Andrographolide protects rat hepatocytes against paracetamol-induced damage

doi:10.1016/0378-8741(93)90058-D

Journal of Ethnopharmacology

Volume 40, Issue 2, October 1993, Pages 131-136

https://doi.org/10.1016/0378-8741(93)90058-D Get rights and content

Abstract

Andrographolide, the active constituent isolated from the plant Andrographis paniculata, showed a significant dose dependent (0.75–12 mg/kg p.o. × 7) protective activity against paracetamol-induced toxicity on ex vivo preparation of isolated rat hepatocytes. It significantly increased the percent viability of the hepatocytes as tested by trypan blue exclusion and oxygen uptake tests. It completely antagonized the toxic effects of paracetamol on certain enzymes (GOT, GPT and alkaline phosphatase) in serum as well as in isolated hepatic cells. Andrographolide was found to be more potent than silymarin, a standard hepatoprotective agent.

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Cited by (146)

Hepatoprotective activity of andrographolide possibly through antioxidative defense mechanism in Sprague-Dawley rats

2022, Toxicology Reports

Citation Excerpt :

This bioactive compound has anti-inflammatory, antiviral, anti-atherosclerotic, anti-thrombotic, anti-neoplastic [16], and neuropharmacological properties, among others [17–20]. Some earlier studies also reported the protective activity of AGL against hepato-toxins induced liver damage [21–23]. Acute and chronic liver damage can be produced by different in vivo models [24].

The aims of this study to assess the efficiency of AGL against acetaminophen (APAP)-induced hepatic toxicity that was generated by mitochondrial oxidative stress and glutathione depletion. Free radical scavenging potentiality was analyzed by using 2, 2-diphenyl-1-picrylhydrazyl (DPPH), hydrogen peroxide, nitric oxide, and hydroxyl radical scavenging assays. APAP-induced liver toxicity was formed at a dose level of 640 mg/kg mg/kg BW each, p.o. for 14 days for all experimental rats except the vehicle control group. AGL (5 and 10 mg/kg) were treated orally with negative control and negative control silymarin (50 mg/kg) group. To assess the protective effect, we looked at the levels of serum biochemical markers, liver histoarchitecture, and hepatic antioxidant enzyme activity. AGL showed in vitro anti-oxidant potentialities by scavenging radicals in the respective assays. As evidenced by serum biochemical indicators and relative liver weight, AGL co-administration substantially reduced toxicant-induced hepatic damage. APAP-intoxication increased the malondialdehyde (MDA) level and declined in cellular endogenous antioxidant enzymes such as reduced catalase, superoxide dismutase, and glutathione, where, AGL treatment amended their level. In the same way, histopathological evaluation further verified that AGL protected the hepatocyte from APAP-induced damage. As AGL scavenges toxic free radicals, thereby protects mitochondria and other organelles from reactive oxygen and nitrogen species-mediated stress and its eventual consequence necrosis. Therefore, we propose the hepatoprotective activity of AGL through its antioxidant mechanism.
Oral andrographolide nanocrystals protect liver from paracetamol induced injury in mice

2020, Journal of Drug Delivery Science and Technology

Citation Excerpt :

AG pre-treatment offered protection against liver injury which is apparent from the reduced serum markers levels (p < 0.05). The observation was found to be in agreement with previous reports on AG in free radical induced liver conditions [43]. Serum marker levels tend to reduce upon pre-treatment with AGNC (low dose), probably due to rapid absorption of AG in nanonized form.

