IJAR.2023.276
Type of Article: Original Research
Volume 12; Issue 2 (June 2024)
Page No.: 8878-8892
DOI: https://dx.doi.org/10.16965/ijar.2023.276
Comparative Brain Microanatomical and Neurochemical Alterations Following the Administration of Seven Oral Artemisinin-Based Combination Therapies in Swiss Mice
PInnocent A. Edagha 1,2, Promise E. Douglas 1, Aniekan I. Peter 1,3, Aquaisua N. Aquaisua 1, Blessing C. Akpan 4, Edelungudi I. Edagha 5, Moses A. Ataben 1haka *, Peter Gichangi, Adel Abdelmalek, Paul Odula, Julius Ogeng’o.
Faculty of Health Sciences, University of Nairobi, P.O. Box 30197-00100 Nairobi, Kenya.
*1 Department of Human Anatomy, Faculty of Basic Medical Sciences, University of Uyo, Nigeria.
2 Department of Human Anatomy, School of Medicine, Moi University, Eldoret, Kenya.
3 Department of Anatomy, College of Health Sciences, Bowen University, Nigeria.
4 Department of Chemical Pathology, Federal Neuropsychiatric Hospital, Calabar, Nigeria.
5 Department of Family Medicine, Faculty of Clinical Science, University of Uyo Teaching Hospital, Nigeria.
ORCiD:
Innocent A. Edagha: 0000-0002-5979-7048
Promise E. Douglas: 0009-0004-6979-2007
Aniekan I. Peter: 0000-0002-1155-6368
Aquaisua N. Aquaisua: 0009-0001-9470-2307
Blessing C. Akpan: 0009-0003-2868-7019
Edelungudi I. Edagha: 0009-0001-4508-3378
Moses A. Ataben: 0000-0001-9312-2362
Corresponding author: Innocent A. Edagha, PhD, Department of Human Anatomy, Faculty of Basic Medical Sciences, University of Uyo, Nigeria. E-Mail: innocentedagha@uniuyo.edu.ng; innocentedagha@mu.ke.a
ABSTRACT
Over a decade after artemisinin-based combination therapy (ACT) approval as the most preferred anti-malarial drug. Seven ACTs can be sourced as over-the-counter medications in most African pharmacies without prescription. A comparative neurotoxicity of these ACTs was investigated in an in vivo experimental model. Swiss mice numbering 40, weighing 18 – 26 g were allotted to eight groups (n = 5). Group 1 (normal control [NC]), received distilled water 10 mL, while groups 2 to 8 were administered (5.71 mg artesunate+amodiaquine [AA]); (19.29 mg artesunate+mefloquine [AM]); (10.36 mg artesunate+sulfadoxine+pyrimethamine [ASP]); (19.29 mg artesunate+pyronaridine [APy]); (12.5 mg artemisinin+piperaquine [AP]); (15.42 mg dihydroartemisinin+piperaquine [DP]); and (8 mg artemether+lumefantrine [AL]) per kg body weights, respectively orally for 3 days, but for 2 days in group 6. Animals were sacrificed 24 hrs after last administration under ketamine anaesthesia (100 mg/kg, i.p), and excised brains were evaluated for neurochemical and neurohistological alterations. Oxidative stress markers: malondialdehyde and reduced glutathione significantly (p < 0.05) increased as well as antioxidant enzymes glutathione peroxidase, catalase, superoxide dismutase in ACT-administered groups compared to NC. Neurohistology of hippocampal cornu ammonis 1 (CA1) and cerebellum demonstrated vacuolations, neuronal hypertrophy and atrophy pyramidal, and Purkinje neurons. Immunohistochemistry with glial fibrillary acidic protein antibody demonstrated mild to mostly severe astrogliosis in the ACT-administered groups. In conclusion, oxidative stress markers and antioxidants were elevated in the order DP>APy>AP>ASP>AA>AL>AM. Together with the neurohistology, neurotoxicity were in the order DP>ASP>APy>AP>AL>AA>AM particularly in the hippocampus compared to the cerebellum.
