Anti-inflammatory and antiulcerogenic effects of the aqueous extract of Lobaria pulmonaria (L.) Hoffm.
An aqeuous extract of Lobaria pulmonaria (L.) Hoffm., from which a tea is prepared and consumed as treatment for various diseases in northeastern Turkey, was tested for its anti-inflammatory and antiulcerogenic effects in rats. The carrageenan-induced paw edema, cotton pellet granuloma and indomethacin-induced gastric damage models were used to determine these effects. The extract exhibited moderate anti-inflammatory and strong antiulcerogenic activities.
Key words: Lobaria pulmonaria, anti-inflammatory effect, paw edema, indomethacin, rat
Lichens are not simple organisms. They are morphological and physiological unions of one or more photosynthetic partner(s), which can be a cyanobacterium from the Monera kingdom or green algae from the Chlorophyta division of the plant kingdom, and one or more fungal partner(s) from the Ascomycetes or Basidiomycetes (Aslan, 2000). The fungal partner provides water and aqueous mineral solutions, while the photosynthetic partner provides organic substances via photosynthesis, for the symbiosis. Lichens have a wide ecological tolerance, and can thus be found nearly in all regions of the globe. Lichens are also known to have therapeutic effects on various diseases, for which various acids are reported to be responsible.
A recognizable characteristic of lichens is their production of various metabolites, "the lichen substances". Numerous metabolites have already been identified. These can be classified in two groups, including aliphatic (acids, zeorin derivatives and polyalcohols) and aromatic (depsides, depsidones, quinones, pulvic acid-, xanthone-, dibenzoburan-, and diketopiperazine-derivatives) substances (Asahina and Shibata, 1971).
Lichens have been used for various purposes; for example, they have been consumed as food, used in dye, brewing and leather industries, and most importantly for uses, they have been used in folk medicine. Medicinal uses of lichens include treatment of fever, epilepsy, coughing, tuberculosis, rabies, gout, external wounds, and hepatitis, among other (Zeybek and John, 1992; Harmala et al. 1992; Elix, 1996; Huneck, 1999).
Lobaria pulmonaria is a foliose (leaf-like) lichen. It is pale brown when dry and bright green when wet. It has been used widely in folk medicine for treatment of various diseases, such as eczema, respiratory diseases, pulmonary diseases and arthritis, as well as being used as food and cosmetics (Biswas, 1956; Wirth, 1987; Zeybek and John, 1992). Major components of this lichen are gyrophoric acid, stictic acid and norstictic acid (Culberson, 1969; Huneck and Yoshimura, 1996). Of these, gyrophoric acid has been shown to have an anti-proliferative effect (Kumar and Muller, 1999). A polysaccharide from this lichen has also been shown to provide a radioprotective effect on bone marrow stromal cells and to support hematopoietic stem cells (Liu, 1991). Tea prepared from Lobaria pulmonaria has been used as laxative and consumed as an aromatic drink and the drug made from this lichen has long been used in respiratory disorders. A laxative cream has also been prepared (Aslan et al. 1998; Ozturk, 1995).
The aim of the present work was to investigate the anti-inflammatory and anti-ulcer effects of L. pulmonaria extracts (named L-1 in the rest of the text) and to compare them with the effects of commercially available anti-inflammatory and anti-ulcer drugs.
* Material and Methods
Lobaria pulmonaria samples were collected from Artvin, Turkey in 2001 for the present work. All samples were identified by Dr. Ali Aslan, a specialist in the lichens of Turkey, and stored in the herbarium of Kazim Karabekir Education Faculty, Ataturk University-Erzurum.
Extraction of plant material
After lichen samples were collected, they were shade-dried at [+ or -] 24 [degrees]C for three days and finely ground using a mortar and pestle under liquid nitrogen. 100 g of the resulting powder were extracted using distilled water (50-60 [degrees]C, 11 x 4) for two days in a water bath with a shaking attachment. After the extract was filtered, it was lyophilized and stored at -18 [degrees]C. The experiments were carried out using an appropriate amount of lyophilized material.
A total of 84 male, albino Wistar rats, weighing 190-200 g each was used for the experiments: The animals were provided by the Experimental Animal Laboratory of Ataturk University, Medicinal Faculty, Department of Pharmacology. The animals were grouped before the experiments and kept under standard conditions.
All chemicals used in this work were purchased from Sigma Chemical (Germany).
