Preparations of Crossopteryx febrifuga Afzel. Rubiaceae are widely used in Northern Nigeria in the therapeutic management of trypanosomiasis, malaria and painful inflammatory disorders. Previous studies have shown that the methanolic stem bark extract of Crossopteryx febrifuga possesses significant analgesic and anti-inflammatory properties possibly mediated via Non-selective inhibition of cyclo-oxygenase pathways. In the present study, the methanolic stem bark extract of Crossopteryx febrifuga was evaluated against ethanol- and piroxicam-induced ulceration in rats. Histopathological studies of the rat stomach tissues were also carried out in order to determine its safety profile on the gastrointestinal tract git.
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Preparations of Crossopteryx febrifuga Afzel. Rubiaceae are widely used in Northern Nigeria in the therapeutic management of trypanosomiasis, malaria and painful inflammatory disorders. Previous studies have shown that the methanolic stem bark extract of Crossopteryx febrifuga possesses significant analgesic and anti-inflammatory properties possibly mediated via Non-selective inhibition of cyclo-oxygenase pathways. In the present study, the methanolic stem bark extract of Crossopteryx febrifuga was evaluated against ethanol- and piroxicam-induced ulceration in rats.
Histopathological studies of the rat stomach tissues were also carried out in order to determine its safety profile on the gastrointestinal tract git. These results showed that the extract had no deleterious effects and was cytoprotective on the gastrointestinal tract git.
It can thus be developed as a safe alternative to conventional non-steroidal anti-inflammatory drugs NSAIDs for the management of painful inflammatory disorders. Nonsteroidal anti-inflammatory drugs NSAIDs , which act as non-selective cyclooxygenase COX inhibitors, are commonly used to treat pain and inflammation despite the risk of major upper gastrointestinal complications Venkova et al.
The primary cause of the pathogenic effects of NSAIDs in the stomach is the deficiency of endogenous prostaglandins required to maintain the mucosal barrier to luminal acid. Oxygen free radicals and lipid peroxidation Takeuchi et al. However, a breakdown in the mucosal barrier against gastric acid is not the only mechanism contributing to mucosal injury during NSAIDs administration. Studies by Santo et al. However in African countries including Nigeria, indigenous herbal medicines are widely used for the management of painful inflammatory disorders, despite an apparent lack of scientific evidence for their quality, safety and efficacy Fennell et al.
One of such therapeutically useful medicinal plant is Crossopteryx febrifuga Benth, Family Rubiaceae , a twisted tree with conspicuous tubular flowers, which is widely distributed throughout the Savannah region of Central, East and West Africa. Preparations of the tree is used traditionally for symptomatic relief of dry cough and for treatment of septic wounds, respiratory infections, fever, dysentery and pain.
In northern Nigeria, the plant has been used for treatment of pain and malaria for many years and its efficacy has been established in our laboratory Salawu et al. Previous studies using crude methanolic extract of C.
Salawu et al. Considering its widespread use in traditional medicine for the management of pain and inflammatory disorders such as arthritis, the need to investigate its safety on the gastrointestinal tract cannot be over emphasized. The present study was therefore designed to study its effect on the gastrointestinal tract when used for management of chronic pain related disorders. Fresh stem bark of C. The stem bark was cleaned, air-dried for seven 7 days and crushed into coarse powder using a pestle and mortar.
Five hundred grams of the coarse powder was cold macerated with 2. The resultant mixture was filtered using Whatman filter paper No. These rats were approved for use by the AFC committee after reviewing the protocol. The studies were carried out following the principles of good laboratory practice and animal handling National Institutes of Health Guide for the Care and use for Laboratory animals; Publication No. The oral median lethal dose LD 50 of the methanolic extract was determined in rats orally using Lorke's method with modifications.
The rats were kept under the same conditions and observed for signs of toxicity which include but not limited to paw-licking, stretching, respiratory distress and mortality for the first critical 4h and thereafter daily for 7 days.
