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Deciphering the Mechanism of action of Trikatu through its Major Active Ingredients - A Comprehensive Review

Anusree P1, Suchanda Sahu2*, Kshirod Kumar Ratha3, Sujata Devi4, M.M.Rao5, Prasant Kumar Sahu6

¹Senior Research Fellow, Department of Biochemistry, AIIMS, Bhubaneswar
²Additional Professor, Department of Biochemistry, AIIMS Bhubaneshwar
³Research Officer, CCRAS-Central Ayurveda Research Institute, Bhubaneshwar
⁴Additional Professor, General Medicine Department, AIIMS, Bhubaneshwar
⁵Director, CCRAS-Central Ayurveda Research Institute, Bhubaneshwar
⁶Senior Medical Officer, AYUSH department, AIIMS Bhubaneshwar

*Corresponding author

Suchanda Sahu, Additional Professor, Department of Biochemistry, AIIMS Bhubaneshwar.

Abstract

Trikatu, a traditional Ayurvedic polyherbal formulation consisting of Piper Longum (Indian long pepper), Piper nigrum (black pepper), and Zingiber officinale (ginger) in equal proportions, has been a cornerstone of Ayurvedic medicine for centuries, used in the treatment of various ailments. This review aims to provide a comprehensive analysis of the phytochemical and pharmaological action of Trikatu, based on an extensive examination of scientific literature and clinical studies.

The review investigates the therapeutic contributions of the active components of Trikatu, primarily focusing on piperine, the key bioactive compound in Piper species, and gingerol and shogaol, the main active ingredients in Zingiber officinale. These compounds are known for their synergistic effects, including enhanced bioavailability of co-administered substances, antioxidant, anti-inflammatory, and antidiabetic properties. Additionally, the bioactivity of piperine in modulating neurotransmitter function and its potential neuroprotective effects are explored. The review also delves into the roles of ginger constituents in mitigating nausea, reducing inflammation, and managing metabolic disorders like diabetes.

By synthesizing data from preclinical and clinical research, this article underscores the potential of Trikatu as a therapeutic agent that bridges traditional Ayurvedic practices with modern pharmacological insights. The collective properties of piperine, gingerol, and related compounds highlight Trikatu’s multifaceted medicinal value, suggesting its potential integration into contemporary healthcare practices.

Key words: Ayurvedic Polyherbal Formulation, Pharmacological Action, Phytochemical Action, Piperine, Gingerol

Introduction

Trikatu is an Ayurvedic polyherbal formulation composed of equal parts of three crude drugs: Piper longum (Indian long pepper), Piper nigrum (Black pepper), and Zingiber officinale (Ginger). It is a vital component in numerous prescriptions and formulations utilized to address a wide array of disorders in Ayurveda. The Handbook of Domestic Medicine and Common Ayurvedic Remedies lists a total of 370 formulations, with 210 containing Trikatu or its individual components.1 According to Ayurvedic principles, Trikatu finds application in various disease conditions such as tastelessness, digestive impairment, products of impaired digestion and metabolism, throat diseases, chronic rhinitis/sinusitis, skin diseases, dyspnoea/asthma, cough, skin diseases, abdominal lump, excessive flow of urine, obesity, and filariasis.2 The synergy among the three constituents in Trikatu results in a unique combination of bioactive chemicals, each contributing to its distinct effects.

This article aims to present a comprehensive review of the phytochemical and pharmacological action of ingredients of trikatu. Through an examination of scientific studies, our objective is to explore the pharmacological and phytochemical characteristics of Trikatu, with a specific focus on their potential applications in modern healthcare. This investigation seeks to bridge the traditional Ayurvedic knowledge with contemporary medical practices.

Trikatu: Ayurvedic Significance and Its Multifaceted Actions

In Ayurveda, Trikatu is a revered formulation composed of three potent herbs: Piper longum (long pepper), Piper nigrum (black pepper), and Zingiber officinale (ginger). This powerful combination is traditionally used to stimulate Agni (digestive fire), enhance digestion, and improve metabolism. Doshas, in Ayurveda are fundamental bio-energetic forces that govern all physiological and psychological functions in the body. They represent combinations of the five elements (Panchamahabhutas) —earth, water, fire, air, and ether (space) and define an individual's mind-body constitution, known as Prakriti. Described in classical texts such as the Charaka Samhita and Ashtanga Hridaya, Trikatu is known for its ability to balance the doshas, particularly Kapha and Vata, by promoting the proper digestion and absorption of food. It helps eliminate Ama (toxins) from the body, acts as a potent bioenhancer to increase the bioavailability of other herbs, and supports respiratory health by clearing excess mucus. Additionally, Trikatu is valued for its thermogenic effects, aiding in weight management and improving circulation. It is commonly used to treat conditions such as indigestion, bloating, cough, sinus congestion, and obesity, making it a versatile remedy for digestive and respiratory health.

