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Pharmacological investigation of Hamelia patens leaves for central nervous system activity in rats
*Corresponding author: Liesl Maria Fernandes e Mendonça, Assistant Professor, Department of Pharmacology, Goa College of Pharmacy, Panaji, Goa, India. lieslpharma@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Azgaonkar SV, Fernandes e Mendonça LM, Katkar AR. Pharmacological investigation of Hamelia patens leaves for central nervous system activity in rats. Indian J Physiol Pharmacol. doi: 10.25259/IJPP_86_2026
Abstract
Objectives:
The present study was undertaken to investigate the antioxidant and anxiolytic potential of the ethanolic leaf extract of Hamelia patens (EEHP) and its acetone-enriched fraction (AEHP) using in vitro antioxidant assays, in vivo central nervous system (CNS) screening models in Wistar albino rats and in silico docking studies.
Materials and Methods:
Leaves of H. patens were subjected to extraction with ethanol by maceration to yield the EEHP, followed by fractionation using acetone to obtain the AEHP. Preliminary qualitative phytochemical screening was carried out to identify major phytoconstituents. In vitro antioxidant activity was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and nitric oxide free radical scavenging assays. Anxiolytic activity was assessed using the Elevated Plus Maze, Light and Dark Model, Mirror Chamber Apparatus and spontaneous locomotor activity using the Opto-Varimex Autotrack system. EEHP and AEHP were administered orally at doses of 100 mg/kg and 200 mg/kg for a duration of 7 days. Diazepam was used as the standard drug. Data were statistically analysed using one-way analysis of variance followed by Dunnett’s test. The phytoconstituents present in H. patens were docked against the GABAA-BZD receptor in silico.
Results:
Phytochemical screening revealed the presence of flavonoids, alkaloids, carbohydrates, proteins, glycosides, tannins and triterpenoids in both EEHP and AEHP. Both extracts demonstrated concentration-dependent free radical scavenging activity in DPPH and nitric oxide assays. In the Elevated Plus Maze, treatment with EEHP and AEHP resulted in a significant increase in percentage open arm entries and percentage time spent in open arms compared to the control. In the Light and Dark Model, the number of entries into the light compartment and time spent in the light compartment were significantly increased. The Mirror Chamber Apparatus showed a significant increase in the number of entries and time spent in the Mirror Chamber. Spontaneous locomotor activity assessment demonstrated a significant increase in resting time compared to the control. In silico molecular docking studies of the phytoconstituents of H. patens exhibited profound receptor binding interactions.
Conclusion:
The findings of the study indicate that H. patens leaf extracts possess significant antioxidant and anxiolytic activity, supporting their traditional use in CNS-related disorders. Furthermore, the phytoconstituents with GABAA-BZD receptor in silico demonstrated strong binding affinities, indicating a possible mechanism underlying their anxiolytic action. The observed effects may be attributed to the presence of bioactive flavonoids and phenolics.
Keywords
Antioxidant activity
Anxiolytic activity
Elevated plus maze
Hamelia patens
Wistar albino rats
INTRODUCTION
The central nervous system plays a critical role in regulating cognition, emotion and behaviour. Anxiety disorders represent one of the most prevalent neuropsychiatric conditions and are characterised by excessive fear, worry and behavioural disturbances. Conventional anxiolytic agents such as benzodiazepines are effective but are often associated with adverse effects, including sedation, tolerance and dependence. This has encouraged the exploration of safer alternatives derived from medicinal plants.[1]
Medicinal plants have been utilised since ancient times for the treatment of various ailments due to their rich content of bioactive phytoconstituents. A significant proportion of the global population continues to rely on plant-based medicines for primary healthcare. Several plant-derived compounds, particularly flavonoids and alkaloids, have demonstrated central nervous system (CNS)-modulating properties, including anxiolytic and antioxidant effects.[1-3]
Oxidative stress has been implicated in the pathogenesis of various neurological disorders. An imbalance between reactive oxygen species and endogenous antioxidant defences may contribute to neuronal damage and behavioural alterations. Antioxidants play a crucial role in mitigating oxidative stress and may indirectly influence CNS function.[4]
Hamelia patens, belonging to the family Rubiaceae, is traditionally used for the treatment of wounds, inflammation, nervous shock, headache and other ailments. Phytochemical investigations have revealed the presence of flavonoids, alkaloids, triterpenoids and phenolic compounds in the plant, which are known to possess antioxidant and neuropharmacological activities. Despite its traditional use, limited scientific data are available regarding its anxiolytic potential.[4-6]
The present study was designed to evaluate the antioxidant activity and anxiolytic effects of the ethanolic leaf extract of H. patens and its acetone fraction using established experimental models.
