Review Article

Physiological mechanisms underlying the use of Kola Heckel in the treatment of asthma M I Ebomoyi and A K Okojie

Introduction Garcinia kola Historically, have provided a source of inspiration Garcinia kola Heckel ‘bitter kola’ is popular in southern for novel drug compounds, as -derived medicines . The plant is extensively used in herbal medicine have made large contributions to human health and and as food. It is usually found in the tropical rain well-being. Their role is two-fold in the development region of West Africa. It prevails as a multi-purpose tree of new drugs: (1) they may become the basis for the de- crop in the home gardens of southern Nigeria.18 The tree velopment of new medicine, i.e. a natural blueprint for is usually cultivated within villages in southern Nigeria. the development of new drugs; or (2) a phytomedicine It grows to a height of about 12–14 m and produces red- to be used for the treatment of disease. Though there is dish, yellowish, or orange-coloured fruit.8,19 Each fruit availability of various orthodox drugs for the treatment contains two to four yellow seeds and a sour tasting pulp. of respiratory tract diseases in Nigeria, there is increasing The seeds when chewed have a bitter, astringent taste. interest in herbal remedies.1 The seeds of Garcinia kola The flowering of the plant occurs between December and (GK) form a major part of the herbal preparation used in January while the fruits mature between June and August. traditional African medicine practice for the treatment Garcinia kola is highly valued for medicinal use.20,21 The of various respiratory tract diseases, including asthma.2 seeds are chewed as an aphrodisiac or used to cure cough, Garcinia kola Heckel belongs to the family Guttiferae, dysentery, or chest colds in herbal medicine.22 This plant and it is commonly called bitter kola. In Nigeria, the has been referred to as a ‘wonder plant’ because every plant is valued because of its edible nuts. The plant part of it has been found to be of medicinal importance.23 exhibits very potent pharmacological activities such GK could serve as a raw material for pharmaceutical as anti-oxidant, anti-bacterial, anti-viral, anti-fungal industries.24 GK is used in folklore remedies for the and anti-inflammatory properties.3–7 The anti-oxidant treatment of ailments such as liver disorders, hepatitis, property of GK is attributed to its very high content of diarrhoea, laryngitis, bronchitis, and gonorrhoea.7,25 The ascorbic acid.8 Phytochemistry of GK has shown its con- seed is used to prevent and relieve colic; it can also be tents to include benzophenones, xanthones, biflavonoids, used to treat headache.26 The plant can be used in the alkaloids, phenols, tannins, and saponins.8–15 treatment of stomach ache and gastritis.27 Iwu7 reported Asthma is characterised by episodic or chronic wheez- the use of this plant for the treatment of jaundice, high ing, cough, and feeling of tightness in the chest as a fever, and as purgative. Administration of GK seed result of bronchoconstriction.16 The fundamental cause extract caused an increase in testosterone production in is still unknown despite intensive research. However, Sprague–Dawley rats which is thought to be due to its three abnormalities are present: airway obstruction that anti-oxidant properties.28,29 Also, Adesanya et al19 con- is at least partially reversible, airway inflammation, and firmed the spermatogenic and tissue enhancing effect airway hyper-responsiveness to a variety of stimuli. A of GK extract in male Wistar rats. David et al30 showed link to allergy has long been recognised, and plasma that GK extract exhibits a dilatory effect on the alveolar immunoglobulin E (IgE) levels are often elevated.17 ducts, alveolar sacs, and alveoli thereby improving Because of the importance of GK as a herb commonly respiratory activities; in Swiss albino mice this may be used in herbal medicine for the treatment of asthma, due to its anti-oxidant properties. GK has been shown it becomes necessary to determine the physiological to inhibit smooth muscle activity. It relaxes the smooth mechanism(s) underlying its use. This paper reviews the muscles of the uterus and the intestine.31 Although GK function(s) of its phytochemical contents and how they lacks caffeine,32 its alkaloid and biflavonoids fractions are beneficial in the treatment of asthma. are said to relax the smooth muscles.31 GK has a bron- chodilatory effect.33,34 M I Ebomoyi and A K Okojie Department of Physiology, School of Basic Medical Sciences, College of Medical Sciences, University of Asthma , Benin City, Nigeria. Asthma is a very common chronic disease involving the Correspondence to: Maureen Ebomoyi. Email: respiratory system. There are three basic abnormalities [email protected] in asthma:

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1. airway obstruction that is at least partially reversible; colony stimulating factor (GM–CSF) and interleukins 2. airway inflammation; (IL)-4, -5, -9, and -13, which attract the active eosinophils 3. airway hyper-responsiveness to a variety of stimuli. and stimulate IgE production by B lymphocytes, are Public attention in the developed world has recently thought to be responsible for more sustained broncho- focused on asthma because of its rapidly increasing constriction, cellular infiltration of the airway mucosa, prevalence, affecting up to one in four urban children.35 and mucus hypersecretion of the late asthmatic reaction.41 Asthma is caused by a complex interaction of environ- These chronic inflammatory disorders of the airways that mental and genetic factors that researchers do not yet lead to tissue injury and subsequent structural changes 36 42 fully understand. are collectively called airway remodelling. TH1 T-cells Environmental tobacco smoke, especially maternal make interferone-g, lymphotoxin, and IL-2. TH1 and TH2 cigarette smoking, is associated with high risk of asthma cells differentiate into polarised populations from a com- prevalence and asthma morbidity, wheeze, and respira- mon precursor. After development, they are believed to 37 tory infections. Poor air quality from traffic pollution inhibit development of other cell types. TH1 cells play or high ozone levels has been repeatedly associated a dominant role in controlling intracellular pathogens with increased asthma morbidity and has a suggested like tuberculosis, while TH2 cells play a dominant role association with asthma development.37 This however in controlling extracellular pathogens like parasites and needs further research. Caesarean sections have been mites, and allergens like dusts and pollens.43 The absence associated with asthma when compared with vaginal of either of these populations leads to enhanced immu- birth; a meta analysis found a 20% increase in asthma nopathology, even in conditions classically thought to prevalence in children delivered by caesarean section depend on the other cell types. compared with those who were not. It was observed Airway remodelling includes: that this was due to modified bacterial exposure during 1. an increase in overall wall thickness; caesarean section compared with vaginal birth, which 2. an increase in airway fibrosis; modifies the immune system.38 There is growing evidence 3. an increase in smooth muscle mass; that stress may influence asthma and other disease by 4. abnormality in composition of the extracellular matrix; influencing the immune system.37 Antibiotic use early in 5. an increase in vascularity.42 life has been linked to development of asthma in several These changes have attracted interest due to the in- studies; it is thought that antibiotics make one susceptible creased realisation that they may account for aspects of to development of asthma because they modify gut flora, asthmatic physiology that are poorly addressed with and thus the immune system.39 current anti–inflammatory strategies.44 A few studies have Over 100 genes have been associated with asthma in addressed the issue of response of putative remodeling at least one genetic association study.40 However, such mediators to therapy. Insulin-like growth factor (IGF)–β studies must be repeated to ensure that the findings appears to be resistant to steroid therapy, whether or not are not due to chance. Many of these genes are related there is a reduction in measures of airway remodelling.45,46 to the immune system or to modulating inflammation. Despite the suggestion that airway remodelling explains Moreover, even among this list of highly replicated the lack of response to therapy of some patients, no study genes associated with asthma, the results have not been has specifically shown that those patients who either fail consistent among all of the populations that have been to respond to therapy or progress despite therapy do in tested.40 This indicates that these genes are not associated fact show airway remodelling that fails to respond or with asthma under every condition, and that researchers progresses despite a reduction in inflammation.47 This need to do further investigation to establish the complex observation could be due to disease heterogeneity. If this interactions that cause asthma. Research suggests that hypothesis was true, it would ultimately be necessary some genetic variants may only cause asthma when they to characterise the pathological basis of each patient’s are combined with specific environmental exposures and physiology before determining which therapy would otherwise may not be risk factors for asthma.36 be most beneficial in reversing or preventing airway The fundamental problem in asthma appears to be remodeling in that individual patient..47 immunological. In the immunologic model, asthma is a The mechanisms underlying bronchial reactivity, such disease mediated by reaginic (IgE) antibodies bound to as ozone exposure, allergen inhalation, and infection with mast cells in the airway mucosa. On re-exposure to an respiratory viruses, also cause airway inflammation. In antigen, antigen–antibody interaction on the surface of humans, the increase in bronchial reactivity induced by mast cells triggers both the release of mediators stored in ozone is associated with an increase in the number of the cells granules and the synthesis and release of other polymorphonuclear leukocytes found in fluid obtained mediators.16 The agents responsible for the early reaction by bronchial lavage or from bronchial mucosa biopsies. mediating bronchoconstriction – including histamine, The increase in reactivity due to allergen inhalation is tryptase and other neural proteases, leukotrienes C4 and associated with an increase in both eosinophils and D4, and prostaglandin – cause muscle contraction and polymorphonuclear leukocytes in bronchial lavage fluid. vascular leakage.16 Cytokines produced by T-helper type 2 Whatever the mechanisms responsible for bronchial