Major Active ingredients in Trikatu

Trikatu contains the three herbal ingredients   Piper longum, Piper nigrum, and Zingiber officinale. Of all the three ingredients, Piperine is isolated as the primary alkaloid from peppers and other constituents in minor quantities. Z. officinale contains chemical constituents such as Gingerols, Gingiberene, Shagols, and other chemical components.

Piper Longum (Pippali): Piper longum, commonly known as long pepper, contains several active compounds responsible for its medicinal properties. The key active ingredient responsible for its effects is Piperine which constitutes about 3–5% of its dry weight. It also contains other active ingredients like  piperlongumine, piperlonguminine, and Piperlonguminine dihydrochloride that contribute to the overall medicinal properties of Piper longum.3

 Piper nigrum(Maricha): Piper nigrum, commonly known as black pepper also contains primarily Piperine as the key active ingredient which is responsible for its pungency and health benefits.4

Zingiber officinale (Sunthi): Thorough chemical screening of Ginger reveals that it contains more than 450 compounds out of which major chemical constituents are Gingerols, Gingiberene, and Shagols.Out of these gingerols and shogaol are found in higher quantities, up to 20–25%.5

Table 1 :Major constituents of Trikatu and their functions

Action Pathway of Key Active Ingredients in Piper longum, Piper nigrum, and Zingiber officinale in Trikatu

In Trikatu, the active ingredients from each component work synergistically to produce the formulation’s therapeutic effects. Piperine, the principal active compound in Piper longum and Piper nigrum, plays an important role in enhancing the bioavailability and efficacy of the formulation. However, the overall therapeutic activity of Trikatu cannot be attributed to one constituent alone.

Piperine: Bioavailability Enhancer: Inhibits P-glycoprotein and CYP3A4.

Neurotransmitter Modulation: Increases serotonin and dopamine levels.

Antioxidant: Reduces oxidative stress via glutathione elevation.

Anti-inflammatory: Inhibits TNF-α, IL-1β, COX enzymes.

Antidiabetic: Enhances insulin sensitivity, modulates GLUT2, PPARγ.

Gingerols and Shogaols: Antioxidant: Scavenges ROS, comparable to ascorbic acid.

Anti-inflammatory: Downregulates cytokines and COX-2 expression.

Antidiabetic: Lowers fasting blood glucose; regulates oxidative stress.

Antiemetic: Inhibits 5-HT3 receptors, reducing nausea.

Bioenhancer: Facilitates absorption of co-administered drugs.

Phytochemical And Pharmacological Profile Of Piperine And Ginger

Enhanced Bioavailability: Piperine is renowned for its capacity to enhance the bioavailability of concurrently administered drugs and nutrients. It accomplishes this by inhibiting enzymes such as P-glycoprotein and CYP3A4 in humans, which are responsible for metabolizing and transporting various metabolites.6 Piperine functions by interacting with proteins located in the membrane of intestinal cells, thereby enhancing the activity of enzymes like leucine aminopeptidase and glycyl-glycine dipeptidase. This suggests that Piperine may influence the dynamics of the cell membrane associated with passive transport mechanisms. This influence stems from its non-polar nature, enabling interactions with surrounding lipids and the hydrophobic domain of cellular proteins. Piperine's ability to enhance the bioavailability of nutrients primarily arises from its thermogenic action. Additionally, the drug's capacity to increase bioavailability is also attributed to improved blood supply in enteric vessels due to local vasodilatation, which enhances drug transport.7