MATERIALS AND METHODS
Study design
An experimental, randomised, controlled animal study design was employed. In vivo animal models, viz, Elevated Plus Maze, Light and Dark model, Mirror Chamber apparatus and Opto-Varimex Autotrack system were used to evaluate anxiolytic activity. The dosing was done daily for 7 days.
The experimental samples were administered to the rats by oral route using oral feeding needles. The standard drug diazepam was administered to the rats by intraperitoneal injection. All experiments were conducted in accordance with CCSEA guidelines, and the study protocol was approved by the Institutional Animal Ethics Committee (IAEC), Goa College of Pharmacy.
Experimental animals
To evaluate the anxiolytic activity of the extract and the biofraction, 36 Wistar albino rats (200–250 g) of either sex were used. Animals were housed under standard laboratory conditions with a 12-h light/dark cycle and provided food and water ad libitum. Animals were acclimatised before experimentation.
Ethics statement
The experimental protocol was reviewed and approved by the IAEC, Goa College of Pharmacy (Approval No.: GCP/ IAEC/2022/01, dated 17-10-2022). The study was conducted in accordance with CCSEA guidelines and ethical principles for animal experimentation.
Plant material and extraction
Fresh leaves of H. patens were collected from Panaji, Goa and authenticated by a qualified taxonomist. Dried powdered leaves (750 g) were macerated with ethanol for 4–5 days. The extract was filtered and concentrated to obtain EEHP. AEHP was prepared by refluxing EEHP with acetone at 45–60°C.
Phytochemical screening
Qualitative phytochemical screening of EEHP and AEHP was performed using standard chemical tests to identify carbohydrates, proteins, flavonoids, alkaloids, glycosides, tannins, steroids and triterpenoids.[7]
Antioxidant activity
DPPH and nitric oxide radical scavenging assays were performed at various concentrations. Absorbance was measured using a ultraviolet (UV)-visible spectrophotometer.[8]
Anxiolytic activity
Animals were divided into groups receiving vehicle, diazepam, EEHP or AEHP. Behavioural assessments were performed using the Elevated Plus Maze,[9,10] Light and Dark Model,[11,12] Mirror Chamber Apparatus,[13] and Opto-Varimex Auto track system,[14-16] using established procedures for a period of 5 min per animal in each group per apparatus.
In silico docking studies
Preparation of the protein
Protein 3D structures were obtained from the Research Collaboratory for Structural Bioinformatics Protein Data Bank database, PDB ID: 6X3X. Files were downloaded in *.pdb format.[17] Proteins were prepared by adding hydrogen and removing water molecules. Moreover, X, Y, and Z coordinates were recorded from BIOVIA Discovery Studio.
Preparation of the ligand
3D structures of the phytoconstituents of H. patens identified in the LC-MS study were used as ligands. Structures were downloaded in *.sdf format. Ligand *.sdf files were converted to *.pdb using an online SMILES translator. Both ligand and protein *.pdb files were converted to *. pdbqt using AutoDockTools 1.5.7.
Docking and visualisation of protein-ligand interactions
Docking simulations were performed using AutoDockTools 1.5.7.[18] Docked ligand–protein complexes were visualised with PyMOL. Interactions were analysed using BIOVIA Discovery Studio 2024.
Statistical analysis
Data were expressed as mean ± standard error of the mean (SEM) and analysed using one-way analysis of variance followed by Dunnett’s test.[19] p < 0.05 were considered statistically significant. Statistical software used: GraphPad Prism version 7.3.