Carrageenan-induced paw edema in rats
In this series of experiments, the effect of L-1 on carrageenan-induced paw edema in rats was investigated (Moncada et al. 1973; Suleyman et al. 2002). Briefly, 50, 100 and 250 mg/kg body wt. doses of L-1 were administered orally to rats for two days, once a day. After the administration of the final doses, the paw volumes of the animals were calculated plethysmometrically and 0.1 ml of 1% carrageenan was injected into the hind paw of each animal 1 h after the last dose. The change in paw volumes was detected as six replicates every 60 min by plethysmometry. The anti-inflammatory potency of L-1 was determined via comparison with the result obtained from animals receiving equal volumes of nimesulide (100 mg/kg body wt.), indomethacin (25 mg/kg body wt.) and distilled water (control).
Cotton pellet granuloma test in rats
In this series of experiments, the effect of L-1 on the proliferative phase of inflammation was investigated using the cotton pellet test (Suleyman et al. 1999). One group of animals received 250 mg/kg body wt. L-1 while the others received 100 mg/kg body wt. nimesulide and 25 mg/kg body wt. indomethacin orally, and the control group received an equal volume of distilled water. Thirty minutes after administration of the drugs, the animals were anesthetized using 25 mg/kg body wt. thiopental sodium. Under sterilized conditions, cotton pellets of 7 [+ or -] 1 mg were implanted subcutaneously in the interscapular area L-1, nimesulide and indomethacin were administrated once a day for seven days at the doses indicated above. On the eighth day, animals were sacrificed via high-dose anesthesia and the cotton pellets with the granuloma tissue around them were removed. The weights of these pellets were measured and the anti-proliferative effects of L-1, numesulide and indomethacin were determined by comparison with the control group.
Indomethacin-induced gastric damage
In this series of experiments, the effects of L-1 and nimesulide on indomethacin-induced gastric damage were determined (Guidobono et al. 1997). The protective effects of L-1 and nimesulide were compared with the [H.sub.2] receptor blocker, ranitidine. L-1 (250 mg/kg body wt.), nimesulide (100 mg/kg body wt.) and ranitidine (150 mg/kg body wt.) administered orally to the designated groups of rats. 5 minutes after L-1 and drug administration, all the animals received 25 mg/kg body wt. indomethacin. After 6 h, animals were sacrificed via high-dose anesthesia (thiopental sodium, 50 mg/kg body wt.). The stomachs were removed and gastric damage (ulcer) in the stomachs was evaluated microscopially. The protective effects of L-1 and nimesulide were determined via comparison with the results obtained for the raniditine and control groups.
The results are shown as mean [+ or -] S.E.M. All the results were analyzed via one-way variance analysis (ANOVA). The differences between groups were considered significant at p < 0.05.
Carrageenan-induced paw edema
50, 100 and 250 mg/kg body wt. doses of L-1 reduced carrageenan-induced paw edema by 14.1, 29.9 and 35.4%, respectively, at the fourth hour (Table 1). Nimesulide (100 mg/kg body wt.) reduced the edema by 51.0%, while indomethacin did so by 95.7%. The paw volume increased by 0.49 ml in the control group relative to the baseline values, while increases of 0.41 ml, 0.34 ml, 0.30 ml, 0.24 m/and 0.02 ml were observed in the L-1 50 mg/kg body wt., L-1 100 mg/kg body wt., L-1 250 mg/kg body wt. nimesulide and indomethacin groups, respectively.
Cotton pellet granuloma test
As shown in Table 2, the mean weight of the cotton pellets in the L-1 250 mg/kg body wt. group was 126.5 [+ or -] 6.78 mg, while it was 98.3 [+ or -] 6.2 and 48.2 [+ or -] 4.57 mg in the nimesulide (100 mg/kg body wt.) and indomethacin (25 mg/kg body wt.), respectively. According to these results, the anti-proliferative effect of L-1 was 21.1%, of nimesulide was 38.7% and of indomethacin was 70%.
Indomethacin-induced gastric damage
The mean damage area in rats receiving L-1 was 6.5 [mm.sup.2], and 23.2 [mm.sup.2] for the control group. No damage was observed in the nimesulide and ranitidine groups (Table 3). Damages in various numbers and diameters were found in the stomachs of L-1 and control groups. The damages (ulcers) were spread homogeneously on the stomach tissue, at various depths, and in circular, oval and irregular defects. The boundaries of the ulcers were recognizable. There were very remarkable hyperemias in the stomachs of the control group rats. In the L-1 group, hyperemias were slight, and in the nimesulide and ranitidine groups, they were even slighter.