Andrographolide (AG) is a labdane di-terpenoid obtained from aerial parts of Andrographis paniculata. Though known as a potent bioactive in a myriad of biological conditions, the applications of AG in translational medicine are mostly limited due to its low aqueous solubility and poor bioavailability. Nanocrystal technology was envisaged as a possible solution. Andrographolide nanocrystals (AGNC) were prepared through solvent-diffusion followed by homogenization. AGNC hydrodynamic diameter of 630 ± 12 nm and crystallinity changes led to significant increase of aqueous solubility and intestinal permeation ex vivo. Pharmacodynamic studies on mice showed that AGNC exerted hepatoprotective activity at a lower dose against paracetamol induced liver injury, in comparison to crude AG. The work highlighted that nanocrystal technology can be considered as one platform for circumventing the biopharmaceutical limitations of AG. This also ensures significant successes in biological applications.
Total Synthesis of Bioactive Natural Products

2019, Total Synthesis of Bioactive Natural Products
Evaluation of the effect of andrographolide and methotrexate combined therapy in complete Freundʼs adjuvant induced arthritis with reduced hepatotoxicity

2018, Biomedicine and Pharmacotherapy

Methotrexate is one of the most widely used disease-modifying anti-rheumatic drugs. The hepatotoxicity of methotrexate resulted in poor compliance with therapy. The current study was designed to analyse the combined therapy of andrographolide (AD) and methotrexate (MTX) for complete Freund's adjuvant (CFA)-induced arthritis, focusing on hepatoprotective effects, oxidative stress and arthritic-related cytokines.

Wistar rats were injected with CFA into the right hind paw. Ten days post-CFA injection, the Wistar rats were administered with 1% CMC-Na solution, methotrexate (2 mg/kg/week), AD (50 mg/kg/d) and combined therapy for 35 days. The anti-arthritic effect was assessed by paw volume, X-ray and serum tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β levels. Serum samples were also analysed for glutamic oxaloacetic transaminases (GOT), serum glutamic pyruvic transaminase (GPT), alkaline phosphatase (AKP) and lactate dehydrogenase (LDH). Liver tissue samples were used to examine the cellular antioxidant defence activities using catalase activity (CAT) and GSH as well as GSH-Px and MDA. Histopathology analysis was conducted to evaluate liver damage.

AD treatment strengthened the anti-arthritic capacity of MTX. AD and MTX-combined therapy additively reduced the inflammatory symptoms in CFA rats. The combined therapy of AD and MTX showed hepatoprotective effect indicated by an improvement in the serum marker, possibly due to antioxidant action and confirmed by liver histopathological changes. Furthermore, the combined therapy significantly reduced serum TNF-α, IL-6 and IL-1β levels.

A combined therapy of AD and methotrexate significantly alleviated MTX-induced hepatocellular injury and strengthened the anti-arthritic effect. Further clinical studies should be done to further verify the possibility of combined its clinical usage.
Natural product andrographolide alleviated APAP-induced liver fibrosis by activating Nrf2 antioxidant pathway

2018, Toxicology

Citation Excerpt :

Previous studies showed that Andro attenuated liver fibrosis induced by thioacetamide and in experimental non-alcoholic steatohepatitis (Lee et al., 2014; Cabrera et al., 2017). Moreover, Andro and its nanoparticle have already been reported to prevent APAP-induced acute liver injury in mice (Visen et al., 1993; Roy et al., 2013). However, whether Andro also alleviates liver fibrosis induced by long-term ingestion of APAP is not known.

As a well-known analgesic drug, acetaminophen (APAP) is commonly used to relieve pain for patients with chronic painful diseases. Our previous study has shown that long-term ingestion of APAP caused liver fibrosis in mice. This study further investigated the critical role of nuclear factor erythroid 2-related factor 2 (Nrf2) in regulating APAP-induced liver fibrosis in mice and the anti-fibrotic effect of natural compound andrographolide (Andro). Our results showed that hepatic collagen deposition and hepatic stellate cells (HSCs) activation induced by APAP were more serious in Nrf2 knock-out mice than in normal wild-type mice. Andro reduced HSCs activation in vitro, and also decreased hepatic collagen deposition and HSCs activation induced by APAP in mice. Andro alleviated liver oxidative stress injury induced by APAP in mice and reduced cellular formation of reactive oxygen species (ROS) in HSCs. Andro enhanced Nrf2 nuclear translocation and increased the expression of Nrf2 downstream antioxidant genes both in vitro and in vivo. Furthermore, the Andro-provided protection against APAP-induced liver fibrosis was diminished in Nrf2 knock-out mice. In summary, Nrf2 is critically involved in preventing liver fibrosis induced by long-term administration of APAP in mice, and Andro alleviates APAP-induced liver fibrosis by attenuating liver oxidative stress injury via inducing Nrf2 activation. This study points out the potential application of Andro in the treatment of liver fibrosis in clinic.
Is there a future for andrographolide to be an anti-inflammatory drug? Deciphering its major mechanisms of action