RESULTS
Phytochemical screening confirmed the presence of multiple bioactive constituents in EEHP and AEHP [Table 1]. EEHP and AEHP exhibited substantial antioxidant activity in DPPH (IC50 = 5.99 µg/mL and 6.5 µg/mL, respectively) as compared to standard ascorbic acid with IC50 = 1.13 µg/mL. In the nitric oxide scavenging assay, EEHP and AEHP demonstrated antioxidant activity with IC50 values of 11.81 µg/mL and 16.39 µg/mL, respectively, when compared to standard ascorbic acid that displayed IC50 of 15.9 µg/mL.
| Phytoconstituents | EEHP | AEHP |
|---|---|---|
| Flavonoids | + | + |
| Alkaloids | + | – |
| Tannins | + | + |
| Carbohydrates | + | + |
| Glycosides | + | + |
| Steroids and terpenoids | + | – |
| Anthraquinones | + | – |
| Saponins | + | – |
| Coumarins | + | – |
EEHP: Ethanolic leaf extract of Hamelia patens, AEHP: Acetone-enriched fraction of Hamelia patens. +: Present, -: Absent.
Elevated plus maze
The results of the present study illustrated that, on the 1st day of treatment with EEHP and AEHP, there was a significant increase in OAE on day 7 with AEHP 100 mg/kg and AEHP 200 mg/Kg with 49.103 ± 0.387 % (p < 0.001) and 48.347 ± 1.597 % (p < 0.001), respectively [Figures 1a and 1b]. AEHP 200 mg/kg showed a significant increase %TSOA on day 7 with 14.26 ± 2.24 % (p < 0.001) [Table 2].
| Treatment | Day 1 | Day 7 | ||
|---|---|---|---|---|
| OAE (%) | TSOA (%) | OAE (%) | TSOA (%) | |
| Group I (control) | 8.27±2.703 | 12.73±5.841 | 4.44±2.810 | 1.18±0.4092 |
| Group II (diazepam) | 27.02±1.769* | 22.69±2.793 | 24.073±1.917*** | 27.13±1.95*** |
| Group III (EEHP 100 mg/kg) | 16.1056±4.6272 | 4.3±2.393 | 7.6±2.637 | 1.72±0.6217 |
| Group IV (EEHP 200 mg/kg) | 17.2685±7.3739 | 4.46±2.633 | 14.351±4.614* | 10.713±3.04** |
| Group V (AEHP 100 mg/kg) | 19.118±3.680 | 14.437±6.998 | 49.103±0.387*** | 12.298±1.56** |
| Group VI (AEHP 200 mg/kg) | 24.480±4.504 | 11.655±1.857 | 48.347±1.597*** | 14.26±2.24*** |
Values are expressed as mean±SEM (n=6), ANOVA, *p<0.05, **p<0.01, ***p<0.001, followed by Dunette’s post hoc analysis. ANOVA: Analysis of variance, SEM: standard error of the mean, EEHP: Ethanolic leaf extract of Hamelia patens, AEHP: Acetone-enriched fraction of Hamelia patens, p < 0.05 were considered statistically significant. (% OAE: Percentage open arm entries, % TSOA: Percentage time spent in open arms).
Light and dark model
Light and dark model also exhibited significant activity on day 1 of dose AEHP 200 mg/kg, with 7.33 ± 1.94 number of light camber entries (p < 0.001) as seen in Figures 2a and 2b. A significant increase in time spent in light chamber was exhibited with the group treated with AEHP 200 mg/kg with 102.66 ± 24.9 s (p < 0.001) on day 1 [Table 3].
| Treatment | Day 1 | Day 7 | ||
|---|---|---|---|---|
| NEL (no.) | TSL (s) | NEL (no.) | TSL (s) | |
| Group I (control) | 1±0.632 | 5.667±3.583 | 1.667±0.557 | 15.333±5.181 |
| Group II (diazepam) | 1.667±0.211 | 18.667±1.173 | 4±0.365 | 44±7.624 |
| Group III (EEHP 100 mg/kg) | 2.3±0.3 | 29.83±7.27 | 3.6±1.20 | 59.16±21.597 |
| Group IV (EEHP 200 mg/kg) | 2.16±0.5426 | 32.5±8.42 | 2.83±0.477 | 77.666±30.087 |
| Group V (AEHP 100 mg/Kg) | 4.66±0.33* | 50.5±9.858 | 5.5±1.0567** | 88.83±14.339* |
| Group VI (AEHP 200 mg/kg) | 7.33±1.94*** | 102.66±24.9*** | 4.5±0.763 | 76.83±7.656 |
Values are expressed as mean±SEM (n=6), ANOVA, *p<0.05, **p<0.01, ***p<0.001, followed by Dunette’s post hoc analysis. ANOVA: Analysis of variance, SEM: standard error of the mean, EEHP: Ethanolic leaf extract of Hamelia patens, AEHP: Acetone-enriched fraction of Hamelia patens, NEL: Number of entries in light chamber, TSL: Time spent in light chamber. p < 0.05 were considered statistically significant.
