Antinociceptive, Anti-Inflammatory, and Antipyretic Activity of Mangrove Plants: A Mini Review

Mangrove plants are specialised plants that grow in the tidal coasts of tropic and subtropic regions of the world. Their unique ecology and traditional medicinal uses of mangrove plants have attracted the attention of researchers over the years, and as a result, reports on biological activity of mangrove plants have increased significantly in recent years. This review has been set out to compile and appraise the results on antinociceptive, anti-inflammatory, and antipyretic activity of mangrove plants. While the Web of Knowledge, Google Scholar, and PubMed were the starting points to gather information, other pieces of relevant published literature were also adequately explored for this purpose. A total of 29 reports on 17 plant species have been found to report such activities. While 19 reports were on the biological activity of the crude extracts, 10 reports identified the active compound(s) of various chemical classes of natural products including terpenes, steroids, and flavonoids. This review finds that antinociceptive, anti-inflammatory, and antipyretic activity appears to be widespread in mangrove plants.


Introduction
Mangrove forests are a special type of vegetation found in the coastal regions of the tropical and subtropical parts of the world. Global area that comprises mangrove forest is about 181000 square km. Majority of the mangrove forests is confined to the South East Asia and Australia, which accounts for 43% of the worldwide mangrove area (Table 1) [1,2]. About 70 plant species of 27 genera have been reported from mangrove forests [2]. However, it should be noted that mangrove forests generally support the growth of nonmangrove plant species as well. For example, 334 plant species of 245 genera have been reported so far from the Sundarbans [3]. Flora of mangrove forests is unique from others in that their habitat extends along the border where the fresh and sea water merge. Therefore, unlike common terrestrial plants, they can withstand high salt concentration, can remain submerged in water, and maintain an efficient nutrient retention mechanism [1].
Mangrove forests are still quite unfamiliar to a vast population due to their limited distribution. However, the people inhabiting areas near mangrove forests heavily depend on these forests to meet their needs including their healthcare. During the early stage of human civilization, mangrove forests drew very little or no attention. This is to some extent because of the difficulty to access these areas. As the population continued to grow, people had to find new and unexplored sources including mangrove forests. In some parts of the world, mangrove forests are over utilised. As a result, human establishment grew in close proximity of With the introduction of rapid and reliable screening methods, researchers around the world have picked plant species of various origins including mangrove plants in the search for new medicine. This review aims to compile and appraise reports on the antinociceptive, anti-inflammatory, and antipyretic activity of mangrove plants.

Methodology
Web of knowledge, Google Scholar, and PubMed were used to search for the published reports since 1950. Other relevant publications, for example, books and journal articles, were also consulted. A total of 57 mangrove species were searched for the activity. The results are presented in three different tables; Table 2 gives a general outline of works that have been carried out so far on various mangrove plants for antinociceptive, anti-inflammatory, and antipyretic activity. It also describes the plant species, family, plant part used for the investigation, reported activity, and the screening method. Table 3 deals with those reports reporting the identification of active compound(s).