Keywords: Artemisinin-based combination therapies, Cerebellum, CA1 region of the hippocampus, Neurodegeneration, Oxidative stress.
REFERENCES
[1]. World Health Organization (WHO). World malaria report 2022. World Health Organization, Geneva, 2022.
[2]. World Health Organization (WHO). Q & A on the malaria vaccine implementation programme (MVIP). Retrieved from https://www.who.int/malaria/media/malaria-vaccine-implementation-qa/en/ (accessed on 30 October 2022), 2022.
[3]. Charle P, Berzosa P, Descalzo M, de Lucio A, Raso J, Obono, J. Efficacy of artesunate + sulphadoxine‑pyrimethamine (AS + SP) and Amodiaquine + sulphadoxine‑pyrimethamine (AQ + SP) for Uncomplicated falciparum malaria in Equatorial Guinea (Central Africa). Journal of Tropical Medicine 2009; 781865.
https://doi.org/10.1155/2009/781865
PMid:20339460 PMCid:PMC2836821
[4]. Xia M, Liu D, LiuY, Liu H. The Therapeutic Effect of Artemisinin and Its Derivatives in Kidney Disease. Front Pharmacol 2020; 11:380.
https://doi.org/10.3389/fphar.2020.00380
PMid:32296335 PMCid:PMC7136752
[5]. Classen W, Altmann B, Gretener P, Souppart C, Skelton-Stroud P, Krinke G. Differential effects of orally versus parenterally administered quinghaosu derivative artemether in dogs. Experimental and Toxicology Pathology 1999; 51, 507-516.
https://doi.org/10.1016/S0940-2993(99)80128-6
PMid:10661809
[6]. Popoola AN, Imosemi, IO. Sub-acute evaluation of artesunate, amodiaquine and their combination on muscular coordination and morphology of the cerebellum of Wistar rats. International Journal of Biological and Chemical Science 2020; 14:1498-1510.
https://doi.org/10.4314/ijbcs.v14i5.1
[7]. Zeng Q, Qiu F, Yuan L. Production of artemisinin by genetically-modified microbes. Biotechnol Lett 2008; 30:581-592.
https://doi.org/10.1007/s10529-007-9596-y
PMid:18008167
[8]. Aronson J. Meyler’s Side Effects of Drugs Artemisinin derivatives, Sixth Edition. Elsevier, Philadelphia 2016; pp. 701-710.
https://doi.org/10.1016/B978-0-444-53717-1.00328-0
[9]. Kavishe R, Koenderink J, Alifrangis M. Oxidative stress in malaria and artemisinin combination therapy: Pros and Cons. FEBS J 2017; 284: 2579 – 2591.
https://doi.org/10.1111/febs.14097
PMid:28467668
[10]. Li W, Mo W, Shen D, Sun L, Wang J, Lu S, Gitschier, J, Zhou B. Yeast model uncovers dual roles of mitochondria in action of artemisinin. PLoS Genet 2005; 1:e36.
https://doi.org/10.1371/journal.pgen.0010036
PMid:16170412 PMCid:PMC1201371
[11]. LiY. Qinghaosu (artemisinin): chemistry and pharmacology. Acta Pharmacol. Sin2012; 33:1141-1146.
https://doi.org/10.1038/aps.2012.104
PMid:22922345 PMCid:PMC4003104
[12]. Davis T, Karunajeewa H, Ilett K. Artemisinin-based combination therapies for uncomplicated malaria. Med J Aust2005; 182:181-185.
https://doi.org/10.5694/j.1326-5377.2005.tb06650.x
PMid:15720175
[13]. Sugiarto S, Davis T, Salman S. Pharmacokinetic considerations for use of artemisinin-based combination therapies against falciparum malaria in different ethnic populations. Expert Opin Drug Metab Toxicol 2017; 13:1115 – 1133.
https://doi.org/10.1080/17425255.2017.1391212
PMid:29027504
[14]. Sidorova Y, Domanskyi A. Detecting Oxidative Stress Biomarkers in Neurodegenerative Disease Models and Patients. Methods Protoc 2020; 24: 3(4):66.