These rats were also observed for signs of toxicity and mortality for the first critical 4h and thereafter daily for 7 days. The number of deaths in each group within 24 h was recorded and the final LD 50 values were calculated as the geometric mean of the highest nonlethal dose with no deaths and the lowest lethal dose where deaths occurred. The method described by Salawu et al. Twenty four hours fasted rats were randomized into 6 groups of 5 rats each.
Group 1 rats served as the normal control received no treatment. Thirty mins later, 1ml of absolute ethanol was administered to all the rats in groups 2—6. One hour after ethanol administration, the rats were sacrificed under diethyl ether anaesthesia. The stomachs were removed, opened along the greater curvature, rinsed with slow running water. The ulcer lesions were scored according to severity Larach and Malagelada, as follows:.
Ulcer index UI defined as the severity of damage caused by an ulcer inducing agent was then calculated using the formula:. Preventive ratio PR defined as the degree of protection offered by a treatment against ulcer causing agent was calculated using the formula:.
Thirty minutes later, all the rats in groups 2—6 were treated with piroxicam. Six hours after piroxicam administration, the rats in all the groups were sacrificed under diethyl ether anesthesia. These were then processed routinely and the tissues were embedded in paraffin wax. These were then examined by a consultant histopathologist. The lesions observed were assessed for the following; mucosal atrophy, presence of inflammatory cells in the wall, eosinophils, lymphocytes and plasma cells.
Photomicrographs of representative lesions were taken at various magnifications. Graph pad prism version 5. The differences between means of the treated and the control groups were compared using One way analysis of variance ANOVA followed by Dunnet's post hoc test. In the first phase of the oral acute toxicity study, no remarkable signs of toxicity were observed in the rats.
Ethanol produced haemorrhagic gastric lesions mainly in the glandular segment of the stomach mucosa. Effect of Crossopteryx febrifuga on ethanol-induced gastric ulceration in rats. Piroxicam produced focal haemorrhagic gastric lesions and inflammation of the stomach mucosa in the rats.
Effect of the Crossopteryx febrifuga extract on piroxicam-induced gastric ulceration. Ethanol caused destruction of several glandular areas and focal infiltration of inflammatory cells into the sub mucosa areas. Piroxicam caused extensive mucosal atrophy, infiltration by eosinophils and lymphoplasma cells of the wall. Magnification x 4. The results obtained from the study showed that the methanolic stem bark extract of Crossopteryx febrifuga possess anti-ulcerogenic activity in rats.
The data obtained in the test for acute toxicity suggest that the extract is moderately toxic Salawu et al. The choice of models used for antiulcer evaluation is very appropriate because the protocols undertaken in the rats are those mostly used for the evaluation of antiulcer agents and are reproducible. Drugs that are effective against peptic ulcer act either by reducing the aggressive factors on the gastro-duodenal mucosa or by increasing mucosal resistance against them Larach and Malagelada, , Salawu et al.
In the ethanol-induced ulcer assay, the control group treated orally with ethanol clearly produced the expected characteristic zone of necrotizing mucosal lesions. It is known that ethanol produces necrotic lesions in the gastric mucosa by its direct toxic effect, by reducing both secretion of bicarbonates and production of mucus Marhuenda et al. The products of the 5-lipoxygenase pathway may also play a key role in the development of ulcer induced by irritant agents such as ethanol Lange et al.
The results obtained showed that the methanolic stem bark extract of Crossoptery febrifuga possesses significant antiulcer effect against ethanol- induced gastrointestinal ulceration in rats. The cytoprotective effect of the extract may have been due to its ability to promote secretion of bicarbonate and production of mucus.
This observation further highlights the safety of the extract as an analgesic without gastrointestinal side effects associated with the traditional NSAIDs. The extract profoundly antagonized the Piroxicam- induced ulceration in rats. The anti-ulcer effect of the extract may have been produced via enhanced prostaglandin synthesis, inhibition of leukotriene biosynthesis and decreased acid secretion.