Antinociceptive, Anti-Inflammatory, and Antipyretic Activity
From the search, 29 hits were found with different mangrove species reporting one or more of these activities: antinociceptive, anti-inlfammatory, and antipyretic activity (Tables  2 and 3) . Some of the reports coincide for a given species, and, therefore, a total of 17 plants were reported to have such activity. However, only one plant, Pongamia pinnata was studied for antipyretic activity. In nine cases, further phytochemical studies were carried out to find out the active constituent(s). One of the studies justified that the activity might be due to betulinic acid since betulinic acid is known for its anti-inflammatory activity and was present in the extract [8]. According to chemical classification, the active compounds, isolated from the mangrove plants, can be classified into diterpenes [11,15], flavonoids [24], isoflavonoids [25,29], monoterpenes [30], phenolics [30], steroids [32], triterpenes [29], xanthones [14], and a compound with unidentified structure [13] ( Table 3). The diterpenoids reported by Yodsaoue et al. [11] from the root extract of Caesalpinia mimosoides showed anti-inflammatory activity in micromolar range. The most potent activity was observed with mimosol D (Figure 1), which showed an IC 50 for the inhibition of nitric oxide production at 3 μM and TNF-α production at 6.5 μM. Among the diterpenoids from the stems and twigs of the Chinese mangrove plant, Excoecaria agallocha, agallochaol O (Figure 2) at 100 μM showed 52.6% inhibition of interleukin-6 (IL-6) and other proinflammatory cytokines induced by lipopolysaccharide (LPS) [15]. Bio-assay guided phytochemical investigation of Ipomoea-pes-caprae resulted in the isolation of eugenol (Figure 3), a well-known analgesic, anti-inflammatory natural product [31,33]. Some studies resulted in the isolation of steroids and triterpenes as the active compounds (Table 3) [32].
Plants often produce secondary metabolites under stressful conditions. Therefore, it is not surprising that mangrove plants, facing various ecological and environmental stresses, biosynthesise a wide range secondary metabolites of potential medicinal importance. The present literature survey has revealed that mangrove plants contain a wide range  [19] 4 Advances in Pharmacological Sciences    Ergosterol peroxide, 6-α-hydroxystigmast-4-en-3-one and stigmast-4-en-3-one [32] Advances in Pharmacological Sciences of compounds showing antinociceptive, anti-inflammatory and or antipyretic activity (Tables 2 and 3). Pain itself is not any disease. It is manifested in certain disease or pathological conditions. Use of natural products in the management of pain goes back to thousands of years. Use of poppy by various civilizations or the use of willow bark to cure fever led to the isolation of morphine and salicylic acid, respectively [34]. These two drugs are still used extensively in modern medical practice. Present trend of the researchers to focus on mangrove plants has opened up an arena to find bioactive compounds from a source that has long been ignored or less explored. It is expected that research on mangrove plants will continue to rise in the coming days.

Possible Mechanism of Actions
It must be stressed that there are no or a few reports available on the possible mechanisms of action of the extracts or isolated compounds from the mangrove plants. However, exploring the methods applied in the published reports on evaluation of antinociceptive, anti-inflammatory, and/or antipyretic activity of mangrove plants , the following assumptions can be made about the possible mechanisms of actions. The sensation of pain can be initiated either peripherally or through the central nervous system. Peripherally mediated pain can be inhibited by NSAIDs which blocks the anti-inflammatory pathways responsible for pain. On the other hand, opioid analgesics are useful for the management of centrally acting pain in which opioid analgesics act by inhibition of opioid receptors. Acetic-acid-induced and formalin-induced paw licking represents peripherally acting pain sensation. Intraperitoneal administration of acetic acid or formalin mediates pain response through the release of inflammatory mediators, mainly prostacycline (PGI 2 ) [35,36]. The hot plate test, the tail flick test, and the Randall-Selitto nociceptive test represent nociception through central mechanism [35,37]. The rat paw oedema is an antiinflammatory model that can be induced by carrageenan, formalin, kaolin, cotton pellet granuloma and granuloma, pouch. Inflammation of the rat paw can also be stimulated by administration of inflammatory mediators like histamine, or eicosanoids like 5-hydroxytryptamine and prostaglandin E-2 [22,25]. Other anti-inflammatory models that have been used in the assessment include nitric oxide, TNF-α, and IL-6 induction by the administration of lipopolysaccharides in cell culture [14].
A wide range of methods were adopted by different research groups for the study of antinociceptive activity of mangrove plants. All these methods can be summed up to two major mechanisms, that is, centrally acting and peripherally mediated pain sensation. Different mangrove plants were able to inhibit pain sensation of both types. Therefore, it is possible to find opioid analgesics as well as analgesics in mangrove plants that act by inhibition of inflammatory pathways responsible for pain. Only in few cases, plants were investigated by methods that represent both of the mechanisms. Interestingly, articles that report the isolation of active compounds used methods representing peripherally acting pain sensation.

Conclusions
This review has revealed that antinociceptive, antiinflammatory, and antipyretic activity appears to be widespread among mangrove plants, and thorough and systematic phytochemical and pharmacological studies are much needed to discover new antinociceptive, antiinflammatory, and antipyretic medicinal entities from mangrove plants.