https://doi.org/10.3390/mps3040066
PMid:32987935 PMCid:PMC7712543
[15]. Borza C, Muntean D, Dehelean C, Săvoiu G, Şerban C, Simu G, Andoni M, Butur M, Drăgan S. Lipid Metabolism, Oxidative stress and lipid peroxidation-A lipid metabolism dysfunction. Rijeka, Croatia 2013; pp. 23-38.
https://doi.org/10.5772/51627
[16]. Pieme C, Tatangmo J, Simo G, Nya P, Moor V, Moukette B, Sobngwi E. Relationship between hyperglycemia, antioxidant capacity and some enzymatic and non-enzymatic antioxidants in African patients with type 2 diabetes. BMC Res. Notes 2017; 10:141.
https://doi.org/10.1186/s13104-017-2463-6
PMid:28356165 PMCid:PMC5372257
[17]. Ighodaro O, Akinloye O. First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): Their fundamental role in the entire antioxidant defence grid. Alex. J. Med 2018; 54: 287-293.
https://doi.org/10.1016/j.ajme.2017.09.001
[18]. Olayemi S, Arikawe A, Akinyede A, Oreagba A, Awodele O. Effect of malarial treatments on biochemical parameters and plasma pH of mice infected with Plasmodium berghei. Int J Pharmacol 2012; 8: 549 – 554.
https://doi.org/10.3923/ijp.2012.549.554
[19]. Bukola A. Biochemical Effect of Artemisinin-based Combination Therapy (ACT) Antimalarial Drugs on Enzymatic Antioxidants in Pregnancy. Advances in Clinical Toxicology 2016; 4: 10.
https://doi.org/10.23880/act-16000151
[20]. Edagha I, Offong O, Ekanem A, Edagha E, Asuquo I, Peter A, Azu O. Efficacy of six artemisinin-based combination therapies in the attenuation of Plasmodium berghei-induced testicular toxicity in Swiss mice. European Journal of Anatomy 2019; 23: 289 – 300.
[21]. Schmuck G, Roehrdanz E, Haynes K, Kahl R. Neurotoxic mode of action of artemisinin. Antimicrobial Agents Chemotherapy 2002; 46: 821 – 827.
https://doi.org/10.1128/AAC.46.3.821-827.2002
PMid:11850267 PMCid:PMC127487
[22]. Petras J, Young G, Bauman R, Kyle D, Gettayacamin M, Webster H. Artemether-induced brain injury in macaca mulatta. I. The precerebellar nuclei: the lateral reticular nuclei, paramedian reticular nuclei, and perihypoglossal nuclei. Anatomy and Embryology 2000; 201: 383 – 397.
https://doi.org/10.1007/s004290050326
PMid:10839633
[23]. Genovese R, Newman B, Li Q, Peggins J, Brewer T. Dose-dependent brainstem neuropathology following repeated arthemether administration in rats. Brain Research Bulletin 1998; 45:199 – 202.
https://doi.org/10.1016/S0361-9230(97)00339-0
PMid:9443840
[24]. Beckman D, Youreneff M, Butt M. Neurotoxicity assessment of artemether in juvenile rats. Birth Defects Research Part B Developmental and Reproductive Toxicology 2013; 98:183-99.
https://doi.org/10.1002/bdrb.21054
PMid:23495177
[25]. Bangirana P, John C, Boivin M. Rehabilitation for cognitive impairments after cerebral malaria in African children: strategies and limitations. Trop Med Int Health 2006; 11(9) :1341 – 1349.
https://doi.org/10.1111/j.1365-3156.2006.01685.x
PMid:16930255
[26]. Mwai L, Gwer S, Gatakaa H, Kokwaro G, Newton C. Neurotoxicity of antimalarial drugs: a systematic review. JBI Libr Syst Rev. 2008;6(12 Suppl):1-14.
https://doi.org/10.11124/jbisrir-2008-824
PMid:27820468
[27]. Fusetti M, Eibenstein A, CorridoreV, Hueck S, Chiti-Batelli S. Mefloquine and ototoxicity: a report of 3 cases. Clin Ter 1999; 150 :379‐82.