Thus, illustrating the pharmacodynamic safety of the extract even in painful conditions associated with gastro-intestinal ulceration. In the stomach, prostaglandins is critical for the maintenance of gastric mucosal integrity, but the mechanism involved in the cytoprotective action of prostaglandins is still incompletely understood.
Factors that may contribute to the protection of mucosa, such as mucus and bicarbonate secretion are dependent on gastric blood flow Guth et al. A severe decrease in gastric mucosal blood flow has been reported after treatment with indomethacin Murai et al.
This observed gastroprotective effect of the methanolic stem bark extract of Crossopteryx febrifuga may have been produced by enhancing gastric mucosal defensive factors through increased gastric blood flow, increased mucus and bicarbonate secretion.
Misoprostol a synthetic analogue of prostaglandin E1 completely protected the mucosal layer against piroxicam-induced lceration. Histopathological studies further confirmed the extract's mucosal protective effect in that it inhibited both piroxicam - and ethanol induced mucosal atrophy, infilteration by eosinophils and lymphoplasma cells in the wall glandular destruction, focal infiltration of inflammatory cells into mucosa areas.
The efficacy of the gastro-histoprotective effects of methanolic extract of Crossopteryx febrifuga against the piroxicam - induced gastric mucosa atrophy and ethanol-induced focal infiltration of inflammatory cells into mucosa areas, were comparable to that of misoprostol and cimetidine respectively. The phytochemical analyses carried out on methanolic stem bark extract of Crossopteryx febrifuga by Salawu et al. Previous studies have shown that some tannins Salawu et al.
Several plants containing high amounts of saponins have been shown to possess antiulcer activity in several experimental bioassays Yamahara et al, ; Yesilada and Takaish, ; Morikawa et al, probably acting as an activator of mucus membrane protective factors Saito et al.
Finally, the flavonoids are the major secondary metabolites class with several descriptions of antiulcer, antioxidant and gastroprotective properties, which involves nitric oxide participation Matsuda et al.
Flavonoids have attracted the attention of many researchers because of their wide range of biological activities Lewis and Hanson, , including antiulcer properties La Casa et al.
This class of secondary compounds is able to protect the gastric mucosa against a variety of antiulcerogenic agents, particularly through scavenging properties on oxygen radicals by inhibition of nitric oxide Synthase activity Di Carlo et al. In conclusion this study illustrated the safety of Crossopteryx febrifuga in gastrointestinal tract when used as an antiinflammatory analgesic agent that could be developed for management of painful inflammatory disorders.
In addition the observed gastro-protective effect of the extract may be related to effects of several classes of active secondary compounds present in this medicinal plant. The authors are grateful to the management of National Institute for Pharmaceutical Research and Development for provision of enabling environment and facilities used for the study.
The technical assistance of the Staff of Animal Facility center is highly appreciated. National Center for Biotechnology Information , U. Published online Apr 2. Author information Copyright and License information Disclaimer. Corresponding author. Traditional Complementary and Alternative Medicines This article has been cited by other articles in PMC. Abstract Preparations of Crossopteryx febrifuga Afzel. Keywords: Crossopteryx febrifuga, extract, analgesic, anti-inflammatory agents, gastrointestinal tract, ulcer.
Introduction Nonsteroidal anti-inflammatory drugs NSAIDs , which act as non-selective cyclooxygenase COX inhibitors, are commonly used to treat pain and inflammation despite the risk of major upper gastrointestinal complications Venkova et al. Materials and Methods Collection plant material Fresh stem bark of C. Preparation of the plant extract The stem bark was cleaned, air-dried for seven 7 days and crushed into coarse powder using a pestle and mortar.
Acute toxicity LD50 study The oral median lethal dose LD 50 of the methanolic extract was determined in rats orally using Lorke's method with modifications. Ethanol-induced gastric ulceration The method described by Salawu et al. Piroxicam-induced gastric ulceration The method described by Salawu et al.
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Crossopteryx febrifuga Benth.