Med 2014; 11(5): 48-53.
[http://dx.doi.org/10.4314/ajtcam.v11i5.8] [PMID: 25395704]
[22]
Rosenthal NE, Sack DA, Gillin JC, et al. Seasonal affective disorder. A description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry 1984; 41(1): 72-80.
[http://dx.doi.org/10.1001/archpsyc.1984.01790120076010] [PMID: 6581756]
[23]
King TE, Howard RL. Preparations and properties of soluble NADH dehydrogenases from cardiac muscle. Methods Enzymol 1967; 10: 275-94.
[http://dx.doi.org/10.1016/0076-6879(67)10055-4]
[24]
Prakash C, Soni M, Kumar V. Mitochondrial oxidative stress and dysfunction in arsenic neurotoxicity: A review. J Appl Toxicol 2016; 36(2): 179-88.
[http://dx.doi.org/10.1002/jat.3256] [PMID: 26510484]
[25]
Sottocasa GL, Kuylenstierna B, Ernster L, Bergstrand A. An electron-transport system associated with the outer membrane of liver mitochondria. A biochemical and morphological study. J Cell Biol 1967; 32(2): 415-38.
[http://dx.doi.org/10.1083/jcb.32.2.415] [PMID: 10976232]
[26]
Keshavarz-Bahaghighat H, Sepand MR, Ghahremani MH, et al. Acetyl-L-carnitine attenuates arsenic-induced oxidative stress and hippocampal mitochondrial dysfunction. Biol Trace Elem Res 2018; 184(2): 422-35.
[http://dx.doi.org/10.1007/s12011-017-1210-0] [PMID: 29189995]
[27]
Sun H, Yang Y, Shao H, et al. Sodium arsenite-induced learning and memory impairment is associated with endoplasmic reticulum stress-mediated apoptosis in rat hippocampus. Front Mol Neurosci 2017; 10: 286.
[http://dx.doi.org/10.3389/fnmol.2017.00286] [PMID: 28936164]
[28]
Yadav RS, Chandravanshi LP, Shukla RK, et al. Neuroprotective efficacy of curcumin in arsenic induced cholinergic dysfunctions in rats. Neurotoxicology 2011; 32(6): 760-8.
[http://dx.doi.org/10.1016/j.neuro.2011.07.004] [PMID: 21839772]
[29]
Jangra A, Sriram CS, Dwivedi S, et al. Sodium phenylbutyrate and edaravone abrogate chronic restraint stress-induced behavioral deficits: Implication of oxido-nitrosative, endoplasmic reticulum stress cascade, and neuroinflammation. Cell Mol Neurobiol 2017; 37(1): 65-81.
[http://dx.doi.org/10.1007/s10571-016-0344-5] [PMID: 26886752]
[30]
Rodríguez-Barranco M, Lacasaña M, Aguilar-Garduño C, et al. Association of arsenic, cadmium and manganese exposure with neurodevelopment and behavioural disorders in children: A systematic review and meta-analysis. Sci Total Environ 2013; 454-455: 562-77.
[http://dx.doi.org/10.1016/j.scitotenv.2013.03.047] [PMID: 23570911]
[31]
Goudarzi M, Amiri S, Nesari A, Hosseinzadeh A, Mansouri E, Mehrzadi S. The possible neuroprotective effect of ellagic acid on sodium arsenate-induced neurotoxicity in rats. Life Sci 2018; 198: 38-45.
[http://dx.doi.org/10.1016/j.lfs.2018.02.022] [PMID: 29455002]
[32]
Guan H, Li S, Guo Y, et al. Subchronic exposure to arsenic represses the TH/TRβ1-CaMK IV signaling pathway in mouse cerebellum. Int J Mol Sci 2016; 17(2): 157.
[http://dx.doi.org/10.3390/ijms17020157] [PMID: 26821021]
[33]
Fan MQ, Zhi-Qu Z, Ping Z. [Effects of arsenic on nerve growth factor and nerve growth related mRNA expression in F1 hippocampal] Sichuan Da Xue Xue Bao Yi Xue Ban 2013; 44(1): 53-6.
