Haloalkane induced hepatic insult in murine model: amelioration by Oleander through antioxidant and anti-inflammatory activities, an in vitro and in vivo study

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Abstract

Background

Nerium oleander L. (syn. Nerium indicum Mill, Nerium odorum Aiton) belongs to the family Apocynaceae. It is used for its anti-inflammatory, anti-diabetic, anti-cancer and hepatoprotective activities in traditional medicine. Previous pharmacognostic studies suggested that 70 % hydro-methanolic extracts of oleander possess potent free radical scavenging and anti-inflammatory activities, both of which are helpful against hepatotoxicity.

Methods

Hydro-methanolic extracts of oleander stem and root were evaluated for their hepatoprotective activities in acute CCl ₄ intoxicated mouse through in vitro and in vivo studies. Silymarin was used as positive reference. Antioxidant enzymes, pro-inflammatory markers and liver enzymatic and biochemical parameters were studied. The extracts were further chemically characterized using Fourier Transform Infrared (FTIR) spectroscopy and Gas chromatography-mass spectrometry (GC-MS).

Results

CCl ₄ toxicity caused fatty liver formation by increase of relative liver weight (32.53 g) compared to control group (16.08 g). The elevated liver enzymatic and biochemical parameters due to CCl ₄ toxicity were considerably normalized by the extracts treatment under both in vivo and in vitro models. Oleander stem (NOSE) and root (NORE) extracts increased the reduced hepatic catalase activity 27.37 and 25.25 %, whereas peroxidase activity was increased 18.19 and 22.78 %, respectively. The extent of lipid peroxidation was significantly ( p < 0.01) lowered 20.76 % (NOSE) and 21.12 % (NORE) compared to CCl ₄ group. The levels of pro-inflammatory tumor necrosis factor-α (TNF-α) was lowered 71.33 % (NOSE) and 61.60 % (NORE). Histopathological study demonstrated substantial reduction of hepatocellular necrosis, fatty infiltration, sinusoidal dilation, bile duct proliferation, vascular congestion, leukocyte infiltration in the silymarin and extract treated groups. Furthermore, various bioactive compounds were identified in the extracts such as apocynin, tocopherol, squalene, vanillin, isoeugenol, amyrin, lupeol etc.

Conclusion

The present study provided convincing evidence that oleander extracts possess potent hepatoprotective capacity which was primarily governed by its antioxidant and anti-inflammatory activities. The collegial bioactivities of the phytochemicals may be accredited behind the hepatoprotective activity of oleander.

Electronic supplementary material

The online version of this article (doi:10.1186/s12906-016-1260-4) contains supplementary material, which is available to authorized users.

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Most cited references 39

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Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model.

Lutz Weber, Meinrad Boll, Andreas Stampfl (2003)

The use of many halogenated alkanes such as carbon tetrachloride (CCl4), chloroform (CHCl3) or iodoform (CHI3), has been banned or severely restricted because of their distinct toxicity. Yet CCl4 continues to provide an important service today as a model substance to elucidate the mechanisms of action of hepatotoxic effects such as fatty degeneration, fibrosis, hepatocellular death, and carcinogenicity. In a matter of dose,exposure time, presence of potentiating agents, or age of the affected organism, regeneration can take place and lead to full recovery from liver damage. CCl4 is activated by cytochrome (CYP)2E1, CYP2B1 or CYP2B2, and possibly CYP3A, to form the trichloromethyl radical, CCl3*. This radical can bind to cellular molecules (nucleic acid, protein, lipid), impairing crucial cellular processes such as lipid metabolism, with the potential outcome of fatty degeneration (steatosis). Adduct formation between CCl3* and DNA is thought to function as initiator of hepatic cancer. This radical can also react with oxygen to form the trichloromethylperoxy radical CCl3OO*, a highly reactive species. CCl3OO* initiates the chain reaction of lipid peroxidation, which attacks and destroys polyunsaturated fatty acids, in particular those associated with phospholipids. This affects the permeabilities of mitochondrial, endoplasmic reticulum, and plasma membranes, resulting in the loss of cellular calcium sequestration and homeostasis, which can contribute heavily to subsequent cell damage. Among the degradation products of fatty acids are reactive aldehydes, especially 4-hydroxynonenal, which bind easily to functional groups of proteins and inhibit important enzyme activities. CCl4 intoxication also leads to hypomethylation of cellular components; in the case of RNA the outcome is thought to be inhibition of protein synthesis, in the case of phospholipids it plays a role in the inhibition of lipoprotein secretion. None of these processes per se is considered the ultimate cause of CCl4-induced cell death; it is by cooperation that they achieve a fatal outcome, provided the toxicant acts in a high single dose, or over longer periods of time at low doses. At the molecular level CCl4 activates tumor necrosis factor (TNF)alpha, nitric oxide (NO), and transforming growth factors (TGF)-alpha and -beta in the cell, processes that appear to direct the cell primarily toward (self-)destruction or fibrosis. TNFalpha pushes toward apoptosis, whereas the TGFs appear to direct toward fibrosis. Interleukin (IL)-6, although induced by TNFalpha, has a clearly antiapoptotic effect, and IL-10 also counteracts TNFalpha action. Thus, both interleukins have the potential to initiate recovery of the CCl4-damaged hepatocyte. Several of the above-mentioned toxication processes can be specifically interrupted with the use of antioxidants and mitogens, respectively, by restoring cellular methylation, or by preserving calcium sequestration. Chemicals that induce cytochromes that metabolize CCl4, or delay tissue regeneration when co-administered with CCl4 will potentiate its toxicity thoroughly, while appropriate CYP450 inhibitors will alleviate much of the toxicity. Oxygen partial pressure can also direct the course of CCl4 hepatotoxicity. Pressures between 5 and 35 mmHg favor lipid peroxidation, whereas absence of oxygen, as well as a partial pressure above 100 mmHg, both prevent lipid peroxidation entirely. Consequently, the location of CCl4-induced damage mirrors the oxygen gradient across the liver lobule. Mixed halogenated methanes and ethanes, found as so-called disinfection byproducts at low concentration in drinking water, elicit symptoms of toxicity very similar to carbon tetrachloride, including carcinogenicity.

