Giulio La Medica Assignment

1. Introduction

Inflammation is the response of body to injury and danger. It is the central communication network and regulatory process that senses and controls threat, damage, containment, and healing, which are all critical aspects in the maintenance of the integrity of an organism [1].

This process occurs as a defensive response, which induces profound physiological adaptions triggered in an attempt to limit tissue damage and remove the pathogenic insult. Such mechanisms involve a complex series of events including dilatation of arterioles, venules and capillaries with increased vascular permeability, exudation of fluids, including plasma proteins, and leukocyte migration into the inflammatory area [2].

In response to injury or infection, the specialized cells of the first line, leukocytes (neutrophils and eosinophils polymorphonuclear-PMNs) migrate to the damaged regions with the aim of neutralizing and eliminating these harmful stimuli [3]. The mechanism of inflammation is attributed, in part, to release of reactive oxygen species (ROS) from activated neutrophils and macrophages [4]. ROS propagate inflammation by stimulating release of cytokines, such as interleukin-1, tumor necrosis factor-α, and interferon-γ, which stimulate recruitment of additional neutrophils and macrophages. Thus free radicals are important mediators that provoke or sustain inflammatory processes and, consequently, their neutralization by antioxidants and radical scavengers can attenuate inflammation [5,6].

A complex network of mediators, including cytokines and lipids, produced by endothelial cells, epithelial cells and tissue infiltrating leukocytes, characterizes the early phases of inflammation [7].

The clinical features of inflammation were described some 2000 years ago listed as the cardinal signs of inflammation: rubor (redness), tumor (swelling), heat (hyperthermia) and pain [8].

The combined action of the molecules attracts and activates leukocytes to the reactive site, promotes angiogenesis and tissue remodeling [7]. If this sequence of steps is rigorously followed, the acute inflammation will resolve without causing excessive damage to tissue, returning to homeostasis [3].

However, there are several clinical conditions where inflammation becomes chronic with excessive production of macrophage-derived mediators may lead to collateral damage to normal cells, which results in diseases, including atherosclerosis, bowel disease, rheumatoid arthritis glomerulonephritis, and septic shock [9].

Therefore, the classical anti-inflammatory agents glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs) can only alleviate symptoms without, however, altering the course of the disease [3].

The current anti-inflammatory therapy aims to control the cardinal signs of inflammation, antagonizing or blocking key pro-inflammatory mediators that are released at the beginning of an acute inflammatory response [3]. NSAIDs typically relieve inflammation and associated pain by inhibiting cyclooxygenase enzymes involved in the production of prostaglandins. These enzymes exist in two isoforms (COX-1 and COX-2) coded by distinct genes on different chromosomes [10]. Compounds that inhibit COX enzymes could therefore be considered to be potential anti-inflammatory drugs. However, many of the commonly used anti-inflammatory agents are becoming less acceptable due to serious adverse reactions such as gastric intolerance, bone marrow depression and water and salt retention, resulting from prolonged use [11].

Within this context, it is of fundamental importance to search for substances that can promote the resolution of inflammation, thus, homeostatic and modulatory, efficient and tolerated by the body [3].

Plants are an important source of biologically active natural products and are considered a promising avenue for the discovery of new drugs due to easy access and relatively low cost, since they naturally grow in relative abundance [12,13]. The development of standardized herbal medicines with proven efficacy and safety of use is an important source for increasing the access of people to medicines and to offer new therapeutic options [14].

So, can cite examples of plants with scientifically proven anti-inflammatory activity: Annona muricata, Glycine max, Orthosiphon stamineus, Caulerpa racemosa and Oenothera speciosa used in folk medicine [15–19].

Therefore, extracts or isolated compounds from natural products seems to be a promising strategy for developing anti-inflammatory drugs in search of a better therapeutic and quality of life for the patient [20].

In the course of our continuing search for bioactive natural products from plants, we have published reviews of extracts and compounds derived from plants with the following potential activities: inhibitors of mammary, uterine cervical and ovarian neoplasia [21–23]; inhibitors of HMG CoA reductase, angiotensina-converting enzyme and the enzyme acetylcholinesterase [24–26]; with central analgesic activity [27]; employed in prevention of osteoporosis [28]; for the treatment of Parkinson’s disease [29]; anticonvulsant and anxiety disorders [30,31]; with antileishmanial [32]; giardicidal [33]; antileprotic [34]; hypoglycemic [35] and antiinflammatory activities [36,37]; for the treatment of malaria [38]; with antiulcer activity [39–41] and effects of plant extracts on HIV-1 Protease [42]. Our group has also reviewed the medicinal and poisonous plants of the Northeastern region of Brazil [43,44], among other review articles [45–54]. So in this work, we reviewed the literature related to anti-inflammatory activity of the plants from South American countries.

