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NEUROLOGY / EXPERIMENTAL RESEARCH
The possible effect of coenzyme Q10 and captopril on acetaminophen-induced encephalopathy in rats: possible influence on autophagy, antioxidant and Na+/K+ ATPase
1
Medical Physiology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
2
Medical Physiology Department, Faculty of Medicine, Jouf University, Sakaka, Saudi Arabia
3
Histology and Cell Biology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
Submission date: 2020-01-10
Final revision date: 2020-04-13
Acceptance date: 2020-04-17
Online publication date: 2020-11-09
Publication date: 2026-01-16
Corresponding author
Heba M. Galal
Medical Physiology Department Faculty of Medicine Assiut University Assiut, Egypt Phone: 01000788437
Medical Physiology Department Faculty of Medicine Assiut University Assiut, Egypt Phone: 01000788437
Arch Med Sci 2025;21(6):2838-2855
KEYWORDS
acetaminophen-induced encephalopathybeclin-1coenzyme Q10captoprilhippocampusmicrotubule-associated protein light chain-3Na+/K+ ATPase
TOPICS
ABSTRACT
Introduction:
Induction of autophagy could protect against acetaminophen (APAP)-induced hepatotoxicity; however, little is known about the role of autophagy in APAP-induced encephalopathy (APAP-E). This study aimed to evaluate the effects of coenzyme Q10 (CoQ10) and captopril on APAP-E.
Material and methods:
Forty-eight rats were randomly allotted to 4 equal groups: control, an APAP-E, coenzyme Q10-treated (CoQ10-treated), and captopril-treated groups. Behavioral tests were conducted. Serum ammonia and total antioxidant capacity (TAC) and hippocampal Na+/K+ ATPase activity were measured. The expression levels of hippocampal microtubule-associated protein light chain 3 (LC3-II) and beclin-1 mRNA were detected using quantitative polymerase chain reaction (qPCR). General histological, immunohistochemical staining for glial fibrillary acid protein (GFAP) and electron microscopy (EM) of the hippocampus were performed.
Results:
In the APAP-E group, serum ammonia was increased significantly, hippocampal LC3-II and beclin-1 mRNA were elevated insignificantly, while serum TAC and the activity of hippocampal Na+/K+ ATPase were reduced significantly compared with the control group. APAP-E rats showed remarkable degenerative changes in CA1 pyramidal neurons in the form of electron-dense cytoplasm with ill-defined nuclei and accumulation of lysosomal structure-like dense bodies. Increased immunoreactivity of astrocytes for GFAP was observed. Treatment with either CoQ10 or captopril significantly reduced ammonia levels, increased hippocampal LC3-II and beclin-1 mRNA, increased serum TAC and Na+/K+ ATPase activity, and noticeably ameliorated the hippocampal neuronal changes. EM revealed restoration of the normal structure of pyramidal neurons. These effects were more obvious in CoQ10-treated than captopril-treated rats.
Conclusions:
CoQ10 and captopril have neuroprotective effects on APAP-E via enhancing LC3-II, beclin-1 mRNA expression, serum TAC level and hippocampal Na+/K+ ATPase activity.
Induction of autophagy could protect against acetaminophen (APAP)-induced hepatotoxicity; however, little is known about the role of autophagy in APAP-induced encephalopathy (APAP-E). This study aimed to evaluate the effects of coenzyme Q10 (CoQ10) and captopril on APAP-E.
Material and methods:
Forty-eight rats were randomly allotted to 4 equal groups: control, an APAP-E, coenzyme Q10-treated (CoQ10-treated), and captopril-treated groups. Behavioral tests were conducted. Serum ammonia and total antioxidant capacity (TAC) and hippocampal Na+/K+ ATPase activity were measured. The expression levels of hippocampal microtubule-associated protein light chain 3 (LC3-II) and beclin-1 mRNA were detected using quantitative polymerase chain reaction (qPCR). General histological, immunohistochemical staining for glial fibrillary acid protein (GFAP) and electron microscopy (EM) of the hippocampus were performed.
