Herbal Induced Hepatoprotection and Hepatotoxicity: A Critical Review.

Traditional herbal drugs are wonderful remedies for the treatment of various devastating disorders. Recently, there has been a change in a universal fashion from synthetic to herbal medicine, which is like homecoming to nature. In the present situation, the dietary changes lead to liver disorders like non-alcoholic and alcoholic fatty liver disorders. India is one of the world's twelve leading biodiversity centers with the presence of over 45,000 diverse plant species, out of this about 15,000-20,000 plants have good medicinal and therapeutic properties of which only about 7,000-7,500 are being used by traditional practitioners. Hepatic injury accounts for 3.5%-9.5% of all adverse drug reaction reports and up to 14.7% of fatal adverse reaction. Hepatic disorders/toxicity can occur by several mechanisms like Cytochrome P450 activation, lipid peroxidation, Induction of nitric acid synthase, mitochondrial dysfunction, activation of pro-inflammatory mediators and Bile acid-induced liver cell death. There are a number of drugs or therapies available for the treatment of hepatic disorders, but still there is a need for the novel drug discovery which can target multiple disease pathways. Traditional medicines have exhaustive ancient and scientific literature for curing a lot of life threatening disorders with less or no side effects. There are number of scientifically proved hepatoprotective herbal drugs like Andrographis paniculata, Ocimum sanctum, Solanum nigrum, Silybum marianum, Phyllanthus niruri etc. which are widely used for the treatment of liver disorders. However, there are various herbal plants and phytoconstituents, which are found to be hepatotoxic like Lanata camra Linn, Symphytum officinale, Azadirachta indica, Amantia phalloides etc. This review emphasizes on both sides of the coin like crucial aspects of phytoconstituents with reference to their hepatoprotective as well as hepatotoxic effects linked to use of herbal preparations.

Effect of chenodeoxycholic acid and sodium hydrogen sulfide in dinitro benzene sulfonic acid (DNBS)--Induced ulcerative colitis in rats.

BACKGROUND: Ulcerative colitis is a chronic inflammatory condition in which the inflammatory response confined to the colon. There is a need to explore the new targets for UC such as Farnesoid X receptor and hydrogen sulfide pathway. METHODS: Wistar rats of either sex (200-250 g) were used. 2,4-Dinitrobenzene sulfonic acid (DNBS) (25mg/rat) given by rectal route into the colon to induced symptoms of ulcerative colitis. Chenodeoxycholic acid (CDCA) (10 and 20mg/kg) and sodium hydrogen sulfide (NaHS) (10 and 30 µmol/kg) and a inhibitor of cystathionine-γ-lyase enzyme (CSE) i.e. dl-propargylglycine (10mg/kg) treatment given along with 2,4-dinitrobenzene sulfonic acid. The disease activity index was assessed by daily change in body weight and rectal bleed score and change in length of colon. Oxidative stress markers (reduced glutathione, malondialdehyde (MDA), nitrite, and catalase and myeloperoxidase enzyme activity), serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels in blood serum, and cardiac hemodynamic were performed on last day. RESULTS: The administration of DNBS intra-rectally in rats produced loss of body weight and bloody diarrhea with significant increase in oxidative stress markers in the colon. CDCA (10 and 20mg/kg) and NaHS (10 and 30 µmol/kg) significantly attenuated DNBS-induced UC in rats. The combination of CDCA (10mg/kg) and NaHS (10 µmol/kg) showed synergetic effect whereas; dl-propargylglycine reversed the protective effect of CDCA. CONCLUSION: The observed beneficial effects following CDCA may be due to its action through activation of CSE enzyme which leads to hydrogen sulfide generation.

Animal models of inflammatory bowel disease: a review.