Neurotransmitter Modulation: Piperine has demonstrated the ability to modulate levels of certain neurotransmitters in the brain, including serotonin and dopamine. These neurotransmitters play crucial roles in mood regulation and may contribute to the potential antidepressant and anxiolytic effects of Piperine. Studies investigating the antidepressant effects of curcumin in combination with Piperine have shown significant enhancements in anti-immobility effects, neurotransmitter enhancement (serotonin and dopamine), and monoamine oxidase inhibitory effects when compared to the effects of curcumin alone.8 Another study similarly reported potentiation of the antidepressant activity of curcumin when administered alongside Piperine.9

Antioxidant Activity: Piperine demonstrates antioxidant properties, aiding in the neutralization of harmful free radicals and the reduction of oxidative stress within the body. This antioxidative action may contribute to its potential protective effects against various diseases and conditions associated with oxidative damage.10 A study investigating the impact of oral curcumin with Piperine on pain and markers of oxidative stress in patients with tropical pancreatitis over six weeks revealed a significant reduction in erythrocyte malonyl dialdehyde levels with combination therapy compared to placebo treatment, along with a notable increase in glutathione levels.11

Anti-inflammatory Effects: Piperine has been investigated for its anti-inflammatory properties, demonstrating promising effects in both rheumatoid arthritis and acute gouty arthritis.12,13 Studies indicate that Piperine can inhibit pro-inflammatory cytokines and enzymes, thereby aiding in the reduction of inflammation within the body. 14

Anti-Diabetic Effects: Piperine has been studied for its potential anti-diabetic effects. It helps manage diabetes in several ways. Piperine has been recognized for its ability to regulate body weight, thereby improving insulin and leptin sensitivity, and consequently, regulating obesity.15 In a study involving twenty piperine derivatives containing the benzothiazole moiety, nine piperine analogs exhibited higher anti-diabetic activity than the standard rosiglitazone.16 Piperine demonstrates anti-hyperglycemic activity in alloxan-induced diabetic mice, with a significant reduction in blood glucose levels observed after 14 days of oral intake at 20 mg/kg. However, the same study noted that high doses (40 mg/kg) acutely raised blood glucose levels.17 In another study on alloxan-induced diabetic rats, the combination of Piperine with a therapeutic dose of metformin (10 mg/kg + 250 mg/kg) resulted in a significantly greater reduction in blood glucose levels compared to metformin alone, both on the 14th and 28th day.18 Additionally, in streptozotocin-induced diabetic rats, the combination of Piperine and glimepiride improved all pharmacokinetic parameters and overall antioxidant status.19 Piperine also dose-dependently reduces ligand-induced liver X receptor α activity, acting as its antagonist. Dietary effects of Piperine in high-fat-diet (HFD) rats showed decreased plasma insulin and glucose concentrations and increased insulin sensitivity,20 down regulating genes involved in endoplasmic reticulum stress and upregulating GLUT2. Furthermore, Piperine inhibits adipocyte differentiation of 3T3-L1 cells by decreasing master adipogenic transcriptional factors PPARγ, SREBP-1c, and C/EBPβ, thereby inhibiting adipogenesis.21 It has been reported that Piperine inhibits uridine diphosphate-glucose dehydrogenase (UDP-GDH), UDP-glucuronosyltransferase (UDP-GT), and decreases UDP-glucuronic acid (UDPGA) in rat and guinea pig liver and intestine.22

While Trikatu's traditional uses are well-established, ongoing research could explore its potential in diabetes, cardiovascular health, and neuroprotection. Innovative formulations and combination therapies could harness Trikatu's synergistic effects for enhanced therapeutic outcomes.Piperine's multifaceted effects make it an exciting compound with potential therapeutic applications.

Action pathway of key active ingredients in Zingiber Officinale

Antioxidant activity: Gingerol, the major bioactive in Zingiber officinale, exerts a wide range of effects. A previous study indicated that ginger extract displays antioxidative properties and functions by scavenging superoxide anion and hydroxyl radicals.23,24 Gingerol was also found to act by inhibiting ascorbate/ferrous complex-induced lipid peroxidation in rat liver microsomes.25 Yet another study supporting Ginger's role as an antioxidant revealed that 6-shogaol possesses powerful antioxidant properties, likely due to its unsaturated ketone structure.26 Another study has demonstrated that phenolic compounds exhibit robust anti-inflammatory and antioxidative properties, along with significant anticarcinogenic and antimutagenic activities.27 These compounds were found to play a role in scavenging hydrogen peroxide (H2O2) by donating electrons to it, thereby neutralizing it into water.28 Research conduted on rats  has additionally indicated   that ginger extract has antioxidant effects comparable to those of ascorbic acid.29

