Natural Occurrence of Alkaloids and Their Therapeutic Potential in Anti-Inflammatory Herbal Drugs

Introduction

The term "inflammation", derived from the Latin word "Inflammare" (to set on fire), describes a complex biological response initiated by vascular tissue in reaction to harmful stimuli such as pathogens, irritants, and damaged cells.¹ The process of inflammation involves various chemical mediators, including prostaglandins, prostacyclin, leukotrienes, lymphokines, and chemokines. Specific inflammatory mediators like interleukin (IL)-1β, IL-6, histamine, 5-hydroxytryptamine (5-HT) and tumor necrosis factor-α (TNF-α) were found to be elevated (Figure 1) in inflammatory conditions. These mediators induce vasodilation and increase vascular permeability, thereby attracting leukocytes. The resulting process of inflammation causes oedema due to the leakage of fluid and proteins from the vascular tissue. Inflammation manifests as pain, redness, warmth and swelling. Vasodilation increases the blood flow, causing redness and warmth while sensitized nerve endings contribute to pain. Inflammation is crucial for healing and immune defence, dysregulation of which can lead to chronic inflammatory disorders. Chronic systemic inflammation is a primary contributor to a number of disorders, including asthma, diabetes, and cancer, thereby necessitating further research into novel potential therapies.^2-3

a. Acute inflammation

It is associated with increased vascular permeability, capillary infiltration and emigration of leukocytes.

b. Chronic inflammation

Inflammation is marked by the infiltration of mononuclear immune cells such as macrophages, monocytes, neutrophils, along with fibroblast activation, angiogenesis and fibrosis. Synthetic medications have been widely used for the rapid treatment of inflammation and related conditions. However, numerous clinical studies have raised concerns regarding the safety profiles of these synthetic agents, with nearly 90% of anti-inflammatory drugs reported to cause significant adverse effects. As a result, there has been a shift in focus from synthetic to natural therapies for the management of inflammatory disorders (Table 1).

Similar to non-steroidal anti-inflammatory drugs (NSAIDs), steroidal agents such as hydrocortisone, betamethasone have also been associated with several adverse effects, including Cushing’s habitus, hypersensitivity reactions, peptic ulceration, hyperglycaemia, osteoporosis, and immunodeficiency-related problems.^4-5

The World Health Organization (WHO) conducted a study which found that none of the evaluated NSAIDs or steroidal anti-inflammatory drugs could be considered safe. Another study reported several drug-related problems, including toxic effects and adverse reactions with long-term use. This prompted researchers to explore herbal medications for the treatment of inflammatory diseases.

Dashamoola, a renowned polyherbal formulation is traditionally used to alleviate inflammation, as noted in the Ayurvedic Pharmacopoeia of India (1990).⁶ Globally, herbal medicines are becoming increasingly popular for treating inflammatory diseases. This growing trend suggests the demand for herbal remedies in upcoming years, highlighting the shift toward natural alternatives for managing inflammatory related diseases. India, with its rich biodiversity has recorded 45,000 plant species, out of which approximately 7,500 are known for their medicinal properties. Research into plant-based antiinflammatory drugs has identified a variety of beneficial compounds including alkaloids, glycosides, terpenoids, flavonoids, phenolic compounds, steroids and even polysaccharides, which are emerging as promising alternatives to synthetic drugs. These phytochemicals derived from both terrestrial and marine plants are being explored for their therapeutic potential in modern medicine.⁷

Alkaloids Responsible for Anti-inflammatory Activity

Alkaloids are basic, organic, complex nitrogenous heterocyclic compounds that are found in nature and exhibit significant physiological effects when taken internally at the recommended dosage. They are the most abundant class of plant secondary metabolites occurring in nature, especially in roots of the medicinal plants. Alkaloids have been shown to have a variety of biological effects, including emetic, anti-inflammatory, analgesic, anti-tumor, sympathomimetic, anti-viral, anti-hypertensive, anti-tussive, anti-microbial and anti-cholinergic properties. Alkaloids are among the most diverse class of phytoconstituents, with approximately 5500 alkaloids known currently. A few have been discovered in microbial species, as well as ergot alkaloids in fungi, namely Claviceps purpurea.⁸

