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. 2024 Jan 18:12:200-214.
doi: 10.1016/j.toxrep.2024.01.011. eCollection 2024 Jun.

Anti-apoptotic and antioxidant mechanisms may underlie the abrogative potential of Ocimum gratissimum Linn. Leaf extract and fractions against trastuzumab-induced cardiotoxicity in Wistar rats

Olufunke Esan Olorundare  1 , Adejuwon Adewale Adeneye  2 , Akinyele Olubiyi Akinsola  1 , Abayomi Mayowa Ajayi  3 , Olubunmi Atolani  4 , Sunday Sokunle Soyemi  5 , Alban Ikenna Mgbehoma  5 , Ralph Muehl Albrecht  6
Affiliations

Anti-apoptotic and antioxidant mechanisms may underlie the abrogative potential of Ocimum gratissimum Linn. Leaf extract and fractions against trastuzumab-induced cardiotoxicity in Wistar rats

Olufunke Esan Olorundare et al. Toxicol Rep. .

Abstract

Clinical use of trastuzumab (TZM), has been widely associated with increased incidence of cardiotoxicity. Ocimum gratissimum Linn. is a household medicinal plant popularly used for treating inflammatory conditions. In this study, we investigated the abrogative potential of 100 mg/kg/day of the ethanol leaf extract of Ocimum gratissimum Linn. (OG) and its petroleum ether (PEOG), ethyl acetate (EAOG) and ethanol (EOG) fractions in TZM intoxicated Wistar rats for 7 days using anthropometric, biochemical, histopathological and immunohistochemical endpoints. In addition, secondary metabolite constituents in OG and its fractions were determined through Gas Chromatography-Mass Spectrometry (GC-MS). The study results showed that oral pretreatments with OG and OG fractions as well as the fixed dose valsartan-lisinopril (VAL-LSP) combination effectively ameliorated and restore nearly normal levels the TZM-altered plasma cardiac troponin I and antioxidant profile which were corroborated by histopathological and immunohistochemical findings as indicated by the inhibition of TZM-induced activation of caspases-3 and - 9 and profound upregulation of BCL-2 expression. Phytoscan of OG and its fractions showed the presence of thymol and in high amount. Overall, our findings revealed the cardioprotective potentials of OG, OG fractions and fixed dose VAL-LSP combination against TZM-induced cardiotoxicity which probably was mediated via abrogation of cardiomyocyte apoptosis and antioxidant mechanisms.

Keywords: Apoptosis markers; Ethanol leaf extract and solvent fractions; Ocimum gratissimum Linn.; Oxidative stress markers; Trastuzumab-induced cardiotoxicity; Wistar rats.

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Conflict of interest statement

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Olufunke Esan OLORUNDARE reports financial support was provided by Tertiary Education Trust Fund. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

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Graphical abstract
Fig. 1
Fig. 1
GC-MS fingerprints/phytoscan showing the relative abundance of the secondary metabolites identifiable in OG(1 A), PEOG(1B), EAOG(1 C) and EOG(1D).
Fig. 2
Fig. 2
Depicts the effect of oral treatments with TZM, OG, PEOG, EAOG and EOG on plasma TG (2 A), TChol. (2B), HDL-c (2 C), LDL-c (2D) and VLDL-c (2E) in TZM-intoxicated rats. Bar represents mean ± SEM (n = 5), significant difference denoted by #p < 0.05 vs Group I or *p < 0.05 vs Group II by one-way ANOVA followed by Tukey’s post hoc test.
Fig. 3
Fig. 3
Effect of OG and fractions on plasma atherogenicity {AI (3 A) and HDL-c ÷ LDL-c ratio (3B)} and plasma coronary artery index (CRI) (3 C) in TZM-treated rats. Bar represents mean ± SEM (n = 5), significant difference denoted by #p < 0.05 vs Veh.only-treated group or *p < 0.05 vs Veh. + TZM-treated group by one-way ANOVA followed by Tukey’s post hoc test.
Fig. 4
Fig. 4
A representative photographic section of (i). Veh.only-treated cardiac tissue showing normal coronary vasculature (indicated in brown thick arrow) and normal cardiomyocytes (indicated in purple thick arrows) (x100 magnification, Hematoxylin & Eosin stains) (4 A); (ii). Veh. + TZM-treated rat cardiac tissue showing myocardiocyte degeneration with cartilaginous degeneration (indicated in black thick arrow) and severe coronary arteriolar congestion indicated in red thick arrow (x100 magnification, Hematoxylin & Eosin stains) (4B); (iii). OG-only pretreated cardiac tissue showing normal cardiomyocytes (indicated in purple thick arrows) (x100 magnification, Hematoxylin & Eosin stains) (4 C); (iv). OG + TZM-treated rat cardiac tissue showing moderate coronary arteriolar congestion and coronary artery tunica media thickening indicated by red thick and blue thick arrows, respectively (x100 magnification, Hematoxylin & Eosin stains) (4D); (v). PEOG-only pretreated rat cardiac tissue showing coronary artery tunica media hyperplasia resulting in its narrowing (x100 magnification, Hematoxylin & Eosin stain) (4E); (vi). PEOG + TZM-treated rat cardiac tissue showing myocardial scarring (indicated in blue thin arrow) (x400 magnification, Hematoxylin & Eosin stain) (4 F); (vii). EAOG-only pretreated cardiac tissue showing normal coronary vessels and cardiomyocytes (x100 magnification, Hematoxylin & Eosin stains) (4 G); (viii). EAOG + TZM-treated rat heart tissue showing coronary artery tunica media hyperplasia and cartilaginous deposits in blue thick and black thick arrows, respectively (x100 magnification, Hematoxylin & Eosin stains) (4 H); EOG-only pretreated cardiac tissue showing diffuse cardiomyocyte hypertrophy indicated in yellow thick arrow (x100 magnification, Hematoxylin & Eosin stains) (4I); EOG + TZM-treated rat heart tissue showing mild coronary artery tunica media thickening/hyperplasia indicated in blue thick arrow (x100 magnification, Hematoxylin & Eosin stains) (4 J); VAL + LSP fixed dose combination-only pretreated cardiac tissue showing normal coronary vessels (indicated in the brown thick arrows) and normal cardiomyocytes (indicated in purple thick arrows) ((x100 magnification, Hematoxylin & Eosin stains) (4 K); VAL-LSP fixed dose combination + TZM-treated rat heart tissue showing coronary artery cystic medial degeneration indicated in orange thin arrow (x400 magnification, Hematoxylin & Eosin stains) (4 L).
Fig. 5
Fig. 5
Effect of oral pretreatment with OG, PEOG, EAOG and EOG on cardiac caspase-3 (5 A) and cardiac caspase-9 (5B) in TZM-intoxicated rats.
Fig. 6
Fig. 6
. (A) Representative section of photomicrographs of immunohistochemical staining of cardiac tissue caspase-3 expression of cardiac tissues pretreated with OG and fractions (magnification x 400), and (B) Intensity score of expressions. Bar represents mean ± SEM (n = 3), significant difference denoted by #p < 0.05 vs Veh.only-treated group or *p < 0.05 vs Veh + TZM-treated group by One-way ANOVA followed by Tukey’s post hoc test.
Fig. 7
Fig. 7
. (A) Representative section of photomicrographs of immunohistochemical staining of cardiac tissue BCL-2 expression (magnification x 400), and (B) Intensity score of expressions. Bar represents mean ± SEM (n = 3), significant difference denoted by #p < 0.05 vs Veh.-only treated or *p < 0.05 vs Veh. + TZM–treated group by One-way ANOVA followed by Tukey’s post hoc test.
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