Antidepressant effects of coumarins and their derivatives: A critical analysis of research advances.

Coumarins and their derivatives are non-flavonoids polyphenols with diverse pharmacological activities including anti-depressant effects. This study systematically examines the antidepressant effects of coumarins and their derivatives in relation to time series of research progress in the pharmacological pathways, association with other diseases, toxicity and bibliometric analysis. The review was approached using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) coupled with R package involving Biblioshiny, a web interface for Bibliometrix analysis and VOSviewer software analytic tools. Literature searches were conducted in Scopus, Web of Science, and PubMed from the inception through January 21, 2023. Coumarins, depression, coumarin derivatives and treatment were the main search terms used which resulted in the inclusion of 46 eligible publications. Scopoletin, psoralen, 7-hydroxycoumarin, meranzin hydrate, osthole, esculetin/umbelliferone were the most studied coumarins with antidepressant effects. Coumarins and their derivatives exerted antidepressant effects with a stronger affinity for monoamine oxidase-B (MAO-B) inhibition and, their inhibitory effect via neurotransmitter pathway on MAO is well-studied. However, epigenetic modification, neuroendocrine, neurotrophic pathways are understudied. Recent research focuses on their antidepressant effects which targeted cytokines and fibromyalgia. There is a link between the gut microbiome, the brain, and depression; meranzin hydrate exerts an antidepressant activity by remodelling the gastrointestinal system. We established that empirical data on some coumarins and their derivatives to support their antidepressant effects are limited. Likewise, the safe dose range for several coumarins and their derivatives is yet to be fully determined.

Development and Biomechanics of Grewia lasiocarpa E. Mey. Ex Harv. Trichomes Exudate.

Grewia lasiocarpa E. Mey. Ex Harv., Malvaceae (forest raisin) is a tropical small tree or shrub valued for its ecological importance as well as its nutritional, antioxidant, antibacterial, and anti-cancer properties as well as its ecological and ornamental importance. Glandular and non-glandular trichomes are present on the fruits, stem bark and leaves of G. lasiocarpa and these trichomes are the first line of defense. They are important structures that plants use to combat biotic and abiotic stress. The development of G. lasiocarpa trichomes and the biomechanics of the exudates present in the glandular (capitate) trichome were investigated for the first time using advanced microscopy techniques [Scanning electron microscope (SEM) and Transmission electron microscope (TEM)]. The pressurized cuticular striations may play a role in the exudates' biomechanics, i.e., releasing secondary metabolites present in the capitate trichome, which was observed to be multidirectional. The presence of many glandular trichomes on a plant implies an increase in the amount of phytometabolites. A common precursor for the development of trichomes (non-glandular and glandular) was observed to be DNA synthesis associated with a periclinal cell division, thus the final fate of the cell is determined by cell cycle regulation, polarity, and expansion. The glandular trichomes of G. lasiocarpa are multicellular and polyglandular, while the non-glandular (glandless) trichomes are either single-celled or multicellular. Since, trichomes 'house' phytocompounds of medicinal, nutritional, and agronomical benefits; the molecular and genetic study of the glandular trichomes of Grewia lasiocarpa will be beneficial to humanity.

Antidepressant Effects of South African Plants: An Appraisal of Ethnobotanical Surveys, Ethnopharmacological and Phytochemical Studies.

Globally, the search for safe and potent natural-based treatment for depression is receiving renewed interest given the numerous side-effects associated with many existing drugs. In South Africa, the use of plants to manage depression and related symptoms is fairly documented among different ethnic groups. In the current study, we reviewed existing ethnobotanical, ethnopharmacological and phytochemical studies on South African medicinal plants used to manage depression. Electronic databases were accessed for scientific literature that meets the inclusion criteria. Plants with ethnobotanical evidence were subjected to a further pharmacological review to establish the extent (if any) of their effectiveness as antidepressants. Critical assessment resulted in 20 eligible ethnobotanical records, which generated an inventory of 186 plants from 63 plant families. Due to the cultural differences observed in the definition of depression, or lack of definition in some cultures, most plants are reported to treat a wide range of atypical symptoms related to depression. Boophone disticha, Leonotis leonurus and Mentha longifolia were identified as the three most popular plants, with over eight mentions each from the ethnobotanical records. The dominant families were Asteraceae (24), Fabaceae (16), Amaryllidaceae (10), and Apocynaceae (10) which accounted for about 32% of the 186 plants. Only 27 (≈14.5%) of the plants have been screened for antidepressant activity using in vitro and in vivo models. Agapanthus campanulatus, Boophone disticha, Hypericum perforatum, Mondia whitei and Xysmalobium undulatum, represent the most studied plants. Phytochemical investigation on nine out of the 27 plants revealed 24 compounds with antidepressant-like effects. Some of these included buphanidrine and buphanamine which were isolated from the leaves of Boophone disticha, Δ9-tetrahydrocannabinol, cannabidiol and cannabichromene obtained from the buds of Cannabis sativa and carnosic acid, rosmarinic acid and salvigenin from Rosmarinus officinalis, A significant portion (≈85%) of 186 plants with ethnobotanical records still require pharmacological studies to assess their potential antidepressant-like effects. This review remains a valuable reference material that may guide future ethnobotanical surveys to ensure their robustness and validity as well as database to identify promising plants to screen for pharmacology efficacy.

