Review Article

Natural Anti-Inflammatory Agents: Recent Progress and Future Perspectives

Ashwani K Dhingra1*, Bhawna Chopra1 and Brahmaiah Bonthagarala2
1Guru Gobind Singh College of Pharmacy, India
2Hindu College of Pharmacy, India


*Corresponding author: Ashwani K Dhingra, Guru Gobind Singh College of Pharmacy, India


Published: 04 Sep, 2018
Cite this article as: Dhingra AK, Chopra B, Bonthagarala B. Natural Anti-Inflammatory Agents: Recent Progress and Future Perspectives. Ann Pharmacol Pharm. 2018; 3(5): 1158.

Abstract

Background: Although, various synthetic anti-inflammatory drugs were reported to be used for the treatment of inflammatory disorders but it is still a challenge for the medicinal chemists to develop more potent therapeutic agents. Since most of the clinically used anti-inflammatory drugs like NSAIDs, Coxibs, GCs and TNF inhibitors etc. are allied with considerable toxicity.
Method: A variety of medicinal plants are known to exhibit a wide range of interesting biological activities like antioxidant, anti-inflammatory, anticonvulsant, analgesic, antimicrobial, anticancer, antiprotozoal, antioxidant, antiparasitic, antiplatelet, cardioprotective, anthelmintic, antidiabetic, antitubercular, trypanocidal and anti-HIV. Reported literature survey has been studied to summarize medicinal plants which were utilized as potential anti-inflammatory agents.
Results: The search of novel anti-inflammatory agent is not an ending process. An array of herbal drugs targeting inflammatory cytokines has been identified in the past regained their popularity due to devoid of toxicity.
Conclusion: The present review summarizes recently explored anti-inflammatory herbal drugs and preparations which will be precious for the researchers to working in the field of anti-inflammatory natural chemistry.
Keywords: Inflammation; Herbal drugs; Anti-inflammatory agents; Phyto-constituents; COX


Abbreviations

NSAIDs: Non Steroidal Anti-inflammatory Drugs; ImSAIDs: Immune Selective Antiinflammatory Derivatives; GCs: Glucocorticoids; TNF-α: Tumor Necrosis Factor–α; COX: Cyclooxigenase; ROS: Reactive Oxygen Species; H2O2: Hydrogen Peroxide; 5-LOX: 5-lipoxigenase; RNA: Ribonucleic Acid; DNA: Deoxyribonucleic Acid; CAPE: Caffeic Acid Phenethyl Ester; PGE2: Prostaglandin E2; NO: Nitric Oxide; IL-1β: Interleukin-1β; LPS: Lipopolysaccharide; TPA: Tissue Plasminogen Activator; AIA: Anti-inflammatory Activity; TLC: Thin Layer Chromatography; HPLC: High Pressure Liquid Chromatography; MPLC: Medium-pressure Liquid Chromatography; iNOS: Inducible Nitric Oxide Synthase; 5-HT: 5-Hydroxytryptamine; NF-kB: Nuclear Factor-kappa B; PAF: Platelet-activating Factor


Introduction

Inflammation is the body's first protective attempt that helps in healing of tissues against injurious stimuli or infection [1]. Sometimes when inflammation goes awry, it seems to produce quite serious events like occurrence of rheumatoid arthritis, heart attacks, colon cancer, Alzheimer's and a host of other diseases which may be life threatening. Current approaches to overcome the inflammation include the use of various synthetic drugs belongs to the class of Non Steroidal Anti- Inflammatory Drugs (NSAIDs), immune Selective Anti-Inflammatory Derivatives (ImSAIDs), synthetic forms of natural cortisol (glucocorticoids) GCs, selective glucocorticoid receptor agonist, resolvins and protectins, Tumor Necrosis Factor (TNF) inhibitors and many more [1]. However, various studies based on the clinical trial, suggest almost 90% of these synthetic molecules produce drug related toxicities including gastric irritation, ulceration, bleeding, renal failure, interstitial nephritis, hepatic failure, headache, thrombocytopenia, hemolytic anaemia, asthma exacerbation, skin rashes, angioedema, pruritis etc [2].
In contrast, numerous plant herbs and particularly plant food supplements receive great potential by European consumers as they can deliver significant health benefits at relatively lower cost. The field in which plant-based anti-inflammatory agents are being explored as a potential alternative tool in this era of 21st century has given rise to several varieties of beneficial compounds isolated from plants. In addition, a variety of chemical constituents such as alkamide [3,4], coumarins [5], carotenoid [6], flavonoids [7], steroids [8,9], fatty acids [8-10], stilbenes [11-12] and terpenoids [13] are isolated from plant origin which significantly shows antiinflammatory activities in different animal models. Hence, this approach for treatment of inflammatory diseases by herbal drugs has keen interest to the researchers. A detailed classification of these herbal anti-inflammatory compounds is provided in Table 1.


