ABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: The bark of Canarium schweinfurthii is used in ethnomedicine for the treatment of diabetes, pain, malaria, fever and diarrhoea. AIM OF THE STUDY: The chemical phytoconstituents, antidiarrheal, anti-inflammatory and antinociceptive effects and safety profile of the aqueous extract of Canarium schweinfurthii bark (AECSB) were investigated. MATERIALS AND METHODS: Gas chromatography-mass spectrometry (GC-MS) was used to analyse the phytochemical composition. In the acute toxicity test, AECSB were administered up to 2 g/kg by oral gavage. For the subacute toxicity test (28 days), rats in group 1 (control) received no AECSB, while rats in groups 2-4 were administered different doses of AECSB. Charcoal meal transit and castor oil-induced diarrhoea models were used to study the antidiarrheal effect, while egg albumin/carrageenan and acetic acid/tail immersion models were used for the anti-inflammatory and antinociceptive studies, respectively. With the exception of the acute toxicity experiment, AECSB was administered orally at doses of 200, 400 and 800 mg/kg. RESULTS: Bioactive phytoconstituents identified include p-cymene, δ-terpinene, linalool and phytol. No adverse effects or mortality were observed in acute and subacute studies. Treatment with AECSB (28 days) had no significant effect on organ weight, biochemical, hematologic and histopathologic parameters compared to the control groups (p > 0.05). Comparable antidiarrheal and antinociceptive effects were observed in both AECSB- and standard drug-treated groups, while the 400 and 800 mg/kg AECSB-treated groups showed remarkable anti-inflammatory effects compared to the standard drug-treated and control groups (p < 0.05). CONCLUSION: AECSB has antidiarrheal, antinociceptive and anti-inflammatory effects and can be safely used for therapeutic purposes.
Subject(s)
Analgesics , Anti-Inflammatory Agents , Antidiarrheals , Burseraceae , Diarrhea , Plant Bark , Plant Extracts , Animals , Analgesics/pharmacology , Analgesics/toxicity , Plant Bark/chemistry , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/toxicity , Plant Extracts/pharmacology , Plant Extracts/toxicity , Plant Extracts/chemistry , Male , Antidiarrheals/pharmacology , Antidiarrheals/toxicity , Antidiarrheals/therapeutic use , Diarrhea/drug therapy , Diarrhea/chemically induced , Rats , Female , Burseraceae/chemistry , Rats, Wistar , Toxicity Tests, Acute , Toxicity Tests, Subacute , Pain/drug therapy , Pain/chemically induced , Phytochemicals/analysis , Phytochemicals/pharmacology , Phytochemicals/toxicity , MiceABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Syagrus coronata, a palm tree found in northeastern Brazil, popularly known as licuri, has socioeconomic importance for the production of vegetable oil rich in fatty acids with nutritional and pharmacological effects. Licuri oil is used in traditional medicine to treat inflammation, wound healing, mycosis, back discomfort, eye irritation, and other conditions. AIM OF THE STUDY: The study aimed to evaluate the antinociceptive, anti-inflammatory, and antipyretic effects of treatment with Syagrus coronata fixed oil (ScFO), as well as to determine the safety of use in mice. MATERIALS AND METHODS: Initially, the chemical characterization was performed by gas chromatography-mass spectrometry. Acute single-dose oral toxicity was evaluated in mice at a dose of 2000 mg/kg. Antinociceptive activity was evaluated through abdominal writhing, formalin, and tail dipping tests, and the anti-inflammatory potential was evaluated through the model of acute inflammation of ear edema, peritonitis, and fever at concentrations of 25, 50, and 100 mg/kg from ScFO. RESULTS: In the chemical analysis of ScFO, lauric (43.64%), caprylic (11.7%), and capric (7.2%) acids were detected as major. No mortality or behavioral abnormalities in the mice were evidenced over the 14 days of observation in the acute toxicity test. ScFO treatment decreased abdominal writhing by 27.07, 28.23, and 51.78% at 25, 50, and 100 mg/kg. ScFO demonstrated central and peripheral action in the formalin test, possibly via opioidergic and muscarinic systems. In the tail dipping test, ScFO showed action from the first hour after treatment at all concentrations. ScFO (100 mg/kg) reduced ear edema by 63.76% and leukocyte and neutrophil migration and IL-1ß and TNF-α production in the peritonitis test. CONCLUSION: Mice treated with ScFO had a reduction in fever after 60 min at all concentrations regardless of dose. Therefore, the fixed oil of S. coronata has the potential for the development of new pharmaceutical formulations for the treatment of pain, inflammation, and fever.