Inflammatory bowel disease (IBD) represents a group of idiopathic chronic inflammatory intestinal conditions associated with various areas of the GI tract, including two types of inflammatory conditions, i.e., ulcerative colitis (UC) and Crohn's disease (CD). Both UC and CD are chronic inflammatory disorders of the intestine; in UC, inflammation starts in the rectum and generally extends proximally in a continuous manner through the entire colon. Bloody diarrhea, presence of blood and mucus mixed with stool, accompanied by lower abdominal cramping, are the characteristic symptoms of the disease. While in CD, inflammatory condition may affect any part of the GI tract from mouth to anus. It mainly causes abdominal pain, diarrhea, vomiting and weight loss. Although the basic etiology of IBD is unknown, there are several factors that may contribute to the pathogenesis of this disease, such as dysregulation of immune system or commensal bacteria, oxidative stress and inflammatory mediators. In order to understand these different etiological factors, a number of experimental models are available in the scientific research, including chemical-induced, spontaneous, genetically engineered and transgenic models. These models represent a major source of information about biological systems and are clinically relevant to the human IBD. Since there is less collective data available in one single article discussing about all these models, in this review an effort is made to study the outline of pathophysiology and various types of animal models used in the research study of IBD and other disease-related complications.

Anti-inflammatory and anti-hyperalgesic effect of all-trans retinoic acid in carrageenan-induced paw edema in Wistar rats: involvement of peroxisome proliferator-activated receptor-ß/δ receptors.

OBJECTIVE: In this study, we investigated the role of peroxisome proliferator-activated receptors (PPAR)-ß/δ receptors in carrageenan-induced inflammation and in the anti-inflammatory effects of all-trans retinoic acid (ATRA). MATERIALS AND METHODS: The λ-carrageenan (0.1 ml of 1% w/v) was injected into intra-plantar (i.pl.) region of the hind paw to produce acute inflammation. Paw volume was measured by using the mercury plethysmography. Further, mechanical and thermal hyperalgesia (TH) were assessed by using the dynamic plantar aesthesiometer and plantar test apparatus, respectively. In addition, markers of oxido-nitrosative stress were assessed spectrophotometrically in the hind paw tissue 5 h post-carrageenan. RESULTS: An i.pl injection of carrageenan has produced a marked mechanical hyperalgesia (MH) and TH in ipsilateral paw, which was associated with significant elevated oxido-nitrosative stress. Treatment with ATRA (5 mg/kg/p.o/4 days) and GW0742, a selective PPAR-ß/δ receptor agonist (0.1 mg/kg/i.p/4 days), significantly decreased the paw volume, mechanical and TH as compared to vehicle control. Administration of GSK0660, selective PPAR-ß/δ receptor antagonist, at a dose of (0.3 mg/kg/i.p/4 days), did not produce a significant effect on carrageenan-induced paw edema, MH and TH. However, co-administration of GSK0660 (0.3 mg/kg/i.p/4 days) along with both ATRA (5 mg/kg/p.o/4 days) and GW0742 (0.1 mg/kg/i.p/4 days), significantly reverse the decreased paw edema, MH, and TH. These observed ameliorative effects on inflammatory pain symptoms are correlated with the extent of reduction of oxido-nitrosative stress. CONCLUSION: From above findings, it can be concluded that ATRA exerts anti-inflammatory and anti-hyperalgesic effect, possibly through activation of PPAR-ß/δ and subsequent reduction of oxido-nitrosative stress.

Pharmacological activation of heme oxygenase (HO)-1/carbon monoxide pathway prevents the development of peripheral neuropathic pain in Wistar rats.