Miscellaneous Anti-inflammatory Agents

Algae and sponges
In search for new biologically active anti-inflammatory natural products, a variety of isolated compounds derived from algae and sponges were evaluated. Out of these, two compounds palisol and dictyol C exhibited most prominent COX-II inhibitory activity [119]. Spirulina fusiformis (Oscillateriaceae), also known as “blue green algae”, shows significant anti-inflammatory activity as compared to adjuvants in rats using carrageenan induced hind paw model [120]. In another study, methanolic extract of Cheilanthes farinosa (Adianthaceae), a fern grown indigenously in southeast Africa, showed significant anti-inflammatory activity. The main chemical constituents responsible for the activity was found to be rutin, cinnamic acids, caffeic acid and its quinic acid derivative, chlorogenic acid [121].
In addition, “marine red algae” obtained from Neorhodomela aculeate showed promising anti-inflammatory and antioxidant properties. The result indicates promising neuroprotective effect produced by glutamate-induced neurotoxicity and inhibition of ROS expression in murine hippocampal HT22 cell line, and inhibition of H2O2-induced lipid peroxidation in rat brain homogenates [122].
Fish oil
Fish oils obtained from marine organisms was found to possess remarkable therapeutic activity in various inflammatory disorders such as psoriasis, eczema, allergy lipid lowering activity. The main constituents responsible for the activity include eicosapentaenoic acid and docosahexaenoic acid. The proposed mechanism of action of oil includes reduction of lipid level which may be due to 5-LOX, 15-LOX, 15-HEPE inhibitory activity when examined on epidermal enzymes and basophilic leukemia cells of rat [123].
Fungal infected peanuts
Resveratrol derivatives are of interest as inhibitors of cyclooxygenase- 2 and as anti-inflammatory agents. The prenylated resveratrol derivative 4-(3-methyl-but-1-enyl)-3,5,3′,4′- tetrahydroxystilbene was purified from fungally infected peanuts by thin layer chromatography and its structure was confirmed by mass spectrometry. 4-(3-Methyl-but-1-enyl)-3,5,3′,4′- tetrahydroxystilbene inhibited lipopolysaccharide-induced expression of cyclo-oxygenase-2 protein and cyclo-oxygenase-2 mRNA in mouse macrophages at concentrations that were noncytotoxic. 4-(3-Methyl-but-1-enyl)-3,5,3′,4′-tetrahydroxystilbene warrants further evaluation as an anti-inflammatory agent [124].
Propolis
The ethanolic extract of propolis, with and without Caffeic Acid Phenethyl Ester (CAPE), and some of its components on cyclooxygenase (COX-I and COX-II) activity in J774 macrophages has been investigated. COX-I and COX-II activity, measured as prostaglandin E2 (PGE2) production, were concentration dependently inhibited by propolis (3 × 10–3–3 × 102 μgml–1) with an IC50 of 2.7 μgml–1 and 4.8 × 10-2 μgml–1, respectively. Among the compounds tested pinocembrin and caffeic, ferulic, cinnamic and chlorogenic acids did not affect the activity of COX isoforms. Conversely, CAPE and galangin were effective, the last being about ten-twenty times less potent. To better investigate the role of CAPE, we tested the action of the ethanolic extract of propolis deprived of CAPE, which resulted about ten times less potent than the extract with CAPE in the inhibition of both COX-I and COX-II. Moreover, the result suggests that both CAPE and galangin contribute to the overall COX inhibitory activity of propolis. However, CAPE was found to be more effective [125].
Herbal preparations
Wen-Pi-Tang-Hab-Wu-Ling-San (WHN): WHN preparation has been widely used traditionally in Korea for significant antiinflammatory activity. The activity of the extract was is due to its strong inhibition of the excessive production of inflammatory mediators like NO, TNF-α, IL-1β and IL-6, respectively [126,127].
Seungma-Galgeun-Tang: Seungma-galgeun-tang, a promising Chinese herb has been widely used in China as a folk medicine recipe for broad-spectrum treatment of acute and chronic inflammatory disorders. It has been found to inhibit the generation of NO, PGE2, COX-II, TNF-α, IL-12, IL-1β, and activation of NF-kB competitively and to inhibit the secretion of NO in BV-2 microglia without affecting cell viability [128].
Cheng-Chi-Tang: Cheng-Chi-Tang, a Chinese traditional herbal decoction type formulation was reported to have significant antiinflammatory activity in several inflammation and related disorders like pain and inflammation produced due to regular use of purgatives, painful abdomen, hard stools and fever [129].
San Huang-Xie-Xin-Tang: San Huang-Xie-Xin-Tang widely used traditionally oriental anti-inflammatory medicine in china. The prominent activity was found to be due to the presence of baicalin using LPS-induced inflammation models [130].
Bolengguazi: Bolengguazi, a formulation used widely in Tibetan medicine in the management of inflammation related disorders. It was reported to contain the seed extract of Herpetospermum pedunculosum, Momordica cochinchinensis and Momordica charantia. The activity of the extracts was evaluated using different animal models of inflammation like egg-albumin–induced paw edema and cotton pellet granuloma tests [131,132].
Kampo medicine, Shosaikoto: Kampo medicines are the traditional medicines that originated in Japan based on the silent concept of treatment of diseases. In a study conducted by Ara et al. [133], they evaluated the efficacy of this system of treatment through clinical trials in vitro against periodontal diseases, where inflammation was induced by LPS. The possible mechanism behind this may involve the inhibition of production of inflammatory mediators like PGE2, IL-6, IL-8 and COX-II in a dose-dependent manner. Trials showed that therapy is quite efficacious in reducing the disease progression upto 24 hr duration without any viable growth of human gingival fibroblasts by Porphyromonas gingivalis [133].
SK Ato formula: Flavonoid isolated from the extract of leaves and roots of Scutellaria baicalensis, Ginkgo biloba and Gentiana scabra were reported to have topical AIA against chronic skin inflammation like atopic dermatitis. The preparation is being available in market as “SK Ato Formula” and is meant for topical application and contains flavonoids like gingkolide A and B (biflavonoids). It shows satisfactory effects in animal models with chronic type of skin inflammation induced by TPA treatment to mouse ear. The probable mechanisms behind its AIA are by inhibition of PGE2 synthesis, COX-II and consequent suppression of proinflammatory gene expression [57].
Kava kava: The roots of plant Piper methysticum (kava kava) was used traditionally for managing inflammatory pains. Ethyl acetate extract of Piper methysticum (kava kava) roots yielded seven biologically active compounds, dihydrokawain, demethoxyangonin, flavokawain A, kawain, dihydromethysticin, yangonin and methysticin. All the compounds were purified using MPLC, preparative TLC and HPLC methods. Both Dihydrokawain and yangonin showed the highest COX-I and COX-II inhibitory activities at 100 microg/ml, respectively [134].
In another study, Milled root of Piper methysticum plant were extracted sequentially with hot water and methanol. The methanol extract yielded bornyl esters of 3,4-methylenedioxy cinnamic acid and cinnamic acid, pinostrobin, flavokawain B, and 5,7-dimethoxyflavanone. The aqueous extract contained previously reported kava lactones, as confirmed by TLC analysis. All these compounds show excellent COX-I and moderate COX-II enzyme inhibitory activities at 100 microg/mL. Flavokawain B showed the highest COX-I inhibitory activity at 100 microg/mL [135].
Safety/Toxicity aspects of herbal preparations
Herbal medicine generally uses various parts of plants or mixtures of plant extracts to treat illness, to promote health, to restore the body's ability to protect, regulate and heal by itself. However, quality and efficacy of herbal medicines and preparations remain a question of concern, and bottlenecks in risk and benefit assessments need to be solved yet plant kingdom received considerable attention due to their wide range of biological activities. But as far as the safety of these medicines is concerned, these do not mean that herbals products are safe to use. Literature survey reveals, about 40% of the anticancer drugs made from plant origin which have been used successfully to treat cancer, but they still have serious side effects. Apart from this, many herbal preparations are reported to possess serious adverse effects and some of them have a tendency to interact with the synthetic preparations [136]. For example, St. John's Wort is used in the treatment of depression, but it interacts with iron to reduce its therapeutic efficacy. However, several clinical trials of herbal drugs have been done, representing them as a better aid in the treatment of anti-inflammatory disorders [137].
Fish oils have been proposed as a reasonable alternative for the treatment of rheumatoid arthritis e.g. cod liver oil and other conditions as a consequence of the fact that they provide less cardiovascular risk than other treatments including NSAIDs [33]. Caution should be exercised in combining low dose aspirin with COX-II inhibitors due to potential increased damage to the gastric mucosa. COX-II is upregulated when COX-I is suppressed with aspirin, which is thought to be important in enhancing mucosal defense mechanisms and lessening the erosion by aspirin [37].