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Idiosyncratic drug hepatotoxicity.

Neil Kaplowitz (2005)

The occurrence of idiosyncratic drug hepatotoxicity is a major problem in all phases of clinical drug development and the most frequent cause of post-marketing warnings and withdrawals. This review examines the clinical signatures of this problem, signals predictive of its occurrence (particularly of more frequent, reversible, low-grade injury) and the role of monitoring in prevention by examining several recent examples (for example, troglitazone). In addition, the failure of preclinical toxicology to predict idiosyncratic reactions, and what can be done to improve this problem, is discussed. Finally, our current understanding of the pathophysiology of experimental drug hepatotoxicity is examined, focusing on acetaminophen, particularly with respect to the role of the innate immune system and control of cell-death pathways, which might provide targets for exploration and identification of risk factors and mechanisms in humans.

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Nitric oxide: a cytotoxic activated macrophage effector molecule.

John Hibbs, Read Taintor, Zdenek Vavrin … (1988)

The experiments reported here identify nitric oxide as a molecular effector of activated macrophage induced cytotoxicity. Cytotoxic activated macrophages synthesize nitric oxide from a terminal guanidino nitrogen atom of L-arginine which is converted to L-citrulline without loss of the guanidino carbon atom. In addition, authentic nitric oxide gas causes the same pattern of cytotoxicity in L10 hepatoma cells as is induced by cytotoxic activated macrophages (iron loss as well as inhibition of DNA synthesis, mitochondrial respiration, and aconitase activity). The results suggest that nitric oxide is the precursor of nitrite/nitrate synthesized by cytotoxic activated macrophages and, via formation of iron-nitric oxide complexes and subsequent degradation of iron-sulfur prosthetic groups, an effector molecule.

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Author and article information

Contributors

Priyankar Dey: +91-9531563048 , priyankardey28@gmail.com

Somit Dutta: +91-7679864902 , somitimmuno@gmail.com

Anashuya Biswas-Raha: +91- 9830825387 , anashuyabiswas88@gmail.com

Mousumi Poddar Sarkar: +91-9433096627 , mpsarkar1@rediffmail.com

Tapas Kumar Chaudhuri: +91-8927884784 , +91-9434377127 , dr_tkc_nbu@rediffmail.com , tapas.chaudhuri@gmail.com

Journal

Journal ID (nlm-ta): BMC Complement Altern Med

Journal ID (iso-abbrev): BMC Complement Altern Med

Title: BMC Complementary and Alternative Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1472-6882

Publication date (Electronic): 11 August 2016

Publication date PMC-release: 11 August 2016

Publication date Collection: 2016

Volume: 16

Electronic Location Identifier: 280

Affiliations

[1 ]Cellular Immunology Laboratory, Department of Zoology, Life Science Building, University of North Bengal, PO: Raja Rammohunpur, Siliguri, 734013 West Bengal India

[2 ]Chemical Signal and Lipidomics Laboratory, Department of Botany, University of Calcutta, Kolkata, 700019 India

Article

Publisher ID: 1260

DOI: 10.1186/s12906-016-1260-4

PMC ID: 4982413

PubMed ID: 27516209

SO-VID: 402aacd6-7bd2-4c5e-b970-ea2ec61d189a

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 28 January 2016

Date accepted : 5 August 2016

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ScienceOpen disciplines: Complementary & Alternative medicine

Keywords: hepatoprotective,inflammation,liver,nerium,oxidative stress,xenobiotic

Data availability:

ScienceOpen disciplines: Complementary & Alternative medicine

Keywords: hepatoprotective, inflammation, liver, nerium, oxidative stress, xenobiotic

Haloalkane induced hepatic insult in murine model: amelioration by Oleander through antioxidant and anti-inflammatory activities, an in vitro and in vivo study

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Most cited references 39

Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model.

Idiosyncratic drug hepatotoxicity.

Nitric oxide: a cytotoxic activated macrophage effector molecule.

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