Subject(s)
Analgesics , Anti-Inflammatory Agents , Edema , Plant Oils , Animals , Analgesics/pharmacology , Analgesics/isolation & purification , Analgesics/toxicity , Mice , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/isolation & purification , Plant Oils/pharmacology , Male , Edema/drug therapy , Edema/chemically induced , Pain/drug therapy , Peritonitis/drug therapy , Antipyretics/pharmacology , Arecaceae/chemistry , Female , Inflammation/drug therapy , Inflammation/chemically induced , Fever/drug therapy , Fever/chemically induced , Administration, Oral , Disease Models, AnimalABSTRACT
OBJECTIVE: To improve the biological and toxicological properties of Mefenamic acid (MA), the galactosylated prodrug of MA named MefeGAL was included in polymeric solid dispersions (PSs) composed of poly(glycerol adipate) (PGA) and Pluronic® F68 (MefeGAL-PS). MefeGAL-PS was compared with polymeric solid formulations of MA (MA-PS) or a mixture of equal ratio of MefeGAL/MA (Mix-PS). METHODS: The in vitro and in vivo pharmacological and toxicological profiles of PSs have been investigated. In detail, we evaluated the anti-inflammatory (carrageenan-induced paw edema test), analgesic (acetic acid-induced writhing test) and ulcerogenic activity in mice after oral treatment. Additionally, the antiproliferative activity of PSs was assessed on in vitro models of colorectal and non-small cell lung cancer. RESULTS: When the PSs were resuspended in water, MefeGAL's, MA's and their mixture's apparent solubilities improved due to the interaction with the polymeric formulation. By comparing the in-vivo biological performance of MefeGAL-PS with that of MA, MefeGAL and MA-PS, it was seen that MefeGAL-PS exhibited the same sustained and delayed analgesic and anti-inflammatory profile as MefeGAL but did not cause gastrointestinal irritation. The pharmacological effect of Mix-PS was present from the first hours after administration, lasting about 44â¯hours with only slight gastric mucosa irritation. In-vitro evaluation indicated that Mix-PS had statistically significant higher cytotoxicity than MA-PS and MefeGAL-PS. CONCLUSIONS: These preliminary data are promising evidence that the galactosylated prodrug approach in tandem with a polymer-drug solid dispersion formulation strategy could represent a new drug delivery route to improve the solubility and biological activity of NSAIDs.