In contrast to synthetic agents, the herbal medicines containing alkaloids offer a promising alternative by providing a more natural and balanced modulation of inflammatory pathways. Although alkaloids are potent bioactive compounds with inherent toxicity, their use in traditional medicine shows that they can be safe and effective when used in controlled dosages. The alkaloidal compounds have been classified into various categories based on their biosynthetic precursor and heterocyclic ring system. The basic moiety such as indole, piperidine, tropane, purine, pyrrolizidine, imidazole, quinoline, isoquinoline, and pyrrolidine type of alkaloids were found. They are widely distributed in families such as Solanaceae, Rubiaceae, Ranunculaceae, Apocynaceae, Papaveraceae.⁹ Alkaloids occur naturally as salts of organic acids such as tartrates, maleates, citrates, oxalates and sulfamates. Morphine, strychnine, quinine, ephedrine, nicotine, etc., are well-known alkaloids used in clinical practice.^10,11

Alkaloid-Containing Herbal Drugs Used in the Treatment of Inflammation

Barberry

Berberis, commonly known as barberry, is defined as the dried roots of Berberis vulgaris Linn., a shrub belonging to the family Berberidaceae. The plant occurs in temperate and subtropical regions like Himalayas and Southern India. It is particularly valued for its rich alkaloidal content, especially berberine which constitutes nearly 0.4% to 1% in its root and bark extracts. Berberine and other alkaloids such as karachine, palmatine, oxycanthine and taxilamine are known for their potent anti-inflammatory activity. Studies indicate that Berberis extracts significantly reduce pro-inflammatory markers like IL-1β, IL-6 and COX-2 in activated macrophages. The anti-iflammatory effects are mediated through several mechanisms including the inhibition of cytokine production where berberine exhibits concentration-dependent inhibition on IL-6 and TNF-α. Further berberine suppresses lipopolysaccharide (LPS)-induced expression of various pro-inflammatory genes, including IL-1β and matrix metalloproteinase-9. Its action is also linked to the modulation of key signalling pathways, particularly NF-kB, which plays a central role in inflammation.¹²

Fenugreek

Fenugreek consists of dried seeds of Trigonella foenum-graecum Linn., an annual herb from the family Leguminosae. The plant is widely cultivated in Europe, India and northern Africa. The seeds are rich in alkaloids, particularly trigonelline (0.1-0.3%), which possess notable anti-inflammatory properties. The seeds also contain essential fatty acids namely linoleic and linolenic acids. Research indicates that fenugreek seeds can significantly lower the pro-inflammatory markers including IL-1β, IL-6, COX-2 and TNF-α. Trigonelline contributes to these effects by inhibiting key inflammatory enzyme namely COX-2 and reducing reactive oxygen species (ROS) levels. This highlights fenugreek's potential as a natural anti-inflammatory agent, emphasizing the therapeutic benefits of its alkaloids.¹³

Areca nut

The areca nut, commonly known as betel nut, is the dried seed of Areca catechu Linn, a tropical plant belonging to the family Palmae. It is primarily cultivated in India, Sri Lanka and East Africa. The nut is approximately 2.5 cm long and contains various alkaloids and tannins. The alkaloids include arecoline (0.1-0.5%), arecaine, guvacine, arecaidine, guvacoline, leucocyanidine. Tannins are mainly catechins including (-) epicatechin. Studies have shown that the ethanol extract of A. catechu reduces nitric oxide generation and inhibits the expression of induced nitric oxide synthase (iNOS) and COX-2. Additionally, the extract and its aqueous fraction exhibit significant anti-inflammatory effect by inhibiting cyclooxygenase and lipoxygenase pathways. The drug potentially acts by promoting degradation and inactivation of PGE2. The extract has also shown efficacy in LPS-induced inflammation and carrageenan-induced paw oedema models, demonstrating its antiinflammatory activity.¹³