Results:
In the APAP-E group, serum ammonia was increased significantly, hippocampal LC3-II and beclin-1 mRNA were elevated insignificantly, while serum TAC and the activity of hippocampal Na+/K+ ATPase were reduced significantly compared with the control group. APAP-E rats showed remarkable degenerative changes in CA1 pyramidal neurons in the form of electron-dense cytoplasm with ill-defined nuclei and accumulation of lysosomal structure-like dense bodies. Increased immunoreactivity of astrocytes for GFAP was observed. Treatment with either CoQ10 or captopril significantly reduced ammonia levels, increased hippocampal LC3-II and beclin-1 mRNA, increased serum TAC and Na+/K+ ATPase activity, and noticeably ameliorated the hippocampal neuronal changes. EM revealed restoration of the normal structure of pyramidal neurons. These effects were more obvious in CoQ10-treated than captopril-treated rats.
Conclusions:
CoQ10 and captopril have neuroprotective effects on APAP-E via enhancing LC3-II, beclin-1 mRNA expression, serum TAC level and hippocampal Na+/K+ ATPase activity.
REFERENCES (77)
1.
Shabrang B, Jamshidzadeh A, Farjam M, Ebrahimpour A, Koohi-Hosseinabadi O. Concurrent assessment of calpain and caspase 3 activities in brains of mice with acetaminophen-induced acute hepatic encephalopathy. Metab Brain Dis 2017; 32: 2139-42.
2.
Posadas I, Santos P, Blanco A, Munoz-Fernandez M, Cena V. Acetaminophen induces apoptosis in rat cortical neurons. PLoS One 2010; 5: e15360.
3.
Essawy AE, Alkhuriji AF, Soffar AA. Paracetamol overdose induces physiological and pathological aberrations in rat brain. J Appl Pharm Sci 2017; 7: 185-90.
4.
Pandurangan AK, Ismail S, Esa NM, Munusamy MA. Inositol-6 phosphate inhibits the mTOR pathway and induces autophagy-mediated death in HT-29 colon cancer cells. Arch Med Sci 2018; 14: 1281-8.
5.
Kiffin R, Bandyopadhyay U, Cuervo AM. Oxidative stress and autophagy. Antioxid Redox Signal 2006; 8: 152-62.
6.
Ni H, Gong Y, Yan JZ, Zhang LL. Autophagy inhibitor 3-methyladenine regulates the expression of LC3, Beclin-1 and ZnTs in rat cerebral cortex following recurrent neonatal seizures. World J Emerg Med 2010; 1: 216-23.
7.
Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature 2008; 451: 1069-75.
8.
Ni HM, Bockus A, Boggess N, Jaeschke H, Ding WX. Activation of autophagy protects against acetaminophen-induced hepatotoxicity. Hepatology 2012; 55: 222-32.
9.
Moazen M, Mazloom Z, Dabbaghmanesh MH, Ahmadi A. Effect of CoQ10 supplementation on blood pressure, inflammation, and lipid profile in type 2 diabetics. Iran J Nutr Sci Food Technol 2013; 8: 145-53.
10.
Alam MA, Rahman MM. Mitochondrial dysfunction in obesity: potential benefit and mechanism of Co-enzyme Q10 supplementation in metabolic syndrome. J Diabetes Metab Disord 2014; 13: 60.
11.
Qu H, Guo M, Chai H, et al. Effects of coenzyme Q10 on statin-induced myopathy: an updated meta-analysis of randomized controlled trials. J Am Heart Assoc 2018; 7: e009835.
12.
Mazidi M, Kengne AP, Banach M. Effects of coenzyme Q10 supplementation on plasma C-reactive protein concentrations: a systematic review and meta-analysis of randomized controlled trials. Pharmacol Res 2018; 128: 130-6.
13.
Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy – European Atherosclerosis Society consensus panel statement on assessment, aetiology and management. Eur Heart J 2015; 36: 1012-22.
14.
Ashby EL, Kehoe PG. Current status of renin-aldosterone angiotensin system-targeting anti-hypertensive drugs as therapeutic options for Alzheimer’s disease. Expert Opin Investig Drugs 2013; 22: 1229-42.
15.