* Discussion and Conclusion
In the presented work, the anti-inflammatory and antiulcer effects of the aqueous extract of Lobaria pulmonaria (L-1) were investigated. The effect of L-1 on the acute phase of inflammation was observed in the carrageenan-induced paw edema test and its anti-inflammatory potency was compared to that of the COX-2 selective anti-inflammatory drug, nimesulide, as well as a nonselective drug, indomethacin. The effect of L-1 on the proliferative phase of inflammation was investigated using the cotton pellet granuloma test. In addition, its protective effect in gastric damage was determined using the indomethacin-induced ulcer model.
L-1 significantly reduced carrageenan-induced paw edema at all doses, except 50 mg/kg body wt. Nimesulide showed a stronger effect and indomethacin, which reduced the increase in paw volume by 95.7%, was found to be the most effective drug in this model of inflammation.
Carrageenan-induced paw edema is widely used for determining the acute phase of inflammation. Inflammation mediators such as free radicals, nitric oxide, prostaglandins and cytokines have a role in the development of this edema (Gualillo et al. 2001). Carrageenan-induced inflammation is a function of polymorphonuclear leukocytes (PMNs) rather than other mediators (Jain et al. 2001). PMNs are the first cells to arrive at the inflammatory site in the body. Free oxygen radical ([O.sub.2.sup.-]) and free hydroxyl radicals are released by these cells (McCord and Ray, 1982).
Carrageenan-induced inflammation is used to determine COX inhibition and to establish inflammation-originated pain (Ogonowski et al. 1997; Sen et al. 1993). In the early phase of carrageenan-induced inflammation, histamine and bradykinine have been shown to be the first detectable mediators (Portanova et al. 1996), and prostaglandins were found to have a role in the late phase of inflammation (Ialenti et al. 1992).
In our experiment, the mean paw volume of the control group reached its peak at the fourth hour. The mean paw volume in groups receiving L-1, nimesulide and indomethacin started to decrease at the third hour.
The inflammatory process is also characterized by the production of leukotrienes from the lypoxygenase pathway (Zhang and Cuzzocrea, 2000; Jain et al. 2001). Kumar and Muller (1999) and Ogmundsdottir et al. (1998) reported that gyrophoric acid, one of the major components of Lobaria pulmonaria, inhibited the 5-lypoxygenase pathway of arachidonic-acid metabolism.
As is known, anti-inflammatory mechanisms of indomethacin and other NSAIDs include inhibition of synthesis of COX and LO products, blocking the release of toxic oxygen radical and lysosome enzymes and hindering the aggregation, adhesion and chemotaxis of neutrophyls and the uncoupling of oxidative phosphorylation and blocking the increase in capillary permeability (Higgs et al. 1980; Abramson and Weissmann, 1989; Insel, 1996; Jacobs and Bijlsma, 1997). Nimesulide inhibits synthesis of COX-2 products more strongly (Cullen et al. 1998).
L-1, at the dose of 250 mg/kg body wt., reduced significantly the weights of the cotton pellets. The cotton pellet granuloma method is frequently used to investigate the chronic phase of inflammation (Olajide et al. 1999). The anti-proliferative potency of indomethacin was higher than that of L-1 or nimesulide in the cotton pellet granuloma test. Little data has been reported about mediators of chronic inflammation. However, the chronic inflammation model, induced by subcutaneous implantation of foreign bodies, is used commonly in experiments (Spicer et al. 1990). Chronic inflammation starts with the occurrence of proliferative cells (Hosseinzadeh et al. 2000). These cells can be spread or can form a granuloma tissue. Inflammatory granuloma tissue is a typical example of chronic inflammation (Olajide et al. 1999). Granuloma formation is initialized by an antigen (for example, cotton pellet). The cotton pellet stimulates the immune system, antibodies and production of interleukins. This stimulation results with the proliferation of lymphocytes and the formation of granulation tissue over the pellets (Kapu et al. 2001). NSAIDs reduce granuloma tissue that is formed with cellular reactions, by inhibiting granulocyte infiltration, while glucocorticoids do it by inhibiting fibrosis and macrophage functions (Ionac et al. 1996; Kayaalp, 2000). In a recent study, gyrophoric acid present in Lobaria pulmonaria has been shown to have an anti-proliferative effect (Kumar and Muller, 1999).
We could not obtain much information about the other major components of Lobaria pulmonaria, namely stictic and norstictic acids and lichenin.
COX-2 selective drugs do not induce gastric damage and prevent this kind of damage, while non-selective drugs (indomethacin, ibuprofen, naproxen etc.) induce damage in stomach tissue (Schnitzer et al. 1999). COX-1 products have been claimed to have a role in the protection of gastric tissues (Peskar et al. 2001).