Black Pepper

Black pepper, commonly known simply as pepper, consists of the dried fruits of Piper nigrum Linn. Pepper is a perennial climbing vine from the Piperaceae family, native to Southern India and other tropical countries. This woody climber can grow up to 10 meters through aerial roots. The chemical composition of black pepper includes alkaloids such as piperine (5-9%), piperidine, piperanine, piperettine and piperyleine. Piperine is the major active component that demonstrated significant anti-inflammatory effects in various experimental models by inhibiting the expression of IL-6 and PGE2 production. Additionally, piperine prevents the migration of activation protein 1 (AP-1) into the nucleus of synoviocytes and reduces the synthesis of prostaglandins, IL-6 and matrix metalloproteinases.¹⁴

Long Pepper

Pippali, also known as Indian long pepper, is obtained from the flowering vine Piper longum Linn., a member of the family Piperaceae. It is cultivated for its fruits which are typically dried and used as a spice and seasoning. Pippali is found in various regions of India, from the central Himalayas to Assam as well as in the forests of the Western Ghats at elevations between 100 to 1000 meters. The fruit of Piper longum contains alkaloids such as piperine, piperlongumine, piperlongminine, piplartine and pipernonaline. Pippali has demonstrated anti-inflammatory activity, with the "Chhoti" variety suppressing inflammation in both the acute and subacute phases, while the "Badi" variety exhibiting effects mainly in the acute phase of inflammation.¹⁵

Periwinkle

Periwinkle, also known as Vinca rosea Linn., is a perennial herb from the Apocynaceae family and is native to the West Indies. It is commonly found in tropical, subtropical regions of India, including Karnataka, Tamil Nadu, Madhya Pradesh, and Assam. The plant grows with trailing stems that can reach 3-6 feet in length and roots upon contact with the ground allowing it to spread widely. V. rosea contains a high concentration of indole alkaloids, primarily vincristine, vinblastine, vinorelbine, and vindesine, along with other alkaloids such as ajmalicine and serpentine. V. rosea extract has shown significant anti-inflammatory effect, particularly in carrageenan-induced rat hind paw oedema model. However, its activity was found to be dose-dependent in experimental models.¹⁶

Dronapuspi

Dronapuspi, scientifically known as Leucas aspera Willd., is an annual herb from the Lamiaceae family, found throughout India ranging from Himalayas to Sri Lanka. The plant grows to a height of 15-60 cm and bears narrow, ovate, yellowish-green leaves with a pungent taste. Its smooth cylindrical roots have wiry rootlets and the stem is light greenish in colour with mild bitter taste. The small white flowers grow in dense axillary whorls, while the fruits are smooth, brown nutlets measuring 3 mm in diameter. Dronapuspi contains pyridine type of alkaloids, namely nicotine and lobeline. The leaf extract of the plant has demonstrated anti-inflammatory activity including the inhibition of carrageenan-induced hind paw oedema, as well as suppression of COX-2 and TNF-α, making it effective in reducing inflammation.¹⁷

Vasaka

Vasaka, also known as Adhatoda vasica Ness., or Malabar nut is a dense shrub from the Acanthaceae family, growing to a height of 1.2-2.4 meters. It is widely distributed across India and the tropical regions of South-east Asia. The plant leaves are 10-30 cm long and its yellow bark is used both in fresh and dried forms. Vasaka primarily contains pyrro-quinazoline type of alkaloids which include vasicine, vassicinone, adhatonine, vasicinol, and vasicinalone, with vasicine being the most significant at a concentration of 1.3%. The plant extract has shown notable anti-inflammatory effect, particularly in reducing airway inflammation by attenuating the elevated levels of transforming growth factor-β1 (TGF-β1) and IL-6.¹⁸

Guduchi

Tinospora cordifolia Willd., commonly known as Guduchi, is a large deciduous climbing shrub from the Meninspermacae family. Plant is native to tropical and sub-tropical regions of the Indian subcontinent. It typically grows to about 1.0 m in height and 0.5 m in width, with greenish-yellow flowers. Guduchi contains various bioactive compounds including berberine, palmatine, magnoflorine, choline, isocolumbin, tembeterine, tetrahydropalmatine and aporphine. It exhibits significant anti-inflammatory activity in rat models, by down-regulating the TNF-α and COX-2 gene expression. Additionally, it inhibits protein kinase, C-Jun/AP-1 activation, prostaglandin biosynthesis, and expression of COX-2, thereby reducing in inflamation effectively.¹⁹