[28]. Ezzet F, van Vugt M, Nosten F, Looareesuwan S, White N. Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol) in acute falciparum malaria. Antimicrob Agents Chemother 2000; 44: 697 – 704.
https://doi.org/10.1128/AAC.44.3.697-704.2000
PMid:10681341 PMCid:PMC89749
[29]. Toovey S, Jamieson A. Response to artemisinin derivatives: toxic for laboratory animals, safe for humans? Toxicology Letters 2004; 151: 491 – 492.
https://doi.org/10.1016/j.toxlet.2004.05.004
[30]. Idro R, Marsh K, John C, Newton C. Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome. Pediatr Res 2010; 68(4):267-74.
https://doi.org/10.1203/PDR.0b013e3181eee738
PMid:20606600 PMCid:PMC3056312
[31]. Rénia L, Howland S, Claser C, Charlotte A, Suwanarusk R, Hui T, Russell B. Cerebral malaria: mysteries at the blood-brain barrier. Virulence 2012; 3(2) :193-201.
https://doi.org/10.4161/viru.19013
PMid:22460644 PMCid:PMC3396698
[32]. Solomon N. Hippocampus: Anatomy and functions. https://www.kenhub.com/en/library/anatomy/hippocampus-structure-and-functions (Retrieved on 22nd August, 2022).
[33]. Standring S. Gray’s Anatomy: The Anatomical Basis of Clinical Practice. 41st Edition. Elsevier Limited, London2016; pp 239, 309-311, 331-334.
[34]. National Research Council. Guide for the Care and Use of Laboratory Animals. The National Academies Press, Washington DC 2011; 246p.
[35]. Tveden-Nyborg P, Bergmann TK, Jessen N, Simonsen U, Lykkesfeldt J. BCPT 2023 policy for experimental and clinical studies. Basic Clin Pharmacol Toxicol. 2023 Oct;133(4):391-396.
https://doi.org/10.1111/bcpt.13944
PMid:37732406
[36]. Toney-Butler TJ, Nicolas S, Wilcox L. Dose Calculation Desired Over Have Formula Method. [Updated 2023 Jun 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. https://www.ncbi.nlm.nih.gov/books/NBK493162/
[37]. Everitt, J. I. and Gross, E. A. Euthanasia and Necropsy. In: The Laboratory Rat (Second Edition). American College of Laboratory Animal Medicine. 2006;665 – 678.
https://doi.org/10.1016/B978-012074903-4/50023-6
[38]. Ariweriokuma V, Arinrotimi A, Gabriel U. Effect of cypermethrin on condition factor and organosomatic indices of Clarias gariepinus. Journal of Agricultural and Social Research 2011; 11: 67-72.
[39]. Sedlak, J., Lindsay, R. Estimation of total, protein-bound and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal. Biochem. 1968;25:192-205.
https://doi.org/10.1016/0003-2697(68)90092-4
PMid:4973948
[40]. Buege, J.A., Aust, S.D. Microsomal lipid peroxidation. Methods Enzymol. 1978;52:302-310.
https://doi.org/10.1016/S0076-6879(78)52032-6
PMid:672633
[41]. Sun, M., Zigma, S., 1978. An improved spectrophotometric assay of superoxide dismutase based on ephinephrine antioxidation. Anal. Biochem. 1978;90:81-89.
https://doi.org/10.1016/0003-2697(78)90010-6
PMid:727489
[42]. Sinha, K.A., Calorimetric assay of catalase. Anal. Biochem. 1971;47:389-394
https://doi.org/10.1016/0003-2697(72)90132-7
PMid:4556490
[43]. Rotruck, JT., Pope AL., Ganther, HE., Swanson AB., Hageman DG., and Hoekstra WG. Selenium: Biochemical Role as a Component of Glutathione Peroxidase. Science 1973;179:588-590.
https://doi.org/10.1126/science.179.4073.588
PMid:4686466
[44]. Bancroft D, Layton C, Suvarna S. Bancroft’s Theory and Practice of Histological Techniques: Expert Consult: Online and Print, 8e. In Churchill Livingstone 2019; pp. 75 – 129.