Anti-inflammatory activity: The anti-inflammatory and analgesic properties of gingerol contribute to abilityof trikatu to relieve pain and inflammation. Ginger plays a crucial role in  suppressing and inhibiting the synthesis of pro-inflammatory cytokines like IL-1, TNF-α , and IL-8.30,31Another study uncovered that the increased expression of TNF-α in rats with liver cancer was inhibited upon treatment with ginger extract at a dosage of 100 mg/kg body weight.32 Ginger also significantly inhibits COX and 5-lipoxygenase, which are crucial enzymes in arachidonate metabolism33, and it down-regulates the induction of inflammatory genes.34,35

Anti-diabetic activity: Ginger and its constituents have played a crucial role in managing diabetes and its complications through their anti-hyperglycemic effects. Although the exact mechanism by which ginger controls diabetes is not fully understood, it may involve the inhibition of oxidative stress and the anti-inflammatory process. A significant discovery, based on a type 1 diabetic rat model treated with STZ, revealed that oral administration of ginger's ethanolic extract significantly reduces fasting blood glucose levels.36 Previous research has also demonstrated a notable decrease in blood glucose levels with the administration of ginger juice in both diabetic and non-diabetic animals.37 Additionally, another study observed significant hypoglycemic activity in rats following the administration of ginger extract.38

Antiemetic effect: Ginger and its components exhibit a significant impact on reducing nausea and vomiting. Although the precise mechanism of Ginger's action in addressing nausea and vomiting remains unclear, this effect is believed to be attributed to its constituents, such as gingerols, shogaols, galanolactone, and diterpenoids.39 Previous research has indicated that the antiemetic effect of ginger is largely dependent on the inhibition of 5-HT3R, primarily mediated by its pharmacologically active constituent gingerols.40 A study focused on understanding the role of ginger in alleviating nausea and vomiting has revealed its effectiveness in reducing the severity of these symptoms. Ginger and its constituents show a significant effect on nausea and vomiting.41

Bioavailability enhancement activity: Ginger also exhibits significant bioavailability enhancement activity by exerting a potent effect on the mucous membrane of the gastrointestinal tract. It plays a regulatory role in intestinal functions, thereby facilitating absorption. When administered at a dose of 10–30 mg/kg body weight, ginger acts as a bioenhancer. Pharmacological studies indicate that it markedly enhances the bioavailability of various medications, notably antibiotics such as amoxicillin, azithromycin, erythromycin, cephalexin, cefadroxil, and cloxacillin.42

Trikatu’s efficacy is not the sum of individual herbs but their synergism:

  • Multi-target Action: Each herb acts on different pathways.
  • Improved Pharmacokinetics: Enhanced drug absorption and activity.
  • Holistic Benefits: Addresses digestion, metabolism, inflammation, and neurological health concurrently.

Clinical Implications & Future Directions

  • Therapeutic Areas: Diabetes, neurodegeneration, cardiovascular risk, drug delivery enhancement.
  • Need for Clinical Trials: Well-designed studies can validate its integration in modern protocols.
  • Formulation Innovations: Combining Trikatu with modern nutraceuticals or pharmaceuticals.

Conclusion

Trikatu's efficacy lies in the intricate interplay of its active ingredients - Piperine, gingerol, and related compounds. Synergism serves as the fundamental and distinctive principle of traditional medicine. It plays a crucial role in enhancing efficacy or minimizing toxicity since traditional medicine prescriptions typically consist of various herbs in their formulations. The diverse components of a prescription exhibit a synergistic effect by acting on multiple targets simultaneously or enhancing pharmacokinetic processes, leading to a more favorable therapeutic outcome compared to using a single herb.43Understanding their actional mechanisms provides insights into Trikatu's diverse applications, spanning digestive health, metabolism, inflammation, and beyond. As modern research continues to unveil its potential, Trikatu stands as a promising bridge between traditional wisdom and contemporary healthcare practices.

While Trikatu's traditional uses are well-established, ongoing research could explore its potential in diabetes, cardiovascular health, and neuroprotection. Innovative formulations and combination therapies could harness enhanced therapeutic outcomes.

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