2. Results and Discussion

It was possible in this review to list 175 species of medicinal plants with anti-inflammatory activity. Those species are distributed in 63 families of which the following stood out: Asteraceae, Fabaceae, Euphorbiaceae, Apocynaceae and Celastraceae with 37, 17, 11, 6 and 6 species, respectively, studied so far (Table 1).

The effectiveness of the plant extracts was dependent on the type of extract used, the model of inflammation induction and the organism tested. Thus, it was possible to classify the extracts as strongly active, active, weakly active, inactive and equivocal.

Different species of Proustia genus have been frequently used as antiinflammatory and analgesic to treat gout and rheumatic illnesses, however, there is little information about their efficacy and acute toxicity [55]. This genus accumulates sesquiterpene α-isocedrene derivatives that are typical for the subtribus Nassauviinae of the family Asteraceae [56], and a guaianolide β-d-glucopyranoside has been previously isolated from Proustia ilicifolia [57].

According to Delporte et al. (2005) [55] in the assays carried out per os crude methanol extract (GME), hexane extract (HE) and methanol extract (ME) exhibited the strongest analgesic activities similar to the reference drug (SN). In relation to the results obtained in per os anti-inflammatory studies, ME showed the strongest effect, and was similar to the reference drug (SN); HE did not present significant antiinflammatory activity. The antiinflammatory activity have been attributed the presence of compounds with a similar mechanism for both activities, as for example inhibition of the synthesis of prostaglandin E2 (PGE2). By the activation of the cyclo-oxygenase enzyme, the level of PGE2 increases markedly, and its production provokes inflammation and pain [58]. Therefore, we assume that some active metabolites of these extracts could inhibit cyclooxygenase activity.

For arachidonic acid (AA) and phorbol 12-myristate 13-acetate (TPA) induced oedema, GME showed significant effect only against AA assay and on the contrary, HE and ME presented important activities only against TPA and dichloromethane extract (DCE) was active in both AA and TPA models. The action’s mechanism of the GME can be explained by inhibition of cyclooxygenase enzymes while the HE and ME may act by inhibiting the synthesis of leukotrienes. Since the DCE in addition to inhibiting the synthesis of leukotrienes may act by blocking production of PGE2 [59].

GME did not show acute toxicity per os up to the maxim dose of 2 g/kg and the weight of the mice had a normal variation after the seven days of observation. Common side effects such as, mild diarrhea, loss of weight and depression were not recorded. It is important to carry out toxicological studies in other animal species in order to demonstrate its lack of toxicity [59].

Ageratum conyzoides (Asteraceae), known commonly as “mentrasto”, has been used in Brazillian folk medicine to treat various ailments (metrorrhagia, fevers, dermatitis, inflammation, rheumatism, diarrhea and diuretics). A large number of pharmacological activities (anti-inflammatory, antipyretic, analgesic) have been attributed to the essential oil of Ageratum conyzoides [60]. The flowers and leaves are used in the form of an infusion for their analgesic and antiinflammatory properties. Literature data indicate its efficacy in alleviating pain caused by human arthritis [61] or induced experimentally [62].

The hydroalcoholic extract (HAE) of the leaves from A. conyzoides was active in both the on subacute (cotton pellet-induced granuloma) and chronic (formaldehyde-induced arthritis) models of inflammation in rats. The weights of cotton pellets were significantly reduced in (38%) after treatment with crude extract of A. conyzoides (250 mg/kg, p. o.) and possibly this effect is related to inhibition of neutrophil migration. Exame macroscopic gastric mucosa did not reveal any tissue damage associated with treatment, which is a collateral effect of many antiinflammatory drugs, including aspirin and related compounds [63,64], this result would be explained by an inhibition of the biosynthesis of prostanoids by cyclooxygenase [65].