Subject(s)
Drug Delivery Systems , Mefenamic Acid , Animals , Mefenamic Acid/pharmacology , Mefenamic Acid/administration & dosage , Mice , Humans , Male , Edema/drug therapy , Edema/chemically induced , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/administration & dosage , Prodrugs/pharmacology , Prodrugs/administration & dosage , Analgesics/pharmacology , Analgesics/administration & dosage , Analgesics/toxicity , Cell Proliferation/drug effects , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/toxicity , Stomach Ulcer/chemically induced , Stomach Ulcer/drug therapy , Stomach Ulcer/pathology , Poloxamer/chemistryABSTRACT
Pain has a negative impact on public health, reducing quality of life. Unfortunately, current treatments are not fully effective and have adverse effects. Therefore, there is a need to develop new analgesic compounds. Due to promising results regarding the antinociceptive effect of N-(3-(phenylselanyl)prop-2-in-1-yl)benzamide (SePB), this study aimed to evaluate the participation of the dopaminergic and noradrenergic systems in this effect in mice, as well as its toxicity. To this, the antagonists sulpiride (D2/D3 receptor antagonist, 5 mg/kg), SCH-23390 (D1 receptor antagonist, 0.05 mg/kg), prazosin (α1 adrenergic receptor antagonist, 0.15 mg/kg), yohimbine (α2-adrenergic receptors, 0.15 mg/kg) and propranolol (non-selective ß-adrenergic antagonist, 10 mg/kg) were administered intraperitoneally to mice 15 min before SePB (10 mg/kg, intragastrically), except for propranolol (20 min). After 26 min of SePB administration, the open field test was performed for 4 min to assess locomotor activity, followed by the tail immersion test to measure the nociceptive response. For the toxicity test, animals received a high dose of 300 mg/kg of SePB. SePB showed an increase in the latency for nociceptive response in the tail immersion test, and this effect was prevented by SCH-23390, yohimbine and propranolol, indicating the involvement of D1, α2 and ß-adrenergic receptors in the antinociceptive mechanism of the SePB effect. No changes were observed in the open field test, and the toxicity assessment suggested that SePB has low potential to induce toxicity. These findings contribute to understanding SePB's mechanism of action, with a focus on the development of new alternatives for pain treatment.
Subject(s)
Propranolol , Quality of Life , Mice , Animals , Propranolol/pharmacology , Propranolol/therapeutic use , Analgesics/toxicity , Pain/drug therapy , Norepinephrine , Yohimbine/toxicity , Yohimbine/therapeutic use , Adrenergic alpha-1 Receptor Antagonists/therapeutic use , Dopamine , Sulpiride , Receptors, Adrenergic, alpha-2ABSTRACT
BACKGROUND: Kaurenol, a diterpene alcohol found in Copaifera langsdorffii Desf. (known as "copaiba"), is historically used in traditional medicine for inflammatory conditions. OBJECTIVES: This study aims to comprehensively assess the potential anti-inflammatory and antinociceptive properties of kaurenol. METHODS: To this end, the following experiments were conducted to evaluated toxicity: locomotor performance and acute toxicity; nociception: acetic acid-induced writhing and formalin-induced antinociception; and anti-inflammatory activity: carrageenan and dextran-induced paw edema at 10, 20, and 40 mg/kg, and measurement of nitric oxide (NO), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10) in macrophages at 1, 3, and 9 µg/ml. RESULTS: Kaurenol did not show significant locomotor changes, acute toxicity, and central analgesic activity in the first phase of formalin test at dosages tested. Kaurenol showed 53%, 64%, 64%, and 58% of inhibition in the acetic acid-induced writhing, second phase of formalin test, carrageenan and dextran-induced paw edema, respectively. CONCLUSION: The anti-inflammatory activity was associated with the regulation of NO release and probably with the regulation of mediators, such as serotonin and prostaglandin in vascular permeability, as well as by being associated with the regulation of IL-6 and IL-10. Kaurenol display anti-inflammatory activity but has no analgesic activity.