[45]. Edagha I, Ekanem A, Usoh I, Umoh V, Ataben M, Akpan A. Brain antioxidants and hippocampal microanatomical alterations following the administration of Efavirenz/Lamivudine/Tenofovir disoproxil fumarate and Lamivudine/Nevirapine/Zidovudine in adult male Wistar rats. IBRO Neurosci Rep 2022; 13 (12): 210-216.
https://doi.org/10.1016/j.ibneur.2022.03.004
PMid:35340763 PMCid:PMC8941179
[46]. Klein, M., Picard, E., Vignaud, J.M., Marie, B., Bresler, L., Toussaint, B., Weryha, G., Duprez, A., Lecl’ere, J. Vascular endothelial growth factor gene and protein: strong expression in thyroiditis and thyroid carcinoma. J. Endocrinol. 1999;161:41-49.
https://doi.org/10.1677/joe.0.1610041
PMid:10194527
[47]. Rizzardi, A.E., Johnson, A.T., Vogel, R.I. et al. Quantitative comparison of immunohistochemical staining measured by digital image analysis versus pathologist visual scoring. Diagn Pathol 2012;7:42.
https://doi.org/10.1186/1746-1596-7-42
PMid:22515559 PMCid:PMC3379953
[48]. Efferth T, Kaina B. Toxicity of the antimalarial artemisinin and its derivatives. Crit Rev Toxicol, 2010; 40:405-21.
https://doi.org/10.3109/10408441003610571
PMid:20158370
[49]. German P, Aweeka F. Clinical pharmacology of artemisinin-based combination therapies. Clinical Pharmacokinetics2008; 47: 91-102.
https://doi.org/10.2165/00003088-200847020-00002
PMid:18193915
[50]. Grabias B, Kumar S. Adverse neuropsychiatric effects of antimalarial drugs. Expert Opin Drug Saf. 2016 Jul;15(7):903-10.
https://doi.org/10.1080/14740338.2016.1175428
PMid:27077782
[51]. Ong W, Go M, Wang Y, Cheah I, Halliwell B. Effects of Antimalarial Drugs on Neuroinflammation-Potential Use for Treatment of COVID-19-Related Neurologic Complications. Mol Neurobiol. 2021;58(1):106-117.
https://doi.org/10.1007/s12035-020-02093-z
PMid:32897518 PMCid:PMC7477069
[52]. Tindana P, de Haan F, Amaratunga C, Dhorda M, van der Pluijm RW, Dondorp AM, Cheah PY. Deploying triple artemisinin-based combination therapy (TACT) for malaria treatment in Africa: ethical and practical considerations. Malar J. 2021 Feb 27;20(1):119.
https://doi.org/10.1186/s12936-021-03649-7
PMid:33639946 PMCid:PMC7910789
[53]. Tilley L, Straimer J, Gnädig NF, Ralph SA, Fidock DA. Artemisinin Action and Resistance in Plasmodium falciparum. Trends Parasitol. 2016 Sep;32(9):682-696. https://doi.org/10.1016/j.pt.2016.05.010
PMid:27289273 PMCid:PMC5007624
[54]. Wang J, Zhang CJ, Chia WN, Loh CC, Li Z, Lee YM, He Y, Yuan LX, Lim TK, Liu M, Liew CX, Lee YQ, Zhang J, Lu N, Lim CT, Hua ZC, Liu B, Shen HM, Tan KS, Lin Q. Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum. Nat Commun. 2015 Dec 22;6:10111.
https://doi.org/10.1038/ncomms10111
PMid:26694030 PMCid:PMC4703832
[55]. Jiang YY, Shui JC, Zhang BX, Chin JW, Yue RS. The Potential Roles of Artemisinin and Its Derivatives in the Treatment of Type 2 Diabetes Mellitus. Front Pharmacol. 2020 Nov 26;11:585487.
https://doi.org/10.3389/fphar.2020.585487
PMid:33381036 PMCid:PMC7768903
[56]. Mamta M, Dhillon S, Brar S., Verma M. Antioxidants. Springer Science and Business media, New York, 2014.
