Therapeutic Potential of Vitex Negundo L. in Managing Inflammatory Induced Disorders

Abstract

Vitex negundo L. (Family: Verbenaceae), commonly known as Nirgundi, is a resilient medicinal herb traditionally valued for its wide-ranging therapeutic applications. Every part of the plant including its leaves, bark, roots, seeds, fruits, and flowers has been utilized in indigenous systems of medicine for treating numerous health conditions.Phytochemical research has revealed the presence of various active constituents such as volatile oils, flavonoids, triterpenes, diterpenes, sesquiterpenes, lignans, glycosides, iridoid glycosides, and stilbene derivatives, which contribute to the plant’s pharmacological versatility.In recent times, there has been a renewed interest in herbal treatments for neurological and mental health disorders. With a significant portion of India’s population affected by mental illnesses and limited access to effective treatments, Vitex negundo offers promising potential as an alternative remedy. Ancient Ayurvedic literature supports its efficacy in this domain.The Charaka Samhita describes it as useful in eliminating parasites (Krimighna), neutralizing toxins (Vishaghna), and managing Vata disorders often linked with nervous system imbalances.In Sushruta Samhita it is placed in the Surasadi Gana, it pacifying Kapha (Shleshma Shamana), while the Ashtanga Hridaya related these properties. Additionally, the Bhavaprakasha Nighantu refers to it as Smritida, indicating its role in enhancing memory.This review compiles both classical and modern findings to present V.negundo as a potent herbal drug for neurological and cognitive disorders. The convergence of traditional knowledge and modern research underscores its potential for future development as a plant-based therapeutic agent for brain and nerve-related conditions.

Keywords

V. negundo , anti-inflammatory, Nirgundi, nirgundoside, vitexin

Introduction

Nirgundoside

Nirgundoside is a secondary metabolite isolated from the leaves of Vitex negundo Linn. Traditionally used in folk medicine, this compound is recognized for its anti-inflammatory and anticonvulsant properties. Chemically, nirgundoside is classified as an iridoid O-glycoside and is also referred to as 2′-p-hydroxybenzoylmussaenosidic acid.^[47]

Agnuside

Iridoids is a cyclopentane ring structure. These are secondary metabolites derived from monoterpenes and are known for their wide range of therapeutic effects. In various species of the Vitex genus, several iridoids-including agnuside, negundoside, nishindaside, and aucubin—have been identified, often working synergistically with other phytochemicals. These iridoids are considered key contributors to the plant’s medicinal properties. Among them, agnuside holds particular importance due to its pharmacological relevance. It also serves as a reliable chemotaxonomic marker, making it useful in the standardization and quality control of Vitex plant extracts to ensure consistency and efficacy. ^[48]

Luteolin (3', 4', 5, 7-tetrahydroxyflavone)

Luteolin is a naturally occurring flavonoid present in the leaves of the Vitex negundo (Nirgundi) plant. Due to its beneficial health properties, luteolin is in high demand and is often included in nutraceutical formulations. It exhibits strong antioxidant and anti-inflammatory effects. Research indicates that luteolin plays a role in several therapeutic actions, including antimicrobial, anticancer, and antiulcer activities. Additionally, it is used in managing fever, treating wounds and diarrhea, and also functions as a natural insect repellent and pesticide.^[49]

Stigmasterol

Stigmasterol, also referred to as Stigmasterin or Wulzen anti-stiffness factor, is an unsaturated phytosterol commonly found in a variety of medicinal plants. It serves as a key raw material in the synthesis of numerous chemical compounds, both synthetic and semi-synthetic, which are widely used in the pharmaceutical industry.^[50] Scientific research has explored its wide-ranging health-promoting properties, including its effectiveness in reducing inflammation, combating oxidative stress, lowering cholesterol levels, managing diabetes, and protecting against cancer. Additionally, stigmasterol has shown potential in supporting joint health, exhibiting anti-osteoarthritic effects, and providing benefits to the central nervous system.^[51]

