Nephroprotective effects of Datura stramonium leaves against methotrexate nephrotoxicity via attenuation of oxidative stress-mediated inflammation and apoptosis in rats

Document Type : Original Research Article

Authors

1 Department of Biochemistry, Faculty of Science, Ebonyi State University, PMB, 053, Abakaliki, Nigeria

2 Department of Medical Biochemistry, Faculty of Basic Medical Sciences, College of Medical Sciences, Alex Ekwueme Federal University, Ndufu-Alike, Ikwo, Ebonyi State, Nigeria. Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka State, India

Abstract

Objective: Methotrexate (MTX) is a frontline antimetabolite anticancer drug which is used in different cancer treatments but its nephrotoxicity is a notable drawback that limits its clinical use. The present study was undertaken to examine whether Datura stramonium leaf extract (DSLE) could block MTX nephrotoxic side effect in rats.
Materials and Methods: Animals were divided randomly into Control, Ethanol extract, MTX, and Extract + MTX groups. DSLE (200 mg/kg bw) was orally administered for 21 days, while MTX was injected intraperitoneally (ip) on the 18th day. Serum levels of urea, creatinine and uric acid were determined. Kidney samples were used to determine glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) activities, and renal levels of malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and caspase-3.
Results: Injection of MTX resulted in considerable increases (p<0.05) in creatinine, urea, and uric acid levels as well as renal MDA, NO, IL-6, TNF-α and caspase-3 compared to the controls. SOD and GPx increased significantly, while GSH was significantly depleted. Interestingly, DSLE markedly reduced (p<0.05) levels of creatinine, urea, uric acid, TNF-α, NO, MDA and caspase-3, whereas renal GSH increased markedly compared to the MTX group.
Conclusion: DSLE has nephroprotective activity against MTX toxicity. However, further mechanistic studies are needed.

Keywords


Abdel-Wahab BA, Ali FE, Alkahtani SA,
Alshabi AM, Mahnashi MH, Hassanein
EH. 2020. Hepatoprotective effect of
rebamipide against methotrexate-induced
hepatic intoxication: role of Nrf2/GSK3β, NF-κβ-p65/JAK1/STAT3, and
PUMA/Bax/Bcl-2 signaling pathways.
Immunopharmacol Immunotoxicol, 42:
493-503.
Afsar T, Razak S, Aldisi D, Shabbir M,
Almajwal A, Al Kheraif AA, Arshad M.
2021. Parker ethylacetate extract
abrogates cisplatin‐induced
nephrotoxicity by targeting ROS and
inflammatory cytokines. Sci Rep, 11:
17248.
Ahmed ZS, Hussein S, Ghandour RA, Azouz
AA, El-Sakhawy MA. 2021. Evaluation
of the effect of methotrexate on the
hippocampus, cerebellum, liver, and
kidneys of adult male albino rat
histopathological, immunohistochemical
and biochemical studies. Acta
Histochemica, 123: 151682.
Alam W, Khan H, Khan SJ, Ali N, Sharif N,
Ghafar R, Daglia M, Nasir S. 2020.
Nephroprotective effects of Datura metel
extract in gentamicin induced mice
model: biochemical and histological
evidences. Cell Mol Biol (Noisy-legrand), 66: 208-213.
Ashrafizadeh M, Zarrabi A, Hashemi F,
Moghadam ER, Hashemi F, Entezari M,
Hushmandi K, Mohammadinejad R,
Najafi M. 2020. Curcumin in cancer
therapy: A novel adjunct for combination
chemotherapy with paclitaxel and
alleviation of its adverse effects. Life Sci,
256: 117984.
Bordbar M, Shakibazad N, Fattahi M,
Haghpanah S, Honar N. 2018. Effect of
ursodeoxycholic acid and vitamin E in the
prevention of liver injury from
methotrexate in pediatric leukemia.
Turkish J Gastroenterol, 29: 203-209.
Bories PN, Bories C. 1995. Nitrate
determination in biological fluids by an
enzymatic one-step assay with nitrate
reductase. Clin Chem, 41: 904-907.
Céspedes-méndez C, Iturriaga-vásquez P,
Hormazábal E. 2021. Secondary
metabolites and biological profiles of
Datura genus. J Chil Chem Soc, 66:
5183-5189.
Ellman GL. 1959. Tissue sulphydryl groups.
Arch Biochem Biophys, 82: 70-77.
Ezhilarasan D. 2021. Hepatotoxic potentials of
methotrexate: Understanding the possible
toxicological molecular mechanisms.
Toxicology, 458: 152840.
Fakurazi S, Sharifudin SA, Arulselvan P.
2012. Moringa oleifera hydroethanolic
extracts effectively alleviate
acetaminophen-induced hepatotoxicity in
experimental rats through their
antioxidant nature. Molecules, 17: 8334-
8350.
Famurewa AC, Aja PM, Maduagwuna EK,
Ekeleme-Egedigwe CA, Ufebe OG,
Azubuike-Osu SO. 2017. Antioxidant and
anti-inflammatory effects of virgin
coconut oil supplementation abrogate
acute chemotherapy oxidative
nephrotoxicity induced by anticancer drug
methotrexate in rats. Biomed
Pharmacother, 96: 905-911.
Famurewa AC, Aja PM, Nwankwo OE,
Awoke JN, Maduagwuna EK, Aloke K.
2019a. Moringa oleifera seed oil or virgin
coconut oil supplementation abrogates
cerebral neurotoxicity induced by
antineoplastic agent methotrexate by
suppression of oxidative stress and
neuroinflammation in rats. J Food
Biochem, 43: e12748.
Famurewa AC, Folawiyo AF, Epete MA, Igwe
EC, Okike PI, Maduagwuna EK. 2019b.
Abrogation of hepatic damage induced by
anticancer drug methotrexate by zobo
(Hibiscus sabdariffa extract)
supplementation via targeting oxidative
hepatotoxicity in rats. J Diet Suppl, 16:
318-330.
Fossati P, Prencipe L, Berti G. 1980. Use of 3,
5-dichloro-2- hydroxybenzenesulfonic
acid 4-aminophenazone chromogenic
system in direct enzymic assay of uric
acid in serum and urine. J Clin Chem, 26:
227-231.
Gupta S, Raghuvanshi M, Jain D. 2010.
Comparative studies on anti-inflammatory
activity of Coriandrum sativum, Datura
stramonium and Azadirachta indica.
Asian J Exp Biol Sci, 1: 151-154.
Hassanein EH, Kamel EO, Ali FE, Ahmed
MA. 2021. Berberine and/or zinc protect
against methotrexate-induced intestinal
damage: Role of GSK-3β/NRF2 and
Alum et al.
AJP, Vol. 13, No. 4, Jul-Aug 2023 386
JAK1/STAT-3 signaling pathways. Life
Sci, 281: 119754.
Hassanein EH, Mohamed WR, Shalkami AS,
Khalaf MM, Hemeida RA. 2018.
Renoprotective effects of umbelliferone
on methotrexate-induced renal injury
through regulation of Nrf-2/Keap-1,
P38MAPK/NF-κB, and apoptosis
signaling pathways. Food Chem Toxicol,
116: 152-160.
Henry RJ, Cannon DC, Winkelman W. 1974.
Clinical Chemistry Principles and
Techniques, pp. 1629, 11th Edn. Harper
and Row Publishers, New York, USA.
Imo C, Arowora KA, Ezeonu CS, Yakubu OE,
Nwokwu CD, Azubuike NC, Sallah YG.
2019. Effects of ethanolic extracts of leaf,
seed and fruit of Datura metel L. on
kidney function of male albino rats. J
Trad and Complem Med, 9: 271-277.
Joshua PE, Asomadu RO, Eze CS, Nnamani
IV, Kingsley CO, Nweje-Anyalowu CP,
Patrick VJ, Obe SA. 2019. Effect of
Datura stramonium on
cyclophosphamide-induced oxidative
stress in albino rats: Study on kidney
markers. Int J Pharmacol, 15: 926-932.
Kelleni MT, Ibrahim SA, Abdelrahman AM.
2016. Effect of captopril and telmisartan
on methotrexate-induced hepatotoxicity in
rats: impact of oxidative stress,
inflammation and apoptosis. Toxicol
Mech Method, 26: 371-377.
Khafaga AF, El-Sayed YS. 2018. Spirulina
ameliorates methotrexate hepatotoxicity
via antioxidant, immune stimulation, and
proinflammatory cytokines and apoptotic
proteins modulation. Life Sci, 196: 9-17.
Khalifa MM, Bakr AG, Osman AT. 2017.
Protective effects of phloridzin against
methotrexate-induced liver toxicity in
rats. Biomed Pharmacother, 95: 529-535.
Mahmoud AM, Germoush MO, Al-Anazi KM,
Mahmoud AH, Abul Farah M, Allam AA.
2019. Commiphora molmol protects
against methotrexate-induced
nephrotoxicity by up-regulating
Nrf2/ARE/HO-1 signaling. Biomed
Pharmacother, 106: 499-509.
Mc-Cord JM, Fridovich I. 1969. Superoxide
dismutase an enzymatic function for
erythrocuperin. J Biol Chem, 244: 6045-
6055.
Melaku BC, Amare GG. 2020. Evaluation of
antidiabetic and antioxidant potential of
hydromethanolic seed extract of Datura
stramonium Linn (Solanaceae). J Exp
Pharmacol, 12: 181-189.
Miyazono Y, Gao F, Horie T. 2004. Oxidative
stress contributes to methotrexateinduced small intestinal toxicity in rats.
Scand J Gastroenterol, 39: 1119-1127.
Moghaddam RH, Samimi Z, Moradi SZ, Little
PJ, Xu S, Farzaei MH. 2020. Naringenin
and naringin in cardiovascular disease
prevention: A preclinical review. Eur J
Pharmacol, 887: 173535.
Nasir B, Baig MW, Majid M, Ali SM, Khan
MZ, Kazmi ST, Haq I. 2020. Preclinical
anticancer studies on the ethyl acetate leaf
extracts of Datura stramonium and
Datura inoxia. BMC Complem Med
Ther, 20: 188-210.
Nasir B, Khan AU, Baig MW, Althobaiti YS,
Faheem M, Haq I. 2022. Datura
stramonium leaf extract exhibits antiinflammatory activity in CCl4-induced
hepatic injury model by modulating
oxidative stress markers and iNOS/Nrf2
expression. BioMed Res Int, 2022:
1382878.
Oluduro AO, Aderiye BI. 2009. Effect of
Moringa oleifera seed extract on vital
organs and tissue enzyme activities of
male albino rats. Afr J Microbiol Res, 3:
537-540.
Paglia DE, Valentine WN. 1967. Studies on
the quantitative and qualitative
characterization oferythrocyte glutathione
peroxidase. J Lab Clin Med, 70: 158-169.
Prasanna PL, Renu K, Gopalakrishnan AV.
2020. New molecular and biochemical
insights of doxorubicin-induced
hepatotoxicity. Life Sci, 250: 117599.
Sayed AM, Hassanein EH, Ali FE, Omar ZM,
Rashwan EK, Mohammedsaleh ZM, Abd
El-Ghafar OA. 2021. Regulation of Keap1/Nrf2/AKT and iNOS/NF-κB/TLR4
signals by apocynin abrogated
methotrexate-induced testicular toxicity:
Mechanistic insights and computational
pharmacological analysis. Life Sci, 284:
119911.
Sharma M, Dhaliwal I, Rana K, Delta AK,
Kaushik P. 2021. Phytochemistry,
pharmacology, and toxicology of Datura
Species—A review. Antioxidants, 10:
1291-1302.
Sinha AK. 1972. Colorimetric assay of
catalase. Anal Biochem, 47: 389-394.
Datura stramonium leaves abrogate MTX toxicity
AJP, Vol. 13, No. 4, Jul-Aug 2023 387
Soni P, Siddiqui AA, Dwivedi J, Soni V. 2012.
Pharmacological properties of Datura
stramonium L. as a potential medicinal
tree: An overview. Asian Pac J Trop
Biomed, 2: 1002-1008.
Stark AN, Jackson G, Carey PJ, Arfeen S,
Proctor SJ. 1989. Severe renal toxicity
due to intermediate-dose methotrexate.
Cancer Chemother Pharmacol, 24: 243-
245.
Uzar E, Koyuncuoglu HR, Uz E, Yilmaz AR,
Kutluhan S, Kilbas S, Gultekin F. 2006.
The activities of antioxidant enzymes and
the level malondialdehyde in cerebellum
of rats subjected to methotrexate:
protective effect of caffeic acid phenetyl
ester. Mol Cell Biochem, 291: 63-68.
Vardi N, Parlakpinar H, Ozturk F, Ates B, Gul
M, Cetin A, Erdogan A, Otlu A. 2008.
Potent protective effect of apricot and bcarotene on methotrexate-induced
intestinal oxidative damage in rats. Food
Chem Toxicol, 46: 3015-3022.
Wallin B, Rosengren B, Shertzer HG, Camejo
G. 1993. Lipoprotein oxidation and
measurement of TBARS formation in a
single microlite plate; its use for
evaluation of antioxidants. Ann Biochem,
208: 10-15.
Wybenga DR, Giorgio JD, Pileggi VJ. 1971.
Manual and automated methods for urea
nitrogen measurement in whole serum.
Clin Chem, 17: 891-895.
Yadav B, Singla A, Srivastava N, Gupta P.
2021. Pharmacognostic and
phytochemical screening of Datura
stramonium by TLC and GC-MS: A
forensic approach. Biomed Pharmacol J,
14: 2221-2226.
Zhang Y, Zhu X, Zhao J, Gao X, Zhang X,
Hou K. 2020. Neuroprotective effect of
resveratrol against radiation after
surgically induced brain injury by
reducing oxidative stress, inflammation,
and apoptosis through NRf2/HO‐1/NF‐κB
signaling pathway. J Biochem Mol
Toxicol, 34: e22600