Aconite

Aconitum heterophyllum Wall., known as Aconite or Ativisha, is an esteemed medicinal plant in Ayurveda, belonging to the Ranunculaceae family. Valued for its antipyretic, anti-inflammatory and digestive properties, its therapeutic effects are concentrated in the roots. Native to the Himalayan region of India, it is often cultivated due to its rarity and high medicinal demand. The primary bioactive compounds are diterpenoid alkaloids, particularly heterophylline (approximately 0.2%), atisine, and aconitine, along with their derivatives. Compared to other Aconitum species, A. heterophyllum has a lower concentration of toxic alkaloids, including aconitine, making it safer for therapeutic use. Its anti-inflammatory effects are well-documented, demonstrating around 60% inhibition of inflammatory markers through cyclooxygenase and lipoxygenase pathway inhibition, alongside reductions in TNF-α, IL-1β, IL-6, NF-κB and iNOS expression. This broad therapeutic profile positions A. heterophyllum as a valuable agent in managing inflammation and related health conditions.²⁰

Coffee bean

Coffee arabica Linn., commonly known as coffee bean, is derived from the dried ripe seeds of C. arabica, belonging to the family Rubiaceae. This evergreen shrub thrives in tropical climates, with significant cultivation in countries like Ethiopia, India, Guatemala, Colombia, and Brazil. Fully grown coffee plants can reach to a height of 15 feet and width of 8 feet. The seeds contain purine alkaloids which are secondary metabolites and derivatives of xanthene. The notable examples include caffeine (2-3%), theobromine, theophylline, and trigonelline. Caffeine exhibits anti-inflammatory effects through several mechanisms, including blocking the actions of molecules involved in inflammation. Caffeine prevents the activation of inflammatory pathways that trigger the release of cytokines such as IL-1β, IL-6, and TNF-α. Additionally caffeine may influence the epigenetic regulation of genes associated with inflammation, altering the status of DNA and affecting the expression of genes related to inflammatory cytokines.²¹

Tea

Camellia sinensis is a species of evergreen shrub belonging to the family Theaceae. Its leaves, leaf buds and stems can be used to produce tea. Caffeine is the most studied stimulant compound found in tea, basically a purine alkaloid present in tea to an extent of nearly 4%. Apart from caffeine, tea decoction is very rich in flavonoids and tannins. Alcoholic extract of fresh tea leaves showed the inhibition of inflammatory mediators namely leukotrienes. This natural product possesses the ability to inhibit 5-lipoxygenase in addition to free radical scavenging activity. The principle catechins, a category of condensed tannins present in the tea leaves include epigallocatechin gallate, gallocatechin, epicatechin, and catechin. The combined anti-oxidant and anti-inflammatory properties of catechins is highly beneficial during chronic inflammatory diseases like atherosclerosis, colitis, pancreatitis, ulceration, and prevention of pre-cancerous lesions.²²

Indigo

Indigofera tinctoria, commonly called true indigo, is a deciduous spreading tropical shrub of the family Fabaceae. Indigo is a blue dye with historical significance and is also extensively used in traditional Chinese medicine. Its phytoconstituents include alkaloids, phenols, tannins, saponins, and flavonoids. It contains indole alkaloids, which have been reported to exhibit significant anti-oxidant and anti-inflammatory effects, making it a promising compound for the treatment of chronic inflammatory diseases. A significant decrease in the inflammatory process was identified by a reduction of TNF-α, NF-kB levels, on inflammatory area of dystrophic muscle cells. Indirubin, hydroxyl-indirubin, isatine, isoindigo, tryptanthrine are the major indole alkaloids present in the leaves of I. tinctoria. The leaves are formulated into an ointment for treating skin diseases, wounds, sores, ulcers, and haemorrhoids. These results suggest the potential of indigo as a therapeutic agent for inflammatory conditions.²³