Mirror chamber apparatus
In the Mirror chamber test, AEHP 100 mg/kg showed a significant increase in mirror chamber entries with 8.5 ± 1.204 no. [Figures 3a and 3b], (p < 0.01) on day 7. AEHP 200 mg/kg exhibited increased time spent in mirror chamber with 132.0 ± 25.152 s (p < 0.001) on day 1 [Table 4].
| Treatment | Day 1 | Day 7 | ||
|---|---|---|---|---|
| NEM (no.) | TSM (s) | NEM (no.) | TSM (s) | |
| Group I (control) | 1±0.365 | 12.333±6.285 | 2.00±0.632 | 5.333±2.1081 |
| Group II (diazepam) | 7±1.264** | 26.667±2.431 | 8.00±0.966** | 78±24.448 |
| Group III (EEHP 100 mg/kg) | 4±1.316561 | 53.5±12.427 | 4.6±1.1155 | 60.83±10.179 |
| Group IV (EEHP 200 mg/kg) | 6.83±1.424** | 89.3±18.391* | 6.5±1.80277 | 114.3±28.695** |
| Group V (AEHP 100 mg/kg) | 5±0.73029 | 61.16±21.536 | 8.5±1.2041** | 65.6±17.200 |
| Group VI (AEHP 200 mg/kg) | 7.5±1.0567*** | 132±25.152*** | 7.6±1.2823* | 131.6±27.93*** |
Values are expressed as mean±SEM (n=6), ANOVA, *p<0.05, **p<0.01, ***p<0.001, followed by Dunette’s post hoc analysis. ANOVA: Analysis of variance, SEM: standard error of the mean, EEHP: Ethanolic leaf extract of Hamelia patens, AEHP: Acetone-enriched fraction of Hamelia patens, NEM: Number of entries in mirror chamber, TSM: Time spent in mirror chamber. p < 0.05 were considered statistically significant.
Opto-Varimex autotrack system
As summarized Figure 4 in the Opto-Varimex Auto track System, the distance travelled [Figure 4a] was significantly reduced with EEHP 100 mg/kg and 200 mg/kg, on day 1 with 355.166 ± 116.508 cm (p < 0.01) and 471.0 ± 186.075 cm (p < 0.01) respectively [Table 5].
| Treatment | Distance travelled DT (cm) | |
|---|---|---|
| Day 1 | Day 7 | |
| Group I (control) | 1267.333±174.578 | 1276.333±147.758 |
| Group II (diazepam) | 923.667±146.253 | 933.0±142.513 |
| Group III (EEHP 100 mg/kg) | 355.166±116.508** | 671.0±129.930* |
| Group IV (EEHP 200 mg/kg) | 471.0±186.075** | 833.0±141.277 |
| Group V (AEHP 100 mg/kg) | 832.333±208.28 | 957.833±146.038 |
| Group VI (AEHP 200 mg/kg) | 550.0±121.457* | 1034.0±187.998 |
Values are expressed as mean±SEM (n=6), ANOVA, *p<0.05, **p<0.01, followed by Dunette’s post hoc analysis. ANOVA: Analysis of variance, SEM: standard error of the mean, EEHP: Ethanolic leaf extract of Hamelia patens, AEHP: Acetone-enriched fraction of Hamelia patens, p < 0.05 were considered statistically significant.