An acute dose-ranging evaluation of the antidepressant properties of Sceletium tortuosum (Zembrin®) versus escitalopram in the Flinders Sensitive Line rat.

ETHNOPHARMACOLOGICAL RELEVANCE: Sceletium tortuosum (L.) N.E.Br. (ST) has been used by the Khoisan people of South Africa as a mood elevator. Its various pharmacological mechanisms of action suggest distinct potential as an antidepressant. Clinical studies in healthy individuals suggest beneficial effects on mood, cognition, and anxiety. AIM OF THE STUDY: To obtain a chromatographic fingerprint of a standardized extract of S. tortuosum (Zembrin®), and to evaluate the acute antidepressant-like properties of Zembrin® versus the reference antidepressant, escitalopram, in the Flinders Sensitive Line (FSL) rat, a genetic rodent model of depression. MATERIALS AND METHODS: The chemical profile of Zembrin® was determined by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) chromatogram method using alkaloid standards. Twelve saline treated FSL and six Flinders Resistant Line (FRL) control rats were used to confirm face validity of the FSL model using the forced swim test (FST). Thereafter, FSL rats (n = 10) received either 5, 10, 25, 50 or 100 mg/kg of Zembrin®, or 5, 10 or 20 mg/kg escitalopram oxalate (ESC), both via oral gavage, and subjected to the open field test (OFT) and FST. RESULTS: Four main ST alkaloids were identified and quantified in Zembrin® viz. mesembrenone, mesembrenol, mesembrine, and mesembranol (47.9%, 32%, 13.2%, and 6.8% of the total alkaloids, respectively). FSL rats showed significantly decreased swimming and climbing (coping) behaviours, and significantly increased immobility (despair), versus FRL controls. ESC 5 mg/kg and Zembrin® 25 mg/kg and 50 mg/kg showed significant dose-dependent reversal of immobility in FSL rats and variable effects on coping behaviours. Zembrin® 50 mg/kg was the most effective antidepressant dose, showing equivalence to ESC 5. CONCLUSIONS: Zembrin® (25 and 50 mg/kg) and ESC (5 mg/kg) are effective antidepressants after acute treatment in the FST, as assessed in FSL rats. Moreover, Zembrin® 50 mg/kg proved equivalent to ESC 5. Further long-term bio-behavioural studies on the antidepressant properties of Zembrin® are warranted.

The development and use of a drug-induced immunosuppressed rat-model to screen Phela for mechanism of immune stimulation.

ETHNOPHARMACOLOGY RELEVANCY: Phela, is code name for a medicinal product made from four South African traditional medicinal plants (Clerodendrum glabrum E. Mey, Polianthes tuberosa (Linn.), Rotheca myricoides (Hochst.) Steane & Mabb. and Senna occidentalis (L.) Link). All these plants have established traditional use in a wide spectrum of diseases. Phela is under development for use as an immune booster in immunocompromised patients, which includes patients with the human immunodeficiency virus (HIV). Already several studies, both pre-clinical and clinical, have shown that Phela is a safe and effective immune booster. Despite some studies on the action of Phela, the mechanism of action by Phela is still not known. Understanding the mechanism of action will enable safer and effective use of the drug for the right indications. Unfortunately, there is no well characterized test-system for screening products for immune stimulant activity. Therefore, the objective of this study was to use Phela as the test article, to develop and validate a rat-model (test system) by which to screen medicines for immune stimulant activity. MATERIAL AND METHODS: First, the batch of Phela used was authenticated by high performance liquid chromatography (HPLC) techniques; analytical methods for the immunosuppressant drugs, cyclosporine A (CsA), cyclophosphamide (CP) and dexamethasone (Dex) were developed and validated; and a slide-A-Lyzer dialysis was used to test for potential interactions in rat plasma of Phela with CsA, CP and Dex. Thereafter, using Sprague Dawley (SD) rats and in separate experiments, the effective dose of Phela in the study animals was determined in a dose ranging study with levamisole, a known immune stimulant as the positive control; the appropriate doses for immunosuppression by CsA, CP and Dex were determined; the time to reach 'established immunosuppression' with each drug was determined (it was also the time for intervention with Phela); and eventually, the effect of Phela on the immune system was tested separately for each drug induced immunosuppression. The immune system was monitored by observing for changes in plasma profiles of IL-2, IL-10, IgG, IgM, CD4 and CD8 cell counts at appropriate intervals, while in addition to function tests, the kidneys, liver, spleen, thymus, were weighed and examined for any pathology. RESULTS: The chromatographic fingerprint certified this batch of Phela as similar to the authentic Phela. There was no significant interaction between Phela and CsA, CP and Dex. The effective dose of Phela was determined to be 15.4mg/kg/day. Phela led to a moderate increase in the immune parameters in the normal rats. Co-administration of Phela 15mg/kg/day orally for 21 days with CsA led to stoppage and reversal of the immunosppressive effects of CsA that were exhibited as increased IL-2, IL-10, CD4 and CD8 counts, implying that Phela stimulates the cell mediate immunity (CMI). For CP, Phela led to stoppage and reversal, though moderate, of CP-induced suppression of IL-10, IgM and IgG only, implying that Phela stimulates the humoral immunity (HI) too. Phela had no effect on Dex induced immunosuppression. Stimulation of the CMI means that Phela clinical testing programme should focus on diseases or disorders that compromise the CMI, e.g., HIV and TB. The stimulation of the HI immunity means that Phela may stimulate existing memory cells to produce antibodies. CONCLUSION: The present study has revealed Phela's mechanism of action as mainly by stimulation of the CMI, implying that the use of Phela as immune booster in HIV patients is appropriate; and that using Phela as the test product, a rat model for screening medicinal products for immune stimulation has been successfully developed and validated, with a hope that it will lead to the testing of other related medicinal products.