Cinchona

Cinchona, commonly known as Jesuit bark, is obtained from the dried bark of Cinchona calisaya Wedd., a member of Rubiaceae family and is native to South America. Cinchona was introduced to India in 1859 and is primarily cultivated in the Nilgiri, Anamalai hills of Tamil Nadu and Darjeeling regions of West Bengal, at altitudes ranging 1500-2000 meters. The plant can grow to a height of 5 to 15 meters. The bark contains a significant amount of alkaloids (at least 6%), with the major ones being quinine, quinidine, cinchonine, and cinchonidine. Cinchona's anti-inflammatory effects are attributed to its ability to inhibit NF-kappa B factors, COX-2 pathways, and TNF-α. Additionally, Cinchona extract inhibits iNOS mRNA expression and reduces inflammatory cytokines such as IL-8, IL-1β, and IL-6.²⁴

Kantakari

Solanum xanthocarpum Schrad. & Wendl., (Family: Solanaceae), also known as yellow-berried nightshade or Kantakari, is a widely used herb in Ayurvedic medicine, recognized for its anti-inflammatory, anti-asthmatic, diuretic, and liver-protective properties. It is distributed throughout the plains and low hills across all districts of India. The primary bioactive constituents are steroidal alkaloids, with solasodine as a major component (approximately 0.2%), along with solasonine and solamargine. S. xanthocarpum exerts strong anti-inflammatory effects by inhibiting NF-κB, cyclooxygenase and lipoxygenase pathways, achieving up to 65% inhibition of inflammatory mediators. This comprehensive activity profile makes S. xanthocarpum a valuable therapeutic agent, bridging its traditional applications with modern pharmacological potential in managing inflammation and related health conditions.²⁵

Ashwagandha

Withaniasomnifera Linn., (Family: Solanaceae), also known as Ashwagandha, Indian ginseng, or winter cherry, is a renowned herb in Ayurvedic medicine, valued as an adaptogen, aphrodisiac, liver tonic, and anti-inflammatory agent. Its medicinal benefits are primarily attributed to its dried roots, which contain bioactive compounds like withanolide C and alkaloids, including cuscobygrine, anahygrine, tropine, and pseudotropine. The total alkaloid concentration in W. somnifera roots typically ranges from 0.13% to 0.31%, contributing significantly to its therapeutic effects. Found across India, W. somnifera demonstrates strong anti-inflammatory action by inhibiting NF-κB, COX2 and LOX enzymes, reducing pro-inflammatory cytokines and oxidative stress. This extensive approach to inflammation positions W. somnifera as a valuable therapeutic agent, bridging traditional and modern medicinal applications in the management of chronic inflammation and improving health resilience.²⁶

Noni

Morinda citrifolia Linn., (Noni) is a fruit-bearing tree from the Rubiaceae family native to Southeast Asia, Australasia and widely spread across the Pacific by Polynesian sailors. Noni is now cultivated in tropical regions and adapts to various environments. The fruit contains several alkaloids such as xeronine, proxeronine, which exhibit anti-inflammatory effects by inhibiting the production of nitric oxide (NO), prostaglandin E2 (PGE-2) and TNF-α in lipopolysaccharide (LPS)-stimulated macrophages. Asperuloside further suppresses iNOS and COX-2 expression, key enzymes involved in inflammatory pathways. Its medicinal applications include the management of chronic inflammation and the enhancement of health resilience.²⁷

Pomegranate

Punica granatum Linn., is a fruit-bearing deciduous shrub belonging to the family Lythraceae., native to regions between modern-day Iran and Northern India. It is cultivated in the Middle East, India, Mediterranean, and parts of the U.S. like California and Arizona. The fruit contains major alkaloids such as pelletierine, pseudopelletierine, and N-methylpelletierine, along with minor alkaloids like isopelletierine and punigratane. Pomegranate peel extract exhibits anti-inflammatory properties by down-regulating inflammatory genes like COX-2, IL-6, and IL-1β, and by inhibiting PGE₂ production, iNOS expression, and nitric oxide (NO) levels. The fruit peel has medicinal applications in the management of chronic inflammation and the enhancement of health resilience.²⁸