(TH2) lymphocytes, especially grannlocyte macrophagen– hyper-reactivity, bronchoconstriction itself seems to 6 African Journal of Respiratory Medicine Vol 8 No 1 September 2012 Review Article

result not simply from the direct effect of the released to produce peptidoleukotrienes. These 5–LO products mediators but also from their activation of neural or mediate constriction of airway smooth muscles, leukocyte humoral pathways. chemotaxis,58,59 and vascular permeability.58,60 Therefore, inhibiting 5–LO can attenuate leukotriene production. Actions of xanthones The presence of phenol in GK further indicated that it Xanthones have anti-asthmatic activity by dependently could act as anti-inflammatory, anti-oxidant and immune inhibiting the Ca2+ influx induced by either norepineph- enhancer.61 Phenols have been shown to block specific rine or high K+, suggesting that xanthone might act as enzymes that cause inflammation. They also modify the a blocker of both receptor–operated and voltage–de- prostaglandin pathways and thereby protect platelets pendent Ca2+ channels.6 Furthermore, xanthone causes from clumping.8 increase in the level of intracellular cyclic adenosine 3’, 5’–monophosphate (cAMP) but not cyclic guanosine 3’, Conclusion 5’–monophosphate (cGMP) content.6 Chairungsrilerd et From this review, the following could be responsible al21 reported that xanthone showed inhibitory effects on for the beneficial effects of underlying physiological cAMP phosphodiesterase. Intracellular levels of cAMP mechanisms of Garcinia kola in the treatment of asthma: can be increased by β-adrenoceptor agonists, which in- • Inhibition of Ca2+ influx by acting as a blocker of both crease the rate of its synthesis by adenyl cyclase (AC) or receptor-operated and voltage-dependent Ca2+ chan- by phosphodiesterase (PDE) inhibitors such as xanthone, nels. which slow the rate of its degradation. • Increasing the intracellular levels of cAMP by inhibit- ing the effects of phosphodiesterase. Actions of flavonoids • Inhibition of histamine release stimulated by IgE- Flavonoids have anti–asthmatic activity by inhibiting dependent ligands. platelet-activating factor (PAF), phospholipase A2 (PLA2) • Inhibition of platelet-activating factor and platelet and phosphodiesterase (PDE).48,49 Flavonoids protect aggregation. against allergies, inflammation, free radicals, and platelet • Reducing the inhibition of the anti-histamine activity aggregation.50-53 These observations support the impor- of flavonoids by copper. tance of GK in traditional medicine for the treatment of • Inhibition of 5-lipoxygenase (5-LO) pathway, thereby various conditions. attenuating leukotriene production. Flavonoids have been shown to exhibit a predilection In conclusion, Garcinia kola appears to be very promis- to inhibit histamine release stimulated by IgE-dependent ing in the treatment and management of asthma. There ligands.54 Copper, a transitional metal, most effectively is therefore the need to further examine the effects of its blocks the inhibitory activity of flavonoids, possibly various phytochemical contents on respiratory smooth through a chelation mechanism.55 Zinc deficiencies can muscle, with a view to possibly formulating its extracts lead to excess copper levels, since zinc and copper com- or active constituents as medicines. pete for absorption. Also, a high intake of vitamin C and zinc decrease the absorption of copper. Intake of GK will References 1. Ebomoyi MI, Iyawe VI. Peak expiratory flow rate (PEFR) in young therefore reduce the inhibition of anti-histamine activity adult Nigerians following ingestion of Garcinia kola (Heckel) of flavonoids by copper because of its high content of seeds. Afr J Biomed Res 2000; 3: 187–9. 56 2. Ebomoyi MI, Iyawe VI, Egbagbe EE. Effect of Garcinia conrauana vitamin C and zinc. 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Flavonoids inhibit phospholipid metabolism and 5- li- 10. Okunyi CO, Tantalia AW, Hicks RP, et al. Capillary electropho- resis determination of biflavonones from Garcinia kola in three poxygenase (5–LO). Leukotrienes are derived from ara- traditional African medicinal formulations. Plant Med 2002; 68: chidonic acid through 5–LO and the nucleophilic attack 440–4.

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