2017, Biochemical Pharmacology

Andrographis paniculata has long been part of the traditional herbal medicine system in Asia and in Scandinavia. Andrographolide was isolated as a major bioactive constituent of A. paniculata in 1951, and since 1984, andrographolide and its analogs have been scrutinized with modern drug discovery approach for anti-inflammatory properties. With this accumulated wealth of pre-clinical data, it is imperative to review and consolidate different sources of information, to decipher the major anti-inflammatory mechanisms of action in inflammatory diseases, and to provide direction for future studies. Andrographolide and its analogs have been shown to provide anti-inflammatory benefits in a variety of inflammatory disease models. Among the diverse signaling pathways investigated, inhibition of NF-κB activity is the prevailing anti-inflammatory mechanism elicited by andrographolide. There is also increasing evidence supporting endogenous antioxidant defense enhancement by andrographolide through Nrf2 activation. However, the exact pathway leading to NF-κB and Nrf2 activation by andrographolide has yet to be elucidated. Validation and consensus on the major mechanistic actions of andrographolide in different inflammatory conditions are required before translating current findings into clinical settings. There are a few clinical trials conducted using andrographolide in fixed combination formulation which have shown anti-inflammatory benefits and good safety profile. A concerted effort is definitely needed to identify potent andrographolide lead compounds with improved pharmacokinetics and toxicological properties. Taken together, andrographolide and its analogs have great potential to be the next new class of anti-inflammatory agents, and more andrographolide molecules are likely moving towards clinical study stage in the near future.

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^☆: CDRI Communication No. 4916.

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Journal of Ethnopharmacology

Abstract

References (14)

A method for the rapid determination of alkaline phosphatase with five cubic millimeters of serum

Journal of Biological Chemistry

Plasma paracetamol half life and hepatic necrosis in patients with paracetamol overdosage

Lancet

Prevention of paracetamol-induced hepatic damage in rats by picroliv, the standardized active fraction from Picrorhiza kurroa

Phytolherapy Research

Mitochondrial respiratory control polarographic measurement of ADP:O ratios

Methods in Enzymology

Hepatoprotective activity of andrographolide from Andrographis paniculata against carbon tetrachloride

Indian Journal of Medical Research

Hepatoprotective activity of andrographolide against galactosamine and paracetamol interaction in rats

Indial Journal of Medical Research

Natural products and plants as liver protecting drugs

Fitolerapia

Cited by (146)

Hepatoprotective activity of andrographolide possibly through antioxidative defense mechanism in Sprague-Dawley rats

Oral andrographolide nanocrystals protect liver from paracetamol induced injury in mice

Total Synthesis of Bioactive Natural Products

Evaluation of the effect of andrographolide and methotrexate combined therapy in complete Freundʼs adjuvant induced arthritis with reduced hepatotoxicity

Natural product andrographolide alleviated APAP-induced liver fibrosis by activating Nrf2 antioxidant pathway

Is there a future for andrographolide to be an anti-inflammatory drug? Deciphering its major mechanisms of action

Andrographolide protects rat hepatocytes against paracetamol-induced damage☆

Abstract

Journal of Biological Chemistry

Lancet

Prevention of paracetamol-induced hepatic damage in rats by picroliv, the standardized active fraction from Picrorhiza kurroa

Phytolherapy Research

Mitochondrial respiratory control polarographic measurement of ADP:O ratios

Methods in Enzymology

Hepatoprotective activity of andrographolide from Andrographis paniculata against carbon tetrachloride

Indian Journal of Medical Research

Hepatoprotective activity of andrographolide against galactosamine and paracetamol interaction in rats

Indial Journal of Medical Research

Natural products and plants as liver protecting drugs

Fitolerapia