Glory Lily

Glory lily consists of the dried seeds and tubers of Gloriosa superba Linn., a member of the family Liliaceae. This herbaceous perennial grows from a fleshy tuber. It is rich in phytochemicals like alkaloids, glycosides, flavonoids, and saponins. Colchicine, the major alkaloid present in the plant, is an effective drug for the treatment of intense pain associated with gout. The anti-inflammatory effect of colchicine is induced by inhibition of the synthesis of TNF-α by macrophages and down regulation of surface expression of TNF-α receptor on macrophages and endothelial cells. Colchicine was also suggested as an antidote against COVID-19, and is the first anti-inflammatory drug approved to treat cardiovascular disease. Gloriosine, superbine, are the other active alkaloids present in the plant. The treatment of ethanolic extract of G. Superba in tumour induced mice showed significant changes in hematological and histopathology parameters indicating its potent anti-tumour activity.²⁹ 

Alstonia

Alstonia, commonly known as the Devil’s tree (Alstonia scholaris), belongs to the family Apocynaceae. The plant is renowned for its medicinal properties, which are attributed to bioactive compounds such as alkaloids, tannins, and flavonoids. The major alkaloid, echitamine, exhibits antipyretic, anti-malarial and anti-inflammatory activities, while the plant also demonstrates potent antimicrobial, antioxidant, and analgesic effects. The anti-inflammatory activity of Alstonia is significant as it inhibits the release of pro-inflammatory mediators like TNF-α, IL-6, and prostaglandins, reduces oxidative stress and stabilizes lysosomal membranes, thereby mitigating swelling, pain, and tissue damage in inflammatory conditions. Traditionally, the bark decoction is used to treat fever, respiratory disorders like asthma and bronchitis and infections. Recent studies highlight its anti-cancer potential through apoptosis induction and modulation of hematological parameters. Additionally, Alstonia has cardioprotective and wound-healing benefits, owing to its antioxidant and anti-inflammatory properties. However, caution is advised in its application due to potential toxicity at higher doses, emphasizing the need for further research to explore its full medicinal potential.³⁰

Autumn Crocus

Autumn crocus known as meadow saffron, belonging to the family Colchicaceae. Colchicine is a historical compound extracted from the flowers and seeds of Colchicum autumnale, primarily found in Europe and Northern Africa. The plant contains 0.2-0.8% of colchicine as a primary alkaloid responsible for its anti-inflammatory and antifibrotic properties. Minor alkaloids such as demecolcine and colchicoside are also present in trace amounts. Colchicine is widely used in the treatment of gouty arthritis, familial Mediterranean fever and various cutaneous diseases (e.g., actinic keratoses, psoriasis). It works by inhibiting microtubule polymerization, reducing neutrophil migration, and suppressing the production of pro-inflammatory cytokines like IL-1β and TNF-α. In addition to its anti-inflammatory effects, colchicine exhibits antiproliferative and anticancer properties. Recent studies also highlight its ability to induce apoptosis in cancer cells, showcasing its potential as a promising anticancer agent.^31,32

Conclusion

Throughout the history, traditional medicinal plants have been pivotal in healthcare and continue to serve as a critical foundation for drug discovery. Inflammation as a part of etiology of several diseases affecting all age groups, especially the aging population, has become a major global health concern. Chronic inflammation plays an important role in many diseases, such as autoimmune disorders, cancer. Alkaloid-containing herbal medicines offer a promising approach in managing inflammation with fewer side effects compared to existing synthetic drugs. Their dose-dependent efficacy, selective action, and ability to work synergistically with other plant compounds make them a reliable alternative from traditional source.

Alkaloids though potent are generally safer when used at appropriate dosages. Many such herbs also possess additional benefits like antioxidant properties, which can further support the healing process and reduce oxidative stress in inflamed tissues. Plants such as berberis, fenu-greek, areca nut, pepper, vinca, and other bioactive alkaloids show promising results in reducing inflammation.

This review emphasizes the importance of medicinal plants, particularly those containing alkaloids, for their anti-inflammatory properties. Advances in isolation and purification techniques have opened new avenues for the discovery of novel and effective plant-derived therapies. As researchers continue to explore the mechanisms of action and therapeutic potential of alkaloids, their role in modern medicine could pave the way for safer and most effective treatments.

Conflict of Interest

Nil