Iranian Veterinary Journal

Iranian Veterinary Journal

The effect of Prosopis Farcta extract on teratogenic effects of valproic acid and expression of BMP4 and Runx2 in skeletal system of rat embryo

Document Type : Research Paper

Authors
1 PhD Student in Comparative Anatomy and Embryology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
2 Professor, Department of Basic Sciences, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
3 Professor, Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran and Department of Basic Sciences, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
4 Associate Professor, Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran and Member of Excellence Center of Warm Water Fish Health, Shahid Chamran University of Ahvaz, Ahvaz, Iran
5 Assistant professor, Department of Basic Sciences, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
Abstract
    Sodium valproate (SV), as a common anti-epileptic drug, causes teratogenic effects on skeletal system by reactive oxygen species (ROS) generation. Herbal extract of Prosopis Farcta (PF), as a natural antioxidant necessary for many physiological activities, can probably ameliorate the teratogenic effects of SV during pregnancy. This study aimed to investigate the possible anti-teratogenic role of PF and Vitamin E (VE) on skeletal anomalies caused by SV in rat fetuses. Adult female rats (n=30) were categorized into 6 groups including control, SV (400 mg/kg), SV+VE (100mg/kg), and three doses of PF (50, 100, and 150 mg/kg) + SV. Each male rat mated with three adult female rats. The rats received SV, PF and VE at the 8th and 9th days of pregnancy by intraperitoneal injection. The animals were anesthetized and the laparotomy was applied at the 20th day of pregnancy. Skeletal abnormalities were analyzed using Alizarin red and Alcian blue staining. The expression of Runx2 and BMP2 genes was assessed using qPCRTM analysis in limbs bones. SV showed significant teratogenic effects including decrease in the rate of animal weight, Crown-rump length (CRL), various skeletal anomalies. The mRNA expression of Runx2 and BMP2 was also reduced in SV exposed animals. Administration of PF (especially 100mg/kg) in SV-exposed animals increased the weight of animals, CRL index, expression of Runx2 and BMP2, and reduced skeletal anomalies. The body weight, CRL index, Runx2 and BMP2 mRNA expression significantly increased, and skeletal anomalies decreased in VE group compared to the SV group. The results showed that PF could ameliorate the skeletal abnormalities and thus decreased osteogenic associated genes induced by SV in rat offsprings.
Keywords