Recent studies have emphasized the contribution of neuroinflammation and oxido-nitrosative stress to neuropathic pain. Both, heme oxygenase (HO)-1 and carbon monoxide (CO) play an important role in regulating free radical generation and inflammation. Herein, we investigated the role of HO-1/CO pathway, by using hemin, a selective HO activator, and CO-releasing molecule (CORM)-2, a CO-releasing agent, in rat sciatic nerve chronic constriction injury (CCI)-induced neuropathic pain. CCI rats exhibited full development of behavioral hypersensitivity symptoms, including cold allodynia, mechanical and thermal hyperalgesia and also exhibit of a significant increase in spinal cord pro-inflammatory cytokines (TNF-α and IL-1ß) and oxido-nitrosative stress markers, both in spinal cord and ipsilateral sciatic nerve homogenate. Spinal (10 and 30 µg/rat, intrathecal (i.t.)), but not systemic (5 and 10 mg/kg, subcutaneous (s.c.)), administration of hemin for 14 days significantly prevented the development of behavioral hypersensitivity. Further, simultaneous administration of hemin via spinal (10 µg/rat, i.t.) and systemic (5 mg/kg, s.c.) routes led to a more pronounced inhibition of the development of behavioral hypersensitivity. Further, administration of CORM-2 (1 and 5 mg/kg, s.c.), dose-dependently and most effectively, prevented the development of behavioral hypersensitivity. Both hemin and CORM-2 produced ameliorative beneficial effects that paralleled with the extent of reduction of oxido-nitrosative stress and pro-inflammatory cytokines. Also, hemin and CORM-2 significantly improved the levels of HO-1 and activity of anti-oxidant enzymes such as superoxide dismutase and catalase. Thus, it may be concluded that chronic pharmacological activation of HO-1/CO pathway may prevent the development of behavioral symptoms of neuropathic pain, through an activation of anti-inflammatory and anti-oxidant mechanisms.

Antiepileptic potential of Anisomeles indica (Linn.) Kuntze aerial parts in pentylenetetrazole-induced experimental convulsions in Wistar rats.

The chloroform (4.20% w/w), ethyl acetate (4.23% w/w) and aqueous decoction (12.11% w/w) extracts of the aerial parts of A. indica were screened for the antiepileptic activity against maximal electroshock (MES) model and pentylenetetrazole (PTZ) models at doses of 200, 400 mg/kg, po once. Phenytoin and diazepam (25 and 2 mg/kg, ip) were used as standard drugs in MES and PTZ model, respectively. Further, ethyl acetate extract (active extract) was fractionated into flavonoid and tannin fraction, which were subsequently evaluated for the antiepileptic potential against both MES and PTZ models at a dose of 50 mg/kg, po. Pretreatment with ethyl acetate extract 200, 400 mg/kg, po, for 1 week showed significant antiepileptic activity against PTZ induced convulsions only. Isolated flavonoid fraction showed more potent antiepileptic activity as compared to ethyl acetate extract, without any neurotoxic effect. However, tannin fraction did not produce antiepileptic activity against PTZ induced convulsions. It may be concluded that the flavonoids fraction of ethyl acetate extract of aerial parts of A. indica, but not the aqueous decoction has antiepileptic potential, without producing neurotoxic effects.

Anti-inflammatory and antihyperalgesic effects of the combination of ibuprofen and hemin in adjuvant-induced arthritis in the Wistar rat.

AIM: Although, pharmacological activation of heme oxygenase (HO)-1 has shown to produce ameliorative effects in various experimental models of inflammation, but such beneficial effects have not been observed in adjuvant-induced arthritis. Further, the upregulated activity of HO-1 has been implicated in the pathogenesis of adjuvant arthritis. The present study was designed to investigate the anti-inflammatory and antihyperalgesic effects of the prophylactic use of hemin alone and/or in combination with ibuprofen using adjuvant-induced arthritis in Wistar rat. METHODS: Arthritis was induced by an intradermal injection of complete Freund's adjuvant (CFA) into left hind paw. Paw volume, thermal hyperalgesia, mechanical allodynia, joint stiffness and mobility behaviors (score) were measured. RESULTS: Administration of ibuprofen (8.75, 17.5, 35 mg/kg/day, p.o.) and hemin (1, 5, 10 mg/kg/day, i.p.) were significantly effective in suppressing CFA-induced paw oedema, thermal and mechanical hyperalgesia, joint stiffness and mobility. The combination of low doses of ibuprofen (8.75 mg/kg, p.o.) and hemin (1 mg/kg, i.p.) significantly reduced paw volume, thermal and mechanical hyperalgesia, as compared to the individual dose of the ibuprofen and hemin alone. CONCLUSIONS: Hence, it may be concluded that the prophylactic administration of either hemin produced significantly enhanced anti-inflammatory and analgesic effects. Further, concurrent low dose administration of hemin and ibuprofen produced significantly enhanced anti-inflammatory and analgesic effects, as compared to the either treatment alone, in CFA-induced arthritis in Wistar rats.