Table 1

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Table 1
Herbs with active constituents having anti-inflammatory activity.

Conclusion

The search of novel anti-inflammatory agent is not an ending process. Although the use of synthetic anti-inflammatory agents often very effective, but long term use of these agents leads to various undesirable side effects like gastric ulceration, infrequently, myocardial infarction and stroke. Nowadays, interest with plant based anti-inflammatory medicine is revived due to the increasing awareness of the health risks linked with the reckless use of current allopathic medicines. Unfortunately, India is still behind to mark its footprints in international business of herbal industry because lack of scientific approach in herbal drugs. Therefore, exploration of the more effective, potent, less toxic therapeutic agents to treat as well as reduce the signs and symptoms of acute and chronic inflammatory diseases is still a challenge for the pharmaceutical chemists. Hence, expert key commentaries are required in the field of herbals regarding their production and marketing in terms of better regulatory checks. However, ongoing experiments and clinical trials should be continued to guide and provide their scientifically based effectiveness to reduce inflammation and promote wellness. It is hoped that this review article can serve as a lead for readers who are interested to work on inflammation and its treatment.


Acknowledgment

Authors want to express their gratitude towards the Management and Principal, Guru Gobind Singh College of Pharmacy, Yamuna Nagar, Haryana for proving us the scientific environment.


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