Subject(s)
Diterpenes , Interleukin-10 , Humans , Carrageenan , Interleukin-6 , Dextrans/adverse effects , Pain/chemically induced , Pain/drug therapy , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Analgesics/toxicity , Diterpenes/adverse effects , Plant Extracts/pharmacology , Acetic Acid/adverse effects , Edema/chemically induced , Edema/drug therapyABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: The stem of Musa paradisiaca (plantain) has found application in traditional medicine for the treatment of diabetes, inflammation, ulcers and wound injuries. AIM OF THE STUDY: This study investigated the phytochemical composition, toxicity profile, wound healing, anti-inflammatory and analgesic effects of aqueous Musa paradisiaca stem extract (AMPSE) in rats. METHODS: Phytochemical analysis of methanol-MPSE was performed by gas chromatography-mass spectrometry (GC-MS). Acute toxicity testing was carried out through oral administration of a single dose of AMPSE up to 5 g/kg. Four separate groups of rats were used for the subacute toxicity testing (n = 6). Group 1 served as a normal control and did not receive AMPSE, groups 2-4 received AMPSE daily by gavage for 28 days. In the experiments with excision and incision wounds, the rats were treated with 10 w/w AMPS extract. The anti-inflammatory and analgesic effects of AMPSE were assessed using egg albumin-induced paw oedema and acetic acid-induced writhing methods, respectively. For the subacute, anti-inflammatory and analgesic studies, AMPSE was administered to the experimental rats at doses of 300, 600 and 900 mg/kg body weight. RESULTS: Bioactive compounds identified include ß-sitisterol, n-hexadecanoic acid, octadecanoic acid, diethyl sulfate, p-hydroxynorephedrine, phenylephrine, nor-pseudoephedrine, metaraminol, pseudoephedrine and vanillic acid. No signs of toxicity and no deaths were observed in all the groups. For the groups treated with AMPSE for 28 days, a significant reduction in alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, urea, sodium, chloride, total cholesterol, triglycerides, and low-density lipoprotein cholesterol were observed while high density lipoprotein cholesterol, glutathione and superoxide dismutase increased compared to control (p < 0.05). In wound healing experiments, AMPSE showed greater percent wound contraction and wound resistance fracture compared to the povidone-iodine (PI) treated and control groups. Treatment with 900 mg/kg AMPSE resulted in significant (p < 0.05) anti-inflammatory and analgesic effects compared to the control. CONCLUSION: This study shows that AMPSE is not toxic but contains biologically active compounds with hepatoprotective, anti-inflammatory, lipid-lowering and wound-healing effects. Treatment of rats with AMPSE has shown that AMPSE has anti-inflammatory, analgesic, hepatoprotective, lipid-lowering and wound-healing effects, supporting its therapeutic use in ethnomedicine.
Subject(s)
Musa , Musaceae , Plantago , Rats , Animals , Musa/chemistry , Plant Extracts/therapeutic use , Plant Extracts/toxicity , Pseudoephedrine/pharmacology , Analgesics/therapeutic use , Analgesics/toxicity , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/toxicity , Wound Healing , Cholesterol/pharmacology , Phytochemicals/therapeutic use , Phytochemicals/toxicity , Lipids/pharmacologyABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Amburana cearensis (Allemão) A.C. Smith is a medicinal plant with wide distribution in South America, popularly known in Brazil as "cumaru" or "amburana de cheiro". In folk medicine, in the semi-arid region of Northeastern Brazil, infusions, teas and decoctions of leaves of Amburana cearensis have their practical use for treating fever, gastrointestinal disorders, inflammation, and inflammation pain. However, none of the ethnopharmacological properties has been scientifically evaluated using volatile compounds obtained from its leaves (essential oil). AIM OF THE STUDY: This study investigated the chemical composition, acute oral toxicity, and antinociceptive and anti-inflammatory activities of the essential oil from the leaves of A. cearensis. MATERIAL AND METHODS: The acute toxicity of the essential oil was investigated in mice. The antinociceptive effect was evaluated using the formalin test and, abdominal writhing induced by acetic acid, being investigated the possible mechanisms of action involved in antinociception. The acute anti-inflammatory effect was investigated through models of carrageenan-induced peritonitis, yeast-induced pyrexia, and carrageenan- and histamine-induced paw inflammation. RESULTS: No acute toxicity was observed at doses up to 2000 mg/kg; p.o. The antinociceptive effect was statistically equal to morphine. In the formalin assay, the oil showed analgesic activity in the neurogenic and inflammatory phases, having as mechanisms the cholinergic, adenosinergic system, and ATP-sensitive potassium channels (K-ATP). In peritonitis, a reduction in TNF-α and IL-1ß levels and leukocyte migration were observed. The antipyretic effect was statistically superior to dipyrone. The reduction in paw edema was statistically superior to the standard in both models. CONCLUSION: The results obtained not only support the traditional use of the species in inflammatory conditions and pain in folk medicine but also demonstrate that this is a rich source of phytocomponents