Evaluation of traditional medicines I: identification of PHELA using different chromatographic techniques.

PHELA is a herbal mixture of four African traditional medicinal plants that has been used for decades in wasting conditions and is now being developed by the Medical Research Council (MRC) as an immune booster for patients with compromised immune system. A chromatographic fingerprint of PHELA was needed for quality control purposes. Here, a comprehensive method for fingerprinting of PHELA using different chromatographic techniques is described. It involved extraction of the PHELA by either acidic or a simple 'salting-out' method, followed by Thin Layer Chromatography (TLC) analysis and/or preparative Column Chromatography (CC). The products were thereafter analyzed by High Performance Liquid Chromatography with UV-detector (HPLC-UV), HPLC with fluorescence-detector (HPLC-FL) and Gas-Chromatography with a Mass Selective Detector spectrometer (GC-MSD). The fingerprints were successfully used to differentiate PHELA from another common herbal product made from Hypericum perforatum (St. John's Wort), thereby illustrating its high potential for use in fingerprinting of PHELA and in differentiating it from other herbal medicines. By validating the different chromatographic techniques on the standardized extraction methods, this approach will enable wide application in quality control of PHELA using acceptable procedures, thereby promoting effective monitoring of the finished product in all countries where it will be used.

Evaluation of traditional medicines III: the mechanism of immune modulation by PHELA.

PHELA is a herbal traditional medicine that is under development for use as an immune booster in immune compromised individuals. Therefore, the aim of this study was to determine PHELA's mechanism of action by observing for changes in cytokine profiles. Four groups of Sprague Dawley rats (n = 8) were treated daily and separately with normal-saline, cyclosporine-A, PHELA-only and PHELA+ cyclosporine-A. Thereafter, 4 animals from each group were sacrificed after 7 and 14 days of treatment. Serum Th1 cytokines (IL-2, IFN-γ and TNF-α) and Th2 cytokines (IL-4 and IL-10) were measured by ELISA. The concentrations of Th1 cytokines in the PHELA-only treated group were similar to the control group on days 7 and 14. However, the Th1 cytokines were higher in the PHELA+cyclosporine-A treated group compared to cyclosporine-A group, and cyclosporine-A concentrations were similar in both groups. These results show that PHELA did not stimulate Th1 cytokines of a normal immune system but stimulated them when the immune system was suppressed by cyclosporine-A. In conclusion, PHELA is an immune-stimulant to a compromised immune system.

Evaluation of traditional medicines II: the use of metabolite peak-kinetics to monitor PHELA in rat plasma.

PHELA is a herbal mixture of four African traditional medicinal plants that is under development by the Medical Research Council (MRC) for use as an immune stimulant in immune compromised individuals. Before major in vivo investigations could be conducted, there was a need to establish a plasma marker for concentration monitoring of PHELA. Chromatographic separation was achieved using a C18 RP column (250 mm × 4.6 mm × 5 µm), 70% acetonitrile in water and fluorescent detection. Three groups of rats (n=5) were administered with PHELA (15.4 mg/kg) and one rat from each group was sacrificed at 1, 2, 4, 6 and 8 hours. Surprisingly, on the HPLC analysis, none of the marker peaks of spiked plasma were detectable in the plasma of treated animals. Instead, a new peak was observed at 9.2 minutes, which implied that it was a metabolite of PHELA. Using peak area per unit plasma volume (PK-area/L), the relevant pharmacokinetic parameters were derived. The metabolite's half-life was 3.47±0.35 hours and reached maximum concentration at 4.67 ± 1.15 hrs. It was estimated that with once daily dosing of PHELA, the concentration at steady state (Css) would be 47.52 ± 5.94 PK-area/L with no drug accumulation (Acc index =.009 ± 0.004). In conclusion, the use of peak area per unit volume to derive pharmacokinetics of unknown compounds (Peak-kinetics) and to confirm ingestion of PHELA were demonstrated with a hope that they may appeal to those experiencing similar problems with monitoring of herbal products of which little is known.