Vitexin

Vitexin is classified as flavonoid present in the leaf extract of V.negundo and can also be produced through synthesis. This compound has demonstrated potent anticancer activity in preclinical studies involving breast, prostate, liver, and cervical cancers. It can be reliably extracted and quantified from the leaves of V. negundo, showing minimal percentage relative standard deviations (% RSDs), which confirms its suitability as a standard marker compound for the plant’s leaf extract.^[52]

Vitexicarpin

The bioassay-guided fractionation of the chloroform-soluble extract obtained from the leaves of Vitex negundo led to the identification of a flavone compound known as vitexicarpin. This compound displayed significant cytotoxic activity against a range of human cancer cell lines. To further boost the cytotoxic potential of vitexicarpin, multiple acylation processes were performed, producing several derivatives, including a methylated variant (3,5,6,7,3′,4′-hexamethoxyflavone), an acetylated form (5,3′-diacetoxy-3,6,7,4′-tetramethoxyflavone), along with six other acylated analogs.^[53]

Vitexicarpin, present in the leaves of Vitex negundo, is known for its wide array of medicinal applications. It possesses antibacterial, antitumor, astringent, and anti-acne properties. Additionally, it is used for alleviating eczema, reducing fever, promoting sedation, treating liver disorders, eliminating intestinal worms, repelling parasites and insects, and reducing inflammation. Furthermore, it is helpful in managing catarrhal fever, relieving cough, healing ulcers, treating skin conditions, and stimulating hair growth.^[54]

Pharmacological Significance:

Recognizing its historical use in folk and traditional medicine, researchers have designed and conducted scientific investigations aimed at validating these ethnomedicinal claims through pharmacological evaluation. Leaf decoctions of Vitex negundo Linn. have traditionally been employed in the management of various ailments such as inflammation, eye disorders, toothaches, leucoderma, splenic enlargement, ulcers, cancerous conditions, catarrhal fevers, rheumatoid arthritis, gonorrhea, sinus infections, scrofulous sores, bronchitis, and also as general tonics. Additionally, the plant exhibits diverse therapeutic properties including antibacterial, antipyretic, antihistaminic, ovicidal, growth inhibitory, and morphogenetic activities. Scientific studies have further confirmed its antigenotoxic, antihistamine, central nervous system depressant, and antifertility effects, particularly associated with its leaves.^[55,56]

Pharmacological Activity on the Nervous System

Anti-Amnesic Activity

The memory-enhancing potential of Vitex negundo Linn extract has been demonstrated in experimental models of scopolamine-induced amnesia in rats. The extract was evaluated for its effect on different phases of memory, such as acquisition, consolidation, and retention. It was observed that the extract significantly reduced memory impairment, likely due to its antioxidant properties, which contributed to improved memory function when compared to a standard anti-amnesic agent.^[57]

Further studies using a hydroalcoholic extract of leaves of Vitex negundo showed enhancement of learning and memory in mice. These effects were evident in both normal animals and those with scopolamine-induced cognitive deficits, as assessed through behavioral tests like the elevated plus maze and object recognition test. The cognitive benefits observed were suggested to be due to the extract’s antioxidant action, possible inhibition of acetylcholinesterase, and enhanced cholinergic neurotransmission.^[58]

In cellular studies, vitegnoside, an active constituent of Vitex negundo, provided neuroprotection in a human neuroblastoma cell model mimicking Alzheimer’s disease. The compound improved cell viability, maintained membrane integrity, and preserved nuclear structure under amyloid beta-induced toxicity conditions. These effects were linked to its ability to reduce neuronal damage, inhibit mitochondrial-mediated cell death, and suppress inflammation, likely through modulation of specific signaling pathways involved in neurodegeneration.^[59]

Anxiolytic Activity

The calming (anxiolytic) properties of the ethanolic root extract of Vitex negundo Linn were investigated through behavioral studies involving the elevated plus maze (EPM) and the light-dark box test. In this study, male mice were orally administered either Vitex negundo root extract or diazepam (used as a standard reference drug) one hour prior to testing. After dosing of Vitex negundo extractin animal demonstrated a noticeable increase in both the amount of time spent in the open arms and the number of entries into them on the EPM. Additionally, mice treated with either diazepam or Vitex negundo extract spent significantly more time in the light compartment of the light-dark box, indicating a reduction in anxiety-like behavior. These findings suggest that the root extract of Vitex negundo exhibits substantial anxiolytic efficacy.^[60]