Antiepileptic potential of flavonoids fraction from the leaves of Anisomeles malabarica.

ETHNOPHARMACOLOGICAL RELEVANCE: The plant Chodara (Anisomeles malabarica R.Br. Family: Lamiaceae) has numerous therapeutic utilities in folk medicine. AIM OF THE STUDY: To isolate and evaluate the anti-epileptic potential of fractions from the ethyl acetate extract (EAE) of Anisomeles malabarica leaves. MATERIALS AND METHODS: The EA extract (2.12% w/w) of the leaves of Anisomeles malabarica was prepared and fractionated into total flavonoids fraction (AMFF) and tannins fraction (AMTF), which subsequently evaluated for the antiepileptic activity against PTZ- and MES model in wistar rats. Diazepam and phenytoin (2mg/kg and 25mg/kg, i.p., respectively), were used as a reference drugs. Further, the presence of flavonoid was confirmed by chemical test, TLC and HPTLC were done for the identification of the number of flavonoids with reference to standard. RESULTS: Single dose pretreatment with AMFF (25 and 50mg/kg, i.p.) has found to be effective against both MES and PTZ-convulsions, but associated with a marked decrease in locomotor activity and motor activity performance (i.e., neurotoxic effects), similar to that of diazepam treatment. Interestingly, chronic treatment with AMFF at lower doses (6.25 and 12.5mg/kg, i.p., 1 week) has also produced significant antiepileptic activity, but without causing neurotoxic effects. CONCLUSION: Thus, it may be concluded that the flavonoids fraction of the EA extract of Anisomeles malabarica leaves has antiepileptic potential against both MES and PTZ convulsion models. Acute treatment (25 and 50mg/kg, i.p.) is associated with neurotoxic activity. Whereas, chronic treatment (6.25 and 12.5mg/kg, i.p., 1 week) also shown significant antiepileptic effect without causing neurotoxic side effects. However, further research is in progress to determine the component(s) of the flavonoids fraction of Anisomeles malabarica involved and their mechanism of action in bringing about the desirable anti-epileptic effect.

Bronchospasm potentiating effect of methanolic extract of Ficus religiosa fruits in guinea pigs.

ETHNOPHARMACOLOGICAL RELEVANCE: The sacred tree Peepal (Ficus religiosa family: Moraceae) has numerous therapeutic utility in folk medicine. AIM OF THE STUDY: It has been reported to be used in ethno medical treatment of asthma and also in epilepsy due to its high serotonin content, which has been implicated in pathophysiology of asthma, this led us to carry out the present study. MATERIALS AND METHODS: The in vivo studies of histamine induced bronchospasm in guinea pigs and in vitro isolated guinea pig tracheal chain and ileum preparation. RESULTS: Pre-treatment of guinea pigs with ketotifen (1 mg/kg, p.o.) has significantly delayed the onset of histamine aerosol induced pre-convulsive dyspnea, compared with vehicle control (281.8(a)±11.7 vs. 112.2±9.8). The administration of methanolic extract (125, 250 and 500 mg/kg, p.o.) did not produced any significant effect on latency to develop histamine induced pre-convulsive dyspnea. On the other hand, methanolic extract of the fruits at the doses employed (i.e., 0.5, 1 and 2 mg/ml) has significantly potentiate the EC(50) doses of both histamine and acetylcholine in isolated guinea pig tracheal chain and ileum preparation. In addition, HPLC analysis of the methanolic extract showed the presence of high amounts of serotonin (2.89%, w/w). CONCLUSIONS: On the basis of data, it may be concluded that Ficus religiosa fruits have been found to be ineffective against histamine induced bronchospasm in guinea pigs. In addition, methanolic extract of the fruits have shown to potentiate the bronchoconstriction induced by both histamine and acetylcholine on guinea pig tracheal chain preparation.