https://doi.org/10.1007/978-1-4614-8005-1_6
[57]. Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev. 2014;2014:360438.
https://doi.org/10.1155/2014/360438
PMid:24999379 PMCid:PMC4066722
[58]. Otuechere CA, Edewor G, Kale OE, Ekor M. Subacute therapeutic dosing of artemether-lumefantrine and artesunate-amodiaquine combination preserves plasma cholesterol, renal antioxidant status, and organ weights in rats. Malar Res Treat;2012:257986.
https://doi.org/10.1155/2012/257986
PMid:22848861 PMCid:PMC3400373
[59]. Kavishe RA, Koenderink JB, Alifrangis M. Oxidative stress in malaria and artemisinin combination therapy: Pros and Cons. FEBS J. 2017 Aug;284(16):2579-2591.
https://doi.org/10.1111/febs.14097
PMid:28467668
[60]. Kumar K, Abbas K, Aster J. Robbins and Cotran Pathologic Basis of Disease,Seventh edition, Elsevier/Saunders, Philadelphia 2014; pp 234.
[61]. Mizuseki K, Diba K, Pastalkova E, Buzsáki G. Hippocampal CA1 pyramidal cells form functionally distinct sublayers. Nat Neurosci. 2011 Aug 7;14(9):1174-81.
https://doi.org/10.1038/nn.2894
PMid:21822270 PMCid:PMC3164922
[62]. DiSabato DJ, Quan N, Godbout JP. Neuroinflammation: the devil is in the details. J Neurochem. 2016 Oct;139 Suppl 2(Suppl 2):136-153.
https://doi.org/10.1111/jnc.13607
PMid:26990767 PMCid:PMC5025335
[63]. Özen I, Mai H, De Maio A. Purkinje cell vulnerability induced by diffuse traumatic brain injury is linked to disruption of long-range neuronal circuits. Acta Neuropathol Commun 2022; 10:129.
https://doi.org/10.1186/s40478-022-01435-3
PMid:36064443 PMCid:PMC9446851
[64]. Ahadiat, SA., Hosseinian, Z. Astrocytes’ innate role in neurodegenerative disorders. Bull Natl Res Cent. 2023;47:105.
https://doi.org/10.1186/s42269-023-01083-0
[65]. Kumar A, Fontana IC, Nordberg A. Reactive astrogliosis: A friend or foe in the pathogenesis of Alzheimer’s disease. J Neurochem. 2023 Feb;164(3):309-324.
https://doi.org/10.1111/jnc.15565
PMid:34931315
[66]. Talevi, A., Bellera, C.L. Enzyme Induction and Drug Metabolism. In: The ADME Encyclopedia. Springer, Cham. 2012;68-1.
https://doi.org/10.1007/978-3-030-51519-5_68-1
[67]. Tiono, A.B., Tinto, H., Alao, M.J. et al. Increased systemic exposures of artemether and dihydroartemisinin in infants under 5 kg with uncomplicated Plasmodium falciparum malaria treated with artemether-lumefantrine (Coartem®). Malar J. 2015;14(157).
https://doi.org/10.1186/s12936-015-0682-7
PMid:25886021 PMCid:PMC4407414
[68]. Gürkov, R. Eshetu, T., I. B. Miranda, I. B., Berens-Riha, N. Mamo, Y. Girma, T. Krause, E. Schmidt, M. Hempel, J. and Löscher, T. Ototoxicity of artemether/lumefantrine in the treatment of falciparum malaria: a randomized trial Malaria Journal 2008;7:179.
https://doi.org/10.1186/1475-2875-7-179
PMid:18796142 PMCid:PMC2559845
[69]. Edagha IA, Ekpo AJ, Edagha EI, Bassey JV, Nyong TP, Akpan AS, Obeten RF, Okon AS, Ating BA. Investigating the Comparative Effects of Six Artemisinin-based Combination Therapies on Plasmodium-induced Hepatorenal Toxicity. Niger Med J. 2019 Jul-Aug;60(4):211-218.
https://doi.org/10.4103/nmj.NMJ_152_18
PMid:31831942 PMCid:PMC6892336