Anticonvulsant Activity

The essential oils extracted from the fruits, leaves, and flowers of Vitex negundo Linn have been evaluated for their potential to prevent seizures. These oils were tested in experimental models that induce seizures in animals, using established methods to assess their effects. In one model, seizures were triggered electrically (maximal electroshock seizures or MES), and in another, chemically induced seizures were produced using pentylenetetrazole (PTZ).(61) Compared to standard anticonvulsant medications such as phenytoin and diazepam, the oil from Vitex negundo fruits significantly reduced the duration of seizures and protected against PTZ-induced clonic convulsions. The oil derived from the leaves showed strong protective effects only in the PTZ model, suggesting selective anticonvulsant activity. Additionally, when given in lower doses (100 mg/kg orally), all tested oils enhanced the effectiveness of both standard drugs. These findings imply that essential oils from Vitex negundo may be beneficial as supplementary treatments to reduce seizure frequency and might help lower the dosage requirements of conventional anti-seizure drugs.^[61]

Moreover, further studies were conducted to explore the effects of Vitex negundo extract on nerve cell activity. A methanolic extract of the plant was applied to cultured mouse nerve cells under controlled conditions. When exposed to the extract, the cells exhibited reduced sodium ion flow across their membranes, as measured by specialized electrophysiological techniques. The extract inhibited sodium currents in a manner that depended on the dose, and it altered the electrical properties of the cells by shifting the sodium channel activity toward a less excitable state. Importantly, the extract did not affect potassium currents, indicating selectivity in its action. Additionally, the extract significantly decreased the frequency of repetitive electrical firing in brain cells derived from young mice. These findings suggest that the plant extract may help reduce nerve excitability, contributing to its potential to manage seizures and possibly reduce nerve-related pain.^[62]

Anti-Nociceptive Activity

The pain-relieving potential of Vitex negundo Linn leaf extract was evaluated using animal models designed to assess both central and peripheral analgesic effects. In one experiment, an ethanolic extract from the leaves was tested using the tail flick method in rats to measure central pain relief, while the acetic acid-induced writhing test in mice assessed peripheral analgesia. Meperidine served as the reference drug in the tail flick test, and aspirin was used as a standard in the writhing test. Comparisons with these standards showed that the Vitex negundo leaf extract exhibited significant anti-nociceptive effects in both models. Additionally, the involvement of central pain pathways was confirmed by observing the interaction of the extract with naloxone hydrochloride, an opioid receptor antagonist, suggesting that the extract has both central and peripheral modes of action in reducing pain.^[63]

Further investigations explored the pain-relieving effects of a fat-soluble (lipophilic) fraction extracted from the seeds of Vitex negundo. Specifically, the petroleum ether fraction (PEF) obtained from an aqueous ethanol seed extract was tested in mice across various pain models. At doses of 12, 24, and 48 mg/kg, PEF produced a clear and dose-dependent reduction in pain responses. Significant analgesic effects were observed in chemical-induced pain models such as acetic acid writhing and the formalin test, as well as in models involving thermal stimuli. These findings highlighted the strong anti-nociceptive properties of the petroleum ether seed extract, demonstrating its effectiveness against different types of pain, including those caused by chemical irritation and heat.^[64]

CNS Depressant Activity

A methanolic extract derived from the leaves of Vitex negundo has been shown to enhance the sedative effects in mice. Specifically, the extract significantly prolonged the duration of sleep induced by drugs such as pentobarbitone sodium, diazepam, and chlorpromazine, in dose dependent manner indicating its central nervous system depressant properties.^[65]

Analgesic Activity

An aqueous extract prepared from fresh leaves of Vitex negundo was tested for its analgesic properties in female Wistar rats using standard methods such as the hot plate test, tail flick test, and formalin-induced pain model. Aspirin (100 mg/kg) was employed as the reference drug in both the hot plate and tail flick tests.^[66]