Subjects


Abdolmaleki, A., Jalili, C., Mansouri, K., & Bakhtiari, M. (2021). New rat to mouse xenograft transplantation of endometrium as a model of human endometriosis. Animal Models and Experimental Medicine, 4(3), 268-277.
Adewole, K. E., Attah, A. F., & Osawe, S. O. (2023). Exploring phytotherapeutic approach in the management of valproic acid-induced toxicity. Advances in Traditional Medicine, 23(2), 347-367.
Cai, H., Zou, J., Wang, W., & Yang, A. (2021). BMP2 induces hMSC osteogenesis and matrix remodeling. Molecular Medicine Reports, 23(2), 1-1.
Duncan, S. (2007). Teratogenesis of sodium valproate. Current opinion in neurology, 20(2), 175-180.
Gebuijs, I. G. E., Metz, J. R., Zethof, J., Carels, C. E. L., Wagener, F. A. D. T. G., & Von den Hoff, J. W. (2020). The anti-epileptic drug valproic acid causes malformations in the developing craniofacial skeleton of zebrafish larvae. Mechanisms of Development, 163, 103632.
Gruppuso, P. A., Ahmed, R., & Adashi, E. Y. (2022). Valproate Teratogenicity: A Moving Target. Obstetrics & Gynecology, 140(3), 408-411.
Holmes, L. B. (2002). Teratogen‐induced limb defects. American journal of medical genetics, 112(3), 297-303.
Jahromi, M. A. F., Etemadfard, H., & Zebarjad, Z. (2018). Antimicrobial and antioxidant characteristics of volatile components and ethanolic fruit extract of Prosopis farcta (Bank & Soland.). Trends in Pharmaceutical Sciences, 4(3), 177-186.
Khan, S., & Jena, G. B. (2013). Effect of sodium valproate on the toxicity of cyclophosphamide in the testes of mice: influence of pre- and post-treatment schedule. Toxicol Int, 20(1), 68-76. doi:10.4103/0971-6580.111562
Kim, W.-J., Shin, H.-L., Kim, B.-S., Kim, H.-J., & Ryoo, H.-M. (2020). RUNX2-modifying enzymes: therapeutic targets for bone diseases. Experimental & Molecular Medicine, 52(8), 1178-1184.
Kirihata, Y., Ban, Y., Nakamori, C., Takagi, H., Hashimoto, T., & Tsutsumi, S. (2018). Repairability of skeletal alterations induced by sodium valproate in rats. Congenital Anomalies, 58(3), 99-101.
Komori, T. (2019). Regulation of proliferation, differentiation and functions of osteoblasts by Runx2. International Journal of Molecular Sciences, 20(7), 1694.
Macfarlane, A., & Greenhalgh, T. (2018). Sodium valproate in pregnancy: what are the risks and should we use a shared decision-making approach? BMC pregnancy and childbirth, 18(1), 1-11.
Massa, V., Cabrera, R. M., Menegola, E., Giavini, E., & Finnell, R. H. (2005). Valproic acid-induced skeletal malformations: associated gene expression cascades. Pharmacogenetics and genomics, 15(11), 787-800.
Menegola, E., Broccia, M. L., Di Renzo, F., & Giavini, E. (2002). Comparative study of sodium valproate-induced skeletal malformations using single or double staining methods. Reproductive Toxicology, 16(6), 815-823.
Mohammed, I. H., & Kakey, E. S. (2020). Effect of Prosopis farcta extracts on some complications (hematology and lipid profiles) associated with alloxan induced diabetic rats. Iraqi J Vet Sci, 34(1), 45-50.
Najafzadeh, V. H., & Khaksari, M. M. (2009). A comparison study of the effects of Echinacea purpurea ethanolic extract and mesna on cyclophosphamide-induced macroscopic fetal defects in rats.
Nie, Q., Su, B., & Wei, J. (2016). Neurological teratogenic effects of antiepileptic drugs during pregnancy. Experimental and therapeutic medicine, 12(4), 2400-2404. doi:10.3892/etm.2016.3628
Noroozi, R., Sadeghi, E., Yousefi, H., Taheri, M., Sarabi, P., Dowati, A., . . . Ghafouri-Fard, S. (2019). Wound healing features of Prosopis farcta: in vitro evaluation of antibacterial, antioxidant, proliferative and angiogenic properties. Gene Reports, 17, 100482.
Ornoy, A., Becker, M., Weinstein-Fudim, L., & Ergaz, Z. (2020). S-adenosine methionine (SAME) and valproic acid (VPA) as epigenetic modulators: Special emphasis on their interactions affecting nervous tissue during pregnancy. International Journal of Molecular Sciences, 21(10), 3721.
Ovchinnikov, D. (2009). Alcian blue/alizarin red staining of cartilage and bone in mouse. Cold Spring Harb Protoc, 2009(3).
Padmanabhan, R., & Ahmed, I. (1996). Sodium valproate augments spontaneous neural tube defects and axial skeletal malformations into mouse fetuses. Reproductive Toxicology, 10(5), 345-363.
Pitetzis, D. A., Spilioti, M. G., Yovos, J. G., & Yavropoulou, M. P. (2017). The effect of VPA on bone: From clinical studies to cell cultures—The molecular mechanisms revisited. Seizure, 48, 36-43.
Procópio, I. M., Pereira-Sampaio, M. A., Costa, W. S., Sampaio, F. J. B., & Souza, D. B. d. (2021). Histomorphometric comparison of the corpus cavernosum of rats submitted to euthanasia with ketamine and xylazine or isoflurane. Acta Cirúrgica Brasileira, 36, e361103.
Rahgazar, O., Ranjbar, R., Varzi, H. N., & Mahabady, M. K. (2011). Prophylactic effects of melatonin on sodium valproate-induced neural tube defects and skeletal malformations in rat embryos. American Journal of Applied Sciences, 8(5), 413.
Saeed, M., Saleem, U., Anwar, F., Ahmad, B., & Anwar, A. (2020). Inhibition of Valproic Acid-Induced Prenatal Developmental Abnormalities with Antioxidants in Rats. ACS Omega, 5(10), 4953-4961. doi:10.1021/acsomega.9b03792
Safdar, A., & Ismail, F. (2023). A comprehensive review on pharmacological applications and drug-induced toxicity of valproic acid. Saudi Pharmaceutical Journal, 31(2), 265-278.
Shakya, P., Shakya, N. K., & Mohanty, C. (2020). Teratogenic effects (resorptions and reduction in weight and crown rump length) of valproate on fetal mice. National Journal of Clinical Anatomy, 9(2), 39.
Sultana, S., Doshi, M., Jayasree, N., & Chandrupatla, M. (2019). Comparative study of drug damage caused on Cerebrum in Chick Embryos administered with Drugs-Cyclophosphamide and Sodium Valproate. Journal of Pharmaceutical Sciences and Research, 11(7), 2774-2777.
Vafaee-Shahi, M., Soheilipour, F., Mohagheghi, P., Riahi, A., Borghei, N.-S., & Talebi, A. (2022). Effect of Sodium Valproate on Weight, Body Mass Index, Uric Acid, Vitamin D3, Blood Insulin, and Serum Lipid Profile in Children. The Open Neurology Journal, 16(1).