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Licensed Unlicensed Requires Authentication Published by De Gruyter March 31, 2021

Modulatory effect of methanol extract of Annona muricata stem bark on mitochondrial membrane permeability transition pore in normal rat liver and monosodium glutamate-induced uterine hyperplasia

Adeola Oluwakemi Olowofolahan ORCID logo, Funmilayo O. Adewoye and Olufunso Olabode Olorunsogo



Uterine fibroids are benign tumors that develop in many women of reproductive age. Surgery is the main approach to treatment while other options are also associated with adverse effects. Studies have shown that certain bioactive agents present in medicinal plants elicit their anti-tumor activity by induction of mitochondrial permeability transition (mPT) opening. This research therefore aimed at investigating the effect of methanol extract of Annona muricata (MEAM) on mPT pore opening in normal and monosodium glutamate-induced uterine hyperplasia using female Wistar rats.


Mitochondria, isolated from rat liver were exposed to different concentrations (20, 60, 100, 140 and 180 μg/mL) of MEAM. The mPT pore opening, cytochrome c release, mitochondrial ATPase (mATPase) activity and the percentage lipid peroxidation were assessed spectrophotometrically. Histological effects of MEAM on the liver, brain and uterus of normal and MSG-treated rats were investigated.


The in vitro results showed a significant induction of mPT pore opening by 2.4, 4.2 and 6.4 folds, release of cytochrome c and enhancement of mATPase activity at 100,140 and 180 μg/mL, respectively. However, oral administration of MEAM did not induce mPT pore opening, neither any significant release of cytochrome c nor enhancement of mATPase activity at all the dosages used. However, histological assay revealed the presence of MSG-induced cellular damage and uterine hyperplasia which was ameliorated by MEAM co-administration.


These findings suggest that MEAM contains phytochemicals that can ameliorate MSG-induced damage and uterine hyperplasia in rats; however, the mechanism might not be via upregulation of mitochondrial-mediated apoptosis.

Corresponding author: Dr. Adeola Oluwakemi Olowofolahan, Department of Biochemistry, Faculty of Basic Medical Sciences, College of Medicine, University of Ibadan, Ibadan, Nigeria, Phone: +234 7030179598, E-mail:

  1. Research funding: The research received no funding from any agency.

  2. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  3. Competing interests: No funding organizations played a role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

  4. Ethical approval: The work was approved by the Departmental Ethical Review Committee and conducted with the guideline of NIH publication 85-23, 1985.


1. Green, DR, Kroemer, G. The pathophysiology of mitochondrial cell death. Science 2004;305:626–9. in Google Scholar

2. Dong, HS, Mi-Kyung, K, Hee, SK, Hyun, HC, Yong, SS. Mitochondrial permeability transition pore as a selective target for anti-cancer therapy. Front Oncol 2013;3:1–11.Search in Google Scholar

3. Levi, CA, Ejere, VC, Asogwa, CN, Iweh, P, Nwatu, KU, Levi, UE. Apoptosis: its physiological implication and therapeutic possibilities. IOSR J Pharm Biol Sci 2014;9:38–45. in Google Scholar

4. Martin, KR. Targeting apoptosis with dietary bioactive agents. Exp Biol Med 2006;231:117–29. in Google Scholar

5. Fischer, U, Schulze, K. Apoptosis-based therapies and drug targets. Cell Death Differ 2005;12:942–61. in Google Scholar

6. Kadir, HA, Moghadamtousi, ZS, Fadaeinasab, M, Nikzad, S, Mohan, G, Ali, HM. Annona muricata (Annonaceae): a review of its traditional uses, isolated acetogenins and biological activities. Int J Mol Sci 2015;16:15625–58. in Google Scholar

7. Morton, JF. Caribbean and Latin American folk medicine and its influence in the United States. Q J Of Crude Drug Res 1980;18:57–75. in Google Scholar