In a separate study, the analgesic properties of an ethanolic extract from Vitex negundo flowers were investigated to determine its effects on both peripheral and central pain mechanisms. Peripheral analgesia was measured using the acetic acid-induced writhing test, while central analgesia was evaluated with the tail flick test, using aspirin as the standard control in both. The findings revealed that the flower extract produced significant pain relief comparable to aspirin in the writhing test and exhibited even stronger analgesic effects than aspirin in the tail flick test, suggesting potent central analgesic activity.^[67]

Neuroprotective Activity

An aqueous leaf extract of Vitex negundo has shown promising potential in enhancing cognitive function in Wistar albino rats. When administered orally at a dose of 1000 mg/kg body weight over a period of 15 days, the extract improved learning and memory, as measured by the classical T-maze behavioral test. Biochemical analysis revealed that the extract helped reduce lipid peroxidation, increased the activity of natural antioxidant enzymes, and lowered acetylcholinesterase levels in the brain, suggesting a protective effect against oxidative damage and cognitive decline.^[68]

In another study, the influence of Vitex negundo on the growth of neuronal extensions (neurites) was examined in hippocampal neurons isolated from newborn mice. In various concentrations of Vitex negundo extract (ranging from 20 to 200 µg/ml) neurons were cultured for 48 hours in a controlled environment. Neurite formation was identified using a specific antibody marker (βIII-tubulin), and detailed measurements were performed using specialized imaging software. The results indicated that lower concentrations of the extract (30 and 40 µg/ml) significantly promoted the elongation of the longest neurites, whereas higher concentrations (150 and 200 µg/ml) reduced the length of the longest neurites. However, the total neurite length across all concentrations remained unchanged. Overall, these findings suggest that the methanolic extract of Vitex negundo may support neuronal growth at specific doses and holds promise as a neuroprotective agent for future therapeutic applications.^[69]

Antioxidant Activity

The protective properties of Vitex negundo leaves against oxidative stress in the brain were evaluated in a rat model exposed to ethanol-induced neurotoxicity. Various fractions of a hydromethanolic extract from the leaves were tested for their ability to counteract oxidative damage in brain tissue. Rats were given 20% ethanol (5 ml per 100 g body weight) daily for 28 days to induce oxidative stress in the brain. Examination of brain tissue from ethanol-treated rats revealed significant signs of damage, including gliosis (a response to injury in the brain). However, rats treated with Vitex negundo extract fractions showed notable protection against this damage. Histological analysis confirmed that the extract helped preserve brain tissue structure and reduced the harmful effects of ethanol exposure. These findings suggest that Vitex negundo leaves offer neuroprotective benefits, likely due to their strong antioxidant properties.^[70]

Biological Activity of Vitex negundo

Many plants produce chemical compounds that serve as defense mechanisms, protecting them from pathogens and predators. Research on the antimicrobial properties of Vitex negundo extracts indicates that this plant functions effectively as a biocontrol agent. Various studies have demonstrated that these extracts possess the ability to inhibit, suppress, and even eliminate numerous harmful biological agents responsible for diseases and damage. The biological effects exhibited by Vitex negundo include.^[71]

Anti -fungal activity

The crude ethanol extract derived from the fruits (seeds) of Vitex negundo Linn demonstrated strong antifungal activity, inhibiting Fusarium solani by 90%, which is comparable to the standard reference drug. Moderate effectiveness was observed against Microsporum canis with a 60% inhibition rate. However, the extract showed negligible antifungal effects on Candida glabrata and Aspergillus flavus strains. To date, there are no prior studies reporting the antifungal properties of Vitex negundo Linn fruits. Understanding the extent and mechanisms by which specific compounds in the plant extracts inhibit pathogens could be valuable for developing natural treatments against fungal and bacterial infections. ^[72]