Thus, we have researched the effects of L-1 and nimesulide on indomethacin-induced gastric damage. L-1 reduced the indomethacin-induced gastric damage by 3.5 times as compared to the control group. Interestingly, no damage was observed in rats receiving nimesulide and ranitidine. In a previous work, nimesulide (100, 300, 500 mg/kg body wt.) and ranitidine (150 mg/kg body wt.) completely prevented indomethacin-induced ulcers and significantly reduced ethanol-induced ulcers (Suleyman et al. 2002). Ranitidine blockades [H.sub.2] receptors and reduces stomach acid secretion as well as increasing the production of bicarbonate, mucus, and cytoprotective prostaglandins, and enhances blood flow (Kayaalp, 2000). The mechanism of prevention of indomethacin-induced gastric damage by nimesulide is similar to that of ranitidine. Nimesulide reduces gastric acid secretion. Maintains the mucosa prostaglandin level, does not affect MPO (myeloperoxidase) activity and very slightly increases motility. Indomethacin acts in a way opposite to nimesulide (Kataoka et al. 2000). Indomethacin increases gastric acidity by 80%, while nimesulide inhibits histamine-induced gastric acid secretion (Khattap et al. 2001; Tavares et al. 2001).
The reduction of indomethacin-induced gastric damage by L-1 implies that its mechanism, at least in part, may be similar to nimesulide. More detailed work is required to completely understand the anti-inflammatory and anti-ulcer effects of L-1.
Table 1. Effects of L-1, Nimesulide and Indomethacin on carrageenan-induced paw edema in rats. Preparate Number Dose Paw volume Paw volume of mg/kg before 4 h after animals body wt. inflammation inflammation ml ml L-1 6 50 0.83 1.24 [+ or -] 0.02 L-1 6 100 0.84 1.18 [+ or -] 0.08 L-1 6 250 0.85 1.15 [+ or -] 0.04 Nimesulide 6 100 0.84 1.08 [+ or -] 0.16 Indomethacin 6 25 0.83 0.85 [+ or -] 0.03 Control 6 0.86 1.35 [+ or -] 0.05 Preparate Difference P Anti- between inflammatory paw volumes effect MI Inhibition % L-1 0.41 >0.05 14.1 L-1 0.34 <0.05 29.9 L-1 0.30 <0.05 35.4 Nimesulide 0.24 <0.05 51 Indomethacin 0.02 <0.05 95.7 Control 0.49 Table 2. Effects of L-1, Nimesulide and Indomethacin on cotton pellet granuloma test in rats. Preparate Number Dose Cotton of mg/kg pellet animals body wt. weight (mg) L-1 6 250 7 [+ or -] 1 Nimesulide 6 100 7 [+ or -] 1 Indomethacin 6 25 7 [+ or -] 1 Control 6 7 [+ or -] 1 Preparate Granuloma Antipro- P weight/mg liferative effect % L-1 126.5 [+ or -] 6.78 21.1 <0.05 Nimesulide 98.3 [+ or -] 6.25 38.7 <0.05 Indomethacin 48.2 [+ or -] 4.57 70.0 <0.05 Control 160.3 [+ or -] 8.46 Table 3. Effects of L-1, Nimesulide and Ranitidine on indomethacin-induced gastric damage. Preparate Number Dose mg/kg Ulcer area P of animals body wt. [mm.sup.2] L-1 6 250 6.5 [+ or -] 1.45 <0.05 Nimesulide 6 100 0 <0.05 Ranitidine 6 150 0 <0.05 Control 6 23.2 [+ or -] 2.56
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H. Suleyman, Ataturk University, Medical Faculty, Dept. of Pharmacology, TR-25240 Erzurum, Turkey
Tel.: ++90-44-22312423; Fax: ++90-44-22360962; e-mail: email@example.com
H. Suleyman (1), F. Odabasoglu (2), A. Aslan (3), A. Cakir (4), Y. Karagoz (3), F. Gocer (1), M. Halici (2), and Y. Bayir (2)
(1) Ataturk University, Faculty of Medicine, Department of Pharmacology, Erzurum, Turkey
(2) Ataturk University, Faculty of Pharmacy, Department of Biochemistry, Erzurum, Turkey
(3) Ataturk University, Kazim Karabekir Education Faculty, Department of Biology, Erzurum, Turkey
(4) Ataturk University, Kazim Karabekir Education Faculty, Department of Chemistry, Erzurum, Turkey
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|Author:||Suleyman, H.; Odabasoglu, F.; Aslan, A.; Cakir, A.; Karagoz, Y.; Gocer, F.; Halici, M.; Bayir, Y.|
|Publication:||Phytomedicine: International Journal of Phytotherapy & Phytopharmacology|
|Date:||Jul 1, 2003|
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