Similarly, the ambulatory time [Figure 4c] was significantly reduced (p < 0.01) with EEHP 100 mg/kg on day 1 with 58.33 ± 16.184 s. AEHP 200 mg/kg depicted a significant reduction in ambulatory time with 75.833 ± 16.152 s (p < 0.05) [Table 6].
| Treatment | Ambulatory time AT (sec) | |
|---|---|---|
| Day 1 | Day 7 | |
| Group I (control) | 155.66±15.19 | 161.66±5.59 |
| Group II (diazepam) | 111.00±19.03 | 80.00±24.70* |
| Group III (EEHP 100 mg/kg) | 58.333±16.284** | 89.333±15.928* |
| Group IV (EEHP 200 mg/kg) | 66.666±24.091* | 111.66±17.954 |
| Group V (AEHP 100 mg/kg) | 114.5±23.566 | 124.833±14.050 |
| Group VI (AEHP 200 mg/kg) | 75.833±16.152* | 140.33±28.401 |
Values are expressed as mean±SEM (n=6), ANOVA, *p<0.05, **p<0.01, followed by Dunette’s post hoc analysis. ANOVA: Analysis of variance, SEM: standard error of the mean, EEHP: Ethanolic leaf extract of Hamelia patens, AEHP: Acetone-enriched fraction of Hamelia patens, AT: Ambulatory time, p < 0.05 were considered statistically significant.
The resting time (RT) [Figure 4b] was significantly increased (p < 0.05) on day 1 with 174.16 ± 26.008 s post treatment with EEHP 100 mg/kg [Table 7]. Moreover, spontaneous locomotor activity of the groups treated with the extract revealed a significant increase in RT, indicating CNS depressant-like activity. There was no significant difference found in stereotypic time [Table 8] [Figure 4d].
| Treatment | Resting time RT (sec) | |
|---|---|---|
| Day 1 | Day 7 | |
| Group I (control) | 71.00±10.513 | 69.33±6.433 |
| Group II (diazepam) | 104.33±23.05 | 157.33±32.79* |
| Group III (EEHP 100 mg/kg) | 174.16±26.008* | 153.66±21.935* |
| Group IV (EEHP 200 mg/kg) | 168.83±37.230 | 102.16±15.885 |
| Group V (AEHP 100 mg/kg) | 118.33±29.442 | 91.666±13.756 |
| Group VI (AEHP 200 mg/kg) | 168.66±22.282 | 115±23.328 |
Values are expressed as mean±SEM (n=6), ANOVA, *p<0.05, followed by Dunette’s post hoc analysis. ANOVA: Analysis of variance, SEM: standard error of the mean, EEHP: Ethanolic leaf extract of Hamelia patens, AEHP: Acetone-enriched fraction of Hamelia patens, RT: Resting time. p < 0.05 were considered statistically significant.
| Treatment | Stereotypic time ST (sec) | |
|---|---|---|
| Day 1 | Day 7 | |
| Group I (control) | 73.333±7.60 | 69.000±1.59 |
| Group II (diazepam) | 84.66±8.83 | 62.66±8.08 |
| Group III (EEHP 100 mg/kg) | 68.0±12.463 | 57.833±8.072 |
| Group IV (EEHP 200 mg/kg) | 65.333±15.259 | 88.5±3.273 |
| Group V (AEHP 100 mg/kg) | 67.666±7.9944 | 79.333±1.801 |
| Group VI (AEHP 200 mg/kg) | 47.0±7.0 | 47.833±11.202 |
Values are expressed as mean±SEM (n=6), ANOVA, followed by Dunette’s post hoc analysis. ANOVA: Analysis of variance, SEM: standard error of the mean, EEHP: Ethanolic leaf extract of Hamelia patens, AEHP: Acetone-enriched fraction of Hamelia patens, ST: Stereotypic time, p < 0.05 were considered statistically significant.
In silico molecular docking
The in silico molecular docking results of selected compounds identified from H. patens by reported liquid chromatography-electrospray ionization-mass spectrometry analysis, namely epicatechin, kaempferol-3-O-rutinoside, scopoletin-7-O- glucoside (scopolin), apigenin-6,8-C-di-glucoside (vicenin II) and caffeic acid-O-glucoside, demonstrated profound binding interactions when docked with GABAA-BZD receptor in complex with diazepam (PDB ID: 6X3X) [Figure 5a-f].