[PMID: 23600209]
[34]
Firdaus F, Zafeer MF, Waseem M, Ullah R, Ahmad M, Afzal M. Thymoquinone alleviates arsenic induced hippocampal toxicity and mitochondrial dysfunction by modulating mPTP in Wistar rats. Biomed Pharmacother 2018; 102: 1152-60.
[http://dx.doi.org/10.1016/j.biopha.2018.03.159] [PMID: 29710533]
[35]
Jomova K, Valko M. Advances in metal-induced oxidative stress and human disease. Toxicology 2011; 283(2-3): 65-87.
[http://dx.doi.org/10.1016/j.tox.2011.03.001] [PMID: 21414382]
[36]
Thakur M, Rachamalla M, Niyogi S, Datusalia AK, Flora SJS. Molecular mechanism of arsenic-induced neurotoxicity including neuronal dysfunctions. Int J Mol Sci 2021; 22(18): 10077.
[http://dx.doi.org/10.3390/ijms221810077] [PMID: 34576240]
[37]
Tyler CR, Allan AM. The effects of arsenic exposure on neurological and cognitive dysfunction in human and rodent studies: A review. Curr Environ Health Rep 2014; 1(2): 132-47.
[http://dx.doi.org/10.1007/s40572-014-0012-1] [PMID: 24860722]
[38]
Dhull DK, Kumar A. Tramadol ameliorates behavioural, biochemical, mitochondrial and histological alterations in ICV-STZ-induced sporadic dementia of Alzheimer’s type in rats. Inflammopharmacology 2018; 26(4): 925-38.
[http://dx.doi.org/10.1007/s10787-017-0431-3] [PMID: 29249049]
[39]
Jangra A, Datusalia AK, Sharma SS. Reversal of neurobehavioral and neurochemical alterations in STZ-induced diabetic rats by FeTMPyP, a peroxynitrite decomposition catalyst and 1,5-Isoquinolinediol a poly(ADP-ribose) polymerase inhibitor. Neurol Res 2014; 36(7): 619-26.
[http://dx.doi.org/10.1179/1743132813Y.0000000301] [PMID: 24620961]
[40]
Kasbe P, Jangra A, Lahkar M. Mangiferin ameliorates aluminium chloride-induced cognitive dysfunction via alleviation of hippocampal oxido-nitrosative stress, proinflammatory cytokines and acetylcholinesterase level. J Trace Elem Med Biol 2015; 31: 107-12.
[http://dx.doi.org/10.1016/j.jtemb.2015.04.002] [PMID: 26004900]
[41]
He F, Cao YP, Che FY, Yang LH, Xiao SH, Liu J. Inhibitory effects of edaravone in β-amyloid-induced neurotoxicity in rats. BioMed Res Int 2014; 2014: 370368.
[http://dx.doi.org/10.1155/2014/370368] [PMID: 24804216]
[42]
Sharma B, Sharma PM. Arsenic toxicity induced endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors. Toxicol Appl Pharmacol 2013; 273(1): 180-8.
[http://dx.doi.org/10.1016/j.taap.2013.07.017] [PMID: 23921152]
[43]
Meyer JN, Leung MC, Rooney JP, et al. Mitochondria as a target of environmental toxicants. Toxicol Sci 2013; 134(1): 1-17.
[http://dx.doi.org/10.1093/toxsci/kft102] [PMID: 23629515]
[44]
Zhang GL, Zhang L, Guo YY, et al. Protective effect of edaravone against Aβ25-35-induced mitochondrial oxidative damage in SH-SY5Y cells. Cell Mol Biol 2017; 63(5): 36-42.
[http://dx.doi.org/10.14715/cmb/2017.63.5.8] [PMID: 28719344]
[45]
Takayasu Y, Nakaki J, Kawasaki T, et al. Edaravone, a radical scavenger, inhibits mitochondrial permeability transition pore in rat brain. J Pharmacol Sci 2007; 103(4): 434-7.
[http://dx.doi.org/10.1254/jphs.SC0070014] [PMID: 17409627]

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