Literature review reports indicate the presence of pyrrolizidine alkaloids in A. conyzoides plants [66,67]. These are known to be hepatotoxic, and to cause lung cancer and variety of other ailments [68]. There was investigated possible hematological and biochemical alteration in animal blood samples following after sub-acute and chronic treatment with the HAE of the plant. To evaluate liver function, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels of plasma were measured. It was observed that during the sub-acute treatment, no significant alteration in serum levels of SGOT and SGPT, however during the chronic treatment with HAE (500 mg/kg body wt.) the value of SGPT (108.5726.6 U/l) showed a statistically significant difference (p < 0,05) to control group (155.6739.6 U/l), reduced significantly [65].

Artemisia copa Phil. (Compositae), commonly known as “copa-copa”, is a small and much branched bush with a height of 30–60 cm that grows in the northwest of Argentina and in the north of Chile. The plant is regularly sold in local markets and herb health stores and the infusion of the aerial parts are used in popular medicine as antitussive, digestive, for lowering fever, for pulmonary diseases, and hypertension [69]. The leaves, macerated in alcohol, are also used locally to rub on rheumatic pains [70].

Anti-inflammatory activity of ethanol and dichloromethane extracts were analyzed in models of carrageenan-induced paw edema in rats and the ear edema induced by 12-O-tetradecanoylphorbol-13 acetate (TPA) and arachidonic acid (AA) in mice. Antiinflammatory activity was observed in both extracts that showed antiinflammatory activity in the TPA (88 and 54%), and the ethanolic extract showed a 37% inhibition in AA test. The results suggested that A. copa was able to prevent the production of proinflammatory mediators specially those related with cyclooxygenase (CO) and Lipoxygenase (LO) pathway. A. copa has no analgesic effect on the central nervous system that would contribute to its peripheral analgesic effect [71].

Bauhinia tarapotensis Benth. (Leguminosae) is a small tree growing in Ecuador (South America), where it is commonly known as “pata de vaca”. The plant leaves are traditionally used for their anti-inflammatory and decongestant properties [72], whereas the bark is employed as antidiarrhoeal remedy [73]. Previous study on the methanol extract of B. tarapotensis leaves revealed antioxidant and radical scavenger properties, due to the presence of different antioxidant principles, such as cyclohexenone, lignans, and phenylethanoids derivatives [74].

The topical anti-inflammatory activity was evaluated as inhibition of the croton oil-induced ear edema in mice [75]. Five extracts of the leaves significantly inhibited the croton oil-induced ear edema in mice, among which the chloroform extract was the most active. The main anti-inflammatory principles of B. tarapotensis leaves are triterpenic acids of ursane and oleanane series. The antiphlogistic activity of mixtures constituted of two ursane and oleanane isomers with different hydroxylation pattern, in the ratio 2:1, is comparable to that of indomethacin [76].

Croton pullei (Euphorbiaceae) is a liana that grows above other trees, distributed in tropical areas with vast distribution in the Amazon forest [77]. In the folk medicine, several plants of the Croton genus have been used with therapeutic purposes in pathologies that involve painful and inflammatory diseases which justify this work [78].

Anti-inflammatory activity was tested in two models that assess inflammatory processes such as edema and leukocyte migration. The crude methanol extract significantly reduced by 72% the ear edema by croton-oil induced, as also was a dose-dependent reduction of leukocyte migration to the peritoneum after induction with carrageenan. The mechanism of action has not yet elucidated [78].

Maytenus ilicifolia Mart. ex. Reiss (Celastraceae), popularly called “espinheira-santa” due to the appearance of its leaves and its therapeutic properties, is utilized in popular medicine in cases of inflammation and gastric ulcer [79–81].

This study evaluated the anti-inflammatory activity, antinociceptive and antiulcer of ethyl acetate and hexane extracts of Maytenus ilicifolia [82].

In the model of paw edema induced by carrageenan was observed that there was no significant difference in inflammatory response between indomethacin and the extracts evaluated. The result of hexane extract showed the anti-inflammatory potential of terpenes whereas for ethylacetate extract the anti-inflammatory response has been attributed to flavonoids, which act by reducing the formation of pro-inflammatory mediators as prostaglandins, leukotrienes, reactive oxygen species and nitric oxide [82]. According to Oliveira et al. (1991) [83], both acute and chronic administration of this species did not induce any apparent toxicity.

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