DISCUSSION
The present investigation demonstrates that H. patens leaf extracts possess significant antioxidant and anxiolytic properties.[20] The behavioural outcomes observed across multiple validated anxiety models suggest a reduction in anxiety-like behaviour following treatment with EEHP and AEHP. The antioxidant activity observed may contribute to the neuroprotective effects of the extracts.[4,21,22]
The presence of flavonoids and alkaloids, known to interact with GABAergic neurotransmission, may underlie the observed anxiolytic effects.[23-25] The findings are consistent with the ethnomedicinal use of H. patens in nervous disorders.[26-28] Flavonoids and other phenolic compounds from medicinal plants are well-known bioactive agents with significant antioxidant and pharmacological properties, including anti-inflammatory,[29] neurodegenerative disorders, including Alzheimer’s disease.[30] Several medicinal plants rich in flavonoids and alkaloids have demonstrated anxiolytic properties in both preclinical and clinical settings.[31] Further studies are warranted to isolate active constituents and elucidate precise mechanisms of action.
Liquid chromatography–mass spectrometry (LC-MS) analysis of the extract suggested the presence of several phytoconstituents with six constituents in prominence.
The identified compounds included scopoletin-7-O- glucoside isomers (MW 355.1 g/mol), epicatechin (MW 290.26 g/mol), (E)Cat–(E)Cat (epicatechin dimer) corresponding to a proanthocyanidin (MW 578.5 g/mol), apigenin-6,8-C-di-glucoside (vicenin II) and its isomer (MW 594.5 g/mol), quercetin-deoxyhexosyl-hexoside (MW 610.5 g/mol), kaempferol-3-O-rutinoside (MW 594.5 g/mol) and caffeic acid-O-glucoside (MW 342.30 g/mol).[32,33] One compound with MW 396 g/mol remained unidentified. Most of the detected constituents belonged to the flavonoid, proanthocyanidin, coumarin and hydroxycinnamic acid classes.[34,35]
The in silico molecular docking of selected phytoconstituents including epicatechin, kaempferol-3-O-rutinoside, scopolin, vicenin II and caffeic acid-O-glucoside, revealed notable binding affinities at the diazepam binding site of the GABAA receptor (PDB ID: 6X3X). Scopolin demonstrated the highest binding affinity among the tested phytoconstituents at −8.5 kcal/mol, followed by kaempferol-3-O-rutinoside and epicatechin (both −8.3 kcal/mol) and caffeic acid-O- glucoside (−8.0 kcal/mol), all of which exhibited binding affinities comparable to the standard diazepam (−8.8 kcal/ mol). Vicenin II (apigenin-6,8-C-di-glucoside) exhibited a comparatively lower binding affinity of −4.5 kcal/mol with hydrogen bonding and hydrophobic interactions comparable to the standard diazepam. These findings provide a plausible mechanistic basis for the observed anxiolytic activity, likely mediated through GABAergic modulation.
CONCLUSION
The study successfully demonstrated that the ethanolic extract and acetone fraction of H. patens leaves exhibited significant antioxidant and anxiolytic activity. EEHP and AEHP depicted the presence of various phytoconstituents with significant antioxidant activities against the DPPH and nitric oxide radical scavenging assays. EEHP and AEHP demonstrated a significant anxiolytic effect in Wistar albino rats using various experimental models. This was confirmed by the strong binding interactions of the identified phytoconstituents present in EEHP and AEHP with GABAA-BZD receptor when docked in silico, highlighting their possible mode of anxiolytic action. The effects may be attributed to the presence of bioactive flavonoids and phenolics, thus supporting the traditional use of the plant in the treatment of CNS disorders and suggesting its potential as a natural anxiolytic.
Acknowledgement:
The authors are extremely grateful to Dr. G.K. Rao, Principal, and Dr. Madhusudan P. Joshi, Ex-Head, Department of Pharmacology, for their support for the research work.
Ethical approval:
The research study was approved by the Institutional Animal Ethics Committee at Goa College of Pharmacy, approval number GCP/IAEC/2022/01, dated 17th October 2022.
Declaration of patient consent:
Patient’s consent is not required as there are no patients in this study.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript, and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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