Anti-bacterial activity

The crude ethanol extract derived from the fruits (seeds) of Vitex negundo Linn demonstrated strong antifungal activity, inhibiting Fusarium solani by 90%, which is comparable to the standard reference drug. Moderate effectiveness was observed against Microsporum canis with a 60% inhibition rate. However, the extract showed negligible antifungal effects on Candida glabrata and Aspergillus flavus strains. To date, there are no prior studies reporting the antifungal properties of Vitex negundo Linn fruits. Understanding the extent and mechanisms by which specific compounds in the plant extracts inhibit pathogens could be valuable for developing natural treatments against fungal and bacterial infections.^[73]

Part used :

Various parts of the Nirgundi plant, including the roots, leaves, flowers, fruits, and bark, are traditionally used for their medicinal value. Each part contributes distinct therapeutic properties, making the plant highly significant in herbal medicine. These components are often employed in the preparation of remedies for a wide range of health conditions due to their diverse biological activities.^[74]

Formulation:^[75]

• Mahavishagarbha taila
• Mahalakshminarayana taila
• Rasnaputeek taila
• Nirgundiyadi upnaha
• Swachchhand bhairav rasa
• Vata vidhwansana rasa

Toxicology study:

Vitex negundo is a widely utilized medicinal plant in the pharmaceutical industry, especially in the development of commercial formulations.Its acute and sub-chronic toxicity profiles have been evaluated following the Organization for Economic Cooperation and Development (OECD) guidelines 402 and 411.^[76] In acute dermal toxicity studies, VN oil was applied at a dose of 2000 mg/kg body weight to both male and female Wistar rats.^[77] For the sub-chronic assessment, rats received dermal applications of VN oil at doses of 250, 500, and 1000 mg/kg body weight, five times a week for a duration of 90 days.^[78]

Throughout the study period, no abnormalities were observed in the animals with respect to behavior, hematological or biochemical parameters, necropsy, or histopathology. According to the Globally Harmonized System (GHS), VN oil falls under Category 5, indicating an LD?? value exceeding 2000 mg/kg. However, individuals with hormone-sensitive conditions such as endometriosis, uterine fibroids, or hormone-related cancers are advised against using Vitex. It is also not recommended during pregnancy. Recent findings suggest that the bioactive chromone compounds found in Vitex possess notable anti-inflammatory and analgesic properties.^[79,80]

Recommended Dosage

Various parts of the plant, including the leaves, roots, bark, fruits, flowers, and seeds, are traditionally used for therapeutic purposes. These can be administered in several forms such as powder, decoction, juice, oil, tincture, paste (with sugar, water, or honey), or as a dry extract. For adults, the suggested dosages are: juice – 10 to 20 ml; decoction – 50 to 100 ml; leaf powder – 1.5 to 3 grams; and dry leaf extract – 300 to 600 mg.^[81]

CONCLUSION

Vitex negundo, widely known as Nirgundi, is a versatile medicinal herb recognized for its therapeutic applications in both traditional healing systems and modern medicine. Extensive experimental studies have confirmed its diverse pharmacological effects, including anticancer, antimicrobial, antifeedant, anti-inflammatory, antihyperpigmentation, hepatoprotective, antihistaminic, and analgesic activities.

Classical Ayurvedic scriptures such as the Charaka Samhita, Sushruta Samhita, and Bhavaprakasha Nighantu describe Nirgundi as a valuable remedy for a variety of health issues. These ancient texts particularly emphasize its effectiveness in addressing inflammation, pain, respiratory ailments, and skin disorders. Various parts of the plant—leaves, roots, bark, seeds, flowers, and fruits—are incorporated into numerous formulations, showcasing its broad-spectrum medicinal utility.

Although traditional and preclinical evidence strongly support the efficacy of V. negundo, there remains a critical need for well-designed clinical trials to validate these findings in human subjects. Its longstanding use in traditional medicine, combined with promising scientific data, makes this plant a strong candidate for development into standardized herbal pharmaceuticals. To fully integrate it into contemporary therapeutic frameworks, rigorous research focusing on its active constituents and clinical effectiveness is essential.

To summarize, Vitex negundo holds significant therapeutic value, as affirmed by classical Ayurvedic literature and modern research. Advancing its development as a scientifically validated herbal medicine will require continued pharmacological investigations and clinical studies to establish its safety, efficacy, and potential role in evidence-based healthcare.

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