Zhang X, Liu H, Hao Y, et al. Coenzyme Q10 protects against hyperlipidemia-induced cardiac damage in apolipoprotein E-deficient mice. Lipids Health Dis 2018; 17: 279.
16.
Vasiliev AV, Martinova EA, Sharanova NV, Gapparov MM. Effects of coenzyme Q10 on rat liver cells under conditions of metabolic stress. Bull Exp Biol Med 2011; 150: 416-9.
17.
Bodiga VL, Bodiga S. Renin angiotensin system in cognitive function and dementia. Asian J Neurosci 2013; 2013: 1-18.
18.
O’Caoimh R, Kehoe PG, Molloy DW. Renin Angiotensin aldosterone system inhibition in controlling dementia-related cognitive decline. J Alzheimers Dis 2014; 42: S575-86.
19.
Onaolapo OJ, Adekola MA, Azeez TO, Salami K, Onaolapo AY. l-Methionine and silymarin: a comparison of prophylactic protective capabilities in acetaminophen-induced injuries of the liver, kidney and cerebral cortex. Biomed Pharmacother 2017; 85: 323-33.
20.
Abd Allah ES, Gomaa AM. Effects of curcumin and captopril on the functions of kidney and nerve in streptozotocin-induced diabetic rats: role of angiotensin converting enzyme 1. Appl Physiol Nutr Metab 2015; 40: 1061-7.
21.
Ashkani Esfahani S, Esmaeilzadeh E, Bagheri F, Emami Y, Farjam M. The effect of co-enzyme q10 on acute liver damage in rats, a biochemical and pathological study. Hepat Mon 2013; 13: e13685.
22.
Guide for the Care and Use of Laboratory Animals. 8th Ed. National Academy Press, Washington, D.C., 2011.
23.
Akkerman S, Blokland A, Reneerkens O, et al. Object recognition testing: methodological considerations on exploration and discrimination measures. Behav Brain Res 2012; 232: 335-47.
24.
Antunes M, Biala G. The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process 2012; 13: 93-110.
25.
Woode E, Amidu N, Owiredu WKBA, et al. Anxiogenic-like effects of a root extract of sphenocentrum jollyanum pierre in murine behavioural models. J Pharma Toxicol 2009; 4: 91-106.
26.
Koracevic D, Koracevic G, Djordjevic V, Andrejevic S, Cosic V. Method for the measurement of antioxidant activity in human fluids. J Clin Pathol 2001; 54: 356-61.
27.
Sehirli O, Sener E, Cetinel S, et al. Alpha-lipoic acid protects against renal ischemia-reperfusion injury in rats. Clin Exp Pharmacol Physiol 2008; 35: 249-55.
28.
Atkinson A, Gatenby AD, Lowe AG. The determination of inorganic orthophosphate in biological systems. Biochim Biophys Acta 1973; 320: 195-204.
29.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent. J Biol Chem 1951; 193: 265-75.
30.
Zhu B, Zheng YF, Zhang YY, et al. Protective effect of L-carnitine in cyclophosphamide-induced germ cell apoptosis. J Zhejiang Univ Sci B 2015; 16: 780-7.
31.
Miyatake Y, Ikeda H, Ishizu A, et al. Role of neuronal interferon-gamma in the development of myelopathy in rats infected with human T-cell leukemia virus type 1. Am J Pathol 2006; 169: 189-99.
32.
Navarro VM, Castellano JM, Fernandez-Fernandez R, et al. Effects of KiSS-1 peptide, the natural ligand of GPR54, on follicle-stimulating hormone secretion in the rat. Endocrinology 2005; 146: 1689-97.
33.
Jin BK, Shin DY, Jeong MY, et al. Melatonin protects nigral dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+) neurotoxicity in rats. Neurosci Lett 1998; 245: 61-4.
34.
Bancroft JD, Gamble M. Theory and Practice of Histological Techniques. Churchill Livingstone, Scotland, London, 2008.
35.
Reilly JF, Maher PA, Kumari VG. Regulation of astrocyte GFAP expression by TGF-beta1 and FGF-2. Glia 1998; 22: 202-10.
36.
Cattoretti G, Pileri S, Parravicini C, et al. Antigen unmasking on formalin-fixed, paraffin-embedded tissue sections. J Pathol 1993; 171: 83-98.
38.
Knapp GR, Miller MC. Tests of Statistical Significance: Regression and Correlation. Williams & Wilkins 1992, Baltimore, Maryland.
39.
Chen XL, Wee NL, Hiong KC, et al. Properties and expression of Na+/K+-ATPase alpha-subunit isoforms in the brain of the swamp eel, Monopterus albus, which has unusually high brain ammonia tolerance. PLoS One 2013; 8: e84298.
40.
Yang L, Wu D, Wang B, et al. The effects of hyperbilirubinaemia on synaptic plasticity in the dentate gyrus region of the rat hippocampus in vivo. Arch Med Sci 2020; 16: 200-4.
41.
Sheu JJ, Sung PH, Leu S, et al. Innate immune response after acute myocardial infarction and pharmacomodulatory action of tacrolimus in reducing infarct size and preserving myocardial integrity. J Biomed Sci 2013; 20: 82.
42.
Erecinska M, Silver IA. Ions and energy in mammalian brain. Prog Neurobiol 1994; 43: 37-71.
43.
de Lores Arnaiz GR, Ordieres MG. Brain Na(+), K(+)-ATPase activity in aging and disease. Int J Biomed Sci 2014; 10: 85-102.
44.
Sheean RK, Lau CL, Shin YS, O’Shea RD, Beart PM. Links between L-glutamate transporters, Na+/K+-ATPase and cytoskeleton in astrocytes: evidence following inhibition with rottlerin. Neuroscience 2013; 254: 335-46.
45.
Khanna A, Kahle KT, Walcott BP, Gerzanich V, Simard JM. Disruption of ion homeostasis in the neurogliovascular unit underlies the pathogenesis of ischemic cerebral edema. Transl Stroke Res 2014; 5: 3-16.
46.
Trumper L, Coux G, Elias MM. Effect of acetaminophen on Na(+), K(+) ATPase and alkaline phosphatase on plasma membranes of renal proximal tubules. Toxicol Appl Pharmacol 2000; 164: 143-8.
47.
Chao X, Wang H, Jaeschke H, Ding WX. Role and mechanisms of autophagy in acetaminophen-induced liver injury. Liver Int 2018; 38: 1363-74.
48.
Soria LR, Allegri G, Melck D, et al. Enhancement of hepatic autophagy increases ureagenesis and protects against hyperammonemia. Proc Natl Acad Sci USA 2018; 115: 391-6.
49.
Fouad AA, Jresat I. Hepatoprotective effect of coenzyme Q10 in rats with acetaminophen toxicity. Environ Toxicol Pharmacol 2012; 33: 158-67.
50.
Al-Shaikh TM, Mudawi MME, Yassin AYA, Habeballa RS, Chidrawar VR. Hepatoprotective Effect of captopril on liver toxicity induced by high and low dose of paracetamol in rats: histological study. Asian J Pharm Res Health Care 2016; 8: 92-9.
51.
de Cavanagh EM, Inserra F, Ferder L, Fraga CG. Enalapril and captopril enhance glutathione-dependent antioxidant defenses in mouse tissues. Am J Physiol Regul Integr Comp Physiol 2000; 278: R572-7.
52.
Raghavendra V, Chopra K, Kulkarni SK. Comparative studies on the memory-enhancing actions of captopril and losartan in mice using inhibitory shock avoidance paradigm. Neuropeptides 2001; 35: 65-9.
53.
Mohamed DI, Khairy E, Tawfek SS, Habib EK, Fetouh MA. Coenzyme Q10 attenuates lung and liver fibrosis via modulation of autophagy in methotrexate treated rat. Biomed Pharmacother 2019; 109: 892-901.
54.
Bartesaghi R, Severi S, Guidi S. Effects of early environment on pyramidal neuron morphology in field CA1 of the guinea-pig. Neuroscience 2003; 116: 715-32.
55.
Aboutaleb N, Shamsaei N, Rajabi H, et al. Protection of hippocampal ca1 neurons against ischemia/reperfusion injury by exercise preconditioning via modulation of Bax/Bcl-2 Ratio and prevention of Caspase-3 activation. Basic Clin Neurosci 2016; 7: 21-9.
56.
Uttara B, Singh AV, Zamboni P, Mahajan RT. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 2009; 7: 65-74.
57.
Salganik RI. The benefits and hazards of antioxidants: controlling apoptosis and other protective mechanisms in cancer patients and the human population. J Am Coll Nutr 2001; 20: 464S-475S.
58.
da Silva MH, da Rosa EJ, de Carvalho NR, et al. Acute brain damage induced by acetaminophen in mice: effect of diphenyl diselenide on oxidative stress and mitochondrial dysfunction. Neurotox Res 2012; 21: 334-44.
59.
Goldman SJ, Taylor R, Zhang Y, Jin S. Autophagy and the degradation of mitochondria. Mitochondrion 2010; 10: 309-15.
60.
Jin S. Autophagy, mitochondrial quality control, and oncogenesis. Autophagy 2006; 2: 80-4.
61.
Gurer H, Neal R, Yang P, Oztezcan S, Ercal N. Captopril as an antioxidant in lead-exposed Fischer 344 rats. Hum Exp Toxicol 1999; 18: 27-32.
62.
Trushina E. A shape shifting organelle: unusual mitochondrial phenotype determined with three-dimensional electron microscopy reconstruction. Neural Regen Res 2016; 11: 900-1.
63.
Youle RJ, van der Bliek AM. Mitochondrial fission, fusion, and stress. Science 2012; 337: 1062-5.
64.
Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol 2010; 119: 7-35.
65.
Becerra-Calixto A, Cardona-Gomez GP. The role of astrocytes in neuroprotection after brain stroke: potential in cell therapy. Front Mol Neurosci 2017; 10: 88.
66.
Ridet JL, Malhotra SK, Privat A, Gage FH. Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 1997; 20: 570-7.
67.
Treuting PM, Dintzis SM, Montine KS. Comparative Anatomy and Histology: A Mouse, Rat, and Human Atlas, 2nd ed. Academic Press 2017.
68.
Bylicky MA, Mueller GP, Day RM. Mechanisms of endogenous neuroprotective effects of astrocytes in brain injury. Oxid Med Cell Longev 2018; 2018: 6501031.
69.
Dringen R, Gutterer JM, Hirrlinger J. Glutathione metabolism in brain metabolic interaction between astrocytes and neurons in the defense against reactive oxygen species. Eur J Biochem 2000; 267: 4912-16.
70.
Won R, Lee KH, Lee BH. Coenzyme Q10 protects neurons against neurotoxicity in hippocampal slice culture. Neuroreport 2011; 22: 721-6.
71.
Bergamini C, Moruzzi N, Sblendido A, Lenaz G, Fato R. A water soluble CoQ10 formulation improves intracellular distribution and promotes mitochondrial respiration in cultured cells. PLoS One 2012; 7: e33712.
72.
Matthews RT, Yang L, Browne S, Baik M, Beal MF. Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proc Natl Acad Sci USA 1998; 95: 8892-7.
73.
Beal MF. Coenzyme Q10 as a possible treatment for neurodegenerative diseases. Free Radic Res 2002; 36: 455-60.
74.
Lee D, Kim KY, Shim MS, et al. Coenzyme Q10 ameliorates oxidative stress and prevents mitochondrial alteration in ischemic retinal injury. Apoptosis 2014; 19: 603-14.
75.
Liang S, Ping Z, Ge J. Coenzyme Q10 regulates antioxidative stress and autophagy in acute myocardial ischemia-reperfusion injury. Oxid Med Cell Longev 2017; 2017: 9863181.
76.
Sonsalla PK, Coleman C, Wong LY, et al. The angiotensin converting enzyme inhibitor captopril protects nigrostriatal dopamine neurons in animal models of parkinsonism. Exp Neurol 2013; 250: 376-83.
77.
Karimani A, Mamashkhani Y, Jafari AM, Akbarabadi M, Heidarpour M. Captopril attenuates diazinon-induced oxidative stress: a subchronic study in rats. Iran J Med Sci 2018; 43: 514-22.
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