8. Alvarez-Gonzalez, I, Garcia-Aguirre, K, Martino-Roaro, L, Zepeda-Vallejo, G, Madrigal-Bujaidar, E. Anticarcinogenic and genotoxic effects produced by acetogenins isolated from Annona muricata. Toxicol Lett 2008;180:S32–246. in Google Scholar

9. Falodun, A, Osakue, J, Uzoekwe, AS, Sheng-Xiang, Q. Phytochemical and anticancer studies on ten medicinal plants used in Nigeria. Bayero J Pure Appl Sci 2010;4:36–9.Search in Google Scholar

10. Padmaa-Paarakh, M, Chansouria, J, Khosa, R. Wound healing activity of Annona muricata extract. J Pharm Res 2009;2:404–6.Search in Google Scholar

11. Eweka, A, Om‘Iniabohs, F. Histological studies of the effects of monosodium glutamate on the fallopian tube of adult female wistar rats. N Am J Med Sci 2010;2:146–9. in Google Scholar

12. Olowofolahan, AO, Aina, OO, Hassan, ET, Olorunsogo, OO. Ameliorative potentials of methanol extract and chloroform fraction of Drymaria cordata on MSG-induced uterine hyperplasia in female wistar rats. Eur J Med Plants 2017;20:1–9. in Google Scholar

13. Johnson, D, Lardy, H. Isolation of liver or kidney mitochondria. Methods Enzymol 1967;10:94–6. in Google Scholar

14. Olorunsogo, OO, Bababunmi, EA, Bassir, O. Uncoupling effect of N – phosphonomethyl glycine on rat liver mitochondria. Biochem Pharmacol 1979;27:925–7.10.1016/0006-2952(79)90377-0Search in Google Scholar

15. Bassir, O. Improving the level of nutrition. West Afr J Biol Appl Chem 1963;7:32–40.Search in Google Scholar

16. Olorunsogo, OO, Malomo, SO. Sensitivity of oligomycin-inhibited respiration of isolated rat liver mitochondria to perfluidone, a fluorinated arylalkylsulfonamide. Toxicology 1985;35:231–40. in Google Scholar

17. Appaix, F, Minatchy, M, Riva-Lavieille, C, Olivaires, J, Antonnson, B, Saks, VA. Rapid spectrophotometric method for quantitation of cytochrome c release from isolated mitochondria or permeabilised cell revisited. Biochim Biophys Acta 2000;145:175–81. in Google Scholar

18. Varshney, R, Kale, RK. Effect of calmodulin antagonists on radiation-induced lipid peroxidation in microsomes. Int J Radiat Biol 1990;58:773–43. in Google Scholar

19. Halestrap, AP, Richardson, AP. The mitochondrial permeability transition: a current perspective on its identity and role in ischaemia/reperfusion injury. J Mol Cell Cardiol 2015;78:129–41. in Google Scholar

20. Faya, N, Millimiuno, J, Dong, LY, Jiang, L, Xiaomeng, L. Targeting apoptosis pathways in cancer and perspectives with compounds from mother nature. Canc Prev Res 2016;7:1081–107.Search in Google Scholar

21. Islam, MS, Akhtar, MM, Ciavattini, A, Giannubilo, SR, Protic, O, Janjusevic, M, et al.. Use of dietary phytochemicals to target inflammation, fibrosis, proliferation, and angiogenesis in uterine tissues: promising options for prevention and treatment of uterine fibroids. Mol Nutr Food Res 2014;58:1667–84. in Google Scholar

22. Islam, MS, Akhtar, MM, Segars, JH, Castellucci, M, Ciarmela, P. Molecular targets of dietary phytochemicals for possible prevention and therapy of uterine fibroids: focus on fibrosis. Crit Rev Food Sci Nutr 2017;57:3583–600. in Google Scholar

23. Minari, JB, Okeke, U. Chemopreventive effect of Annona muricata on DMBA-induced cell proliferation in the breast tissues of female albino mice. Egypt J Med Hum Genet 2014;15:327–34. in Google Scholar

Received: 2020-02-12
Accepted: 2020-07-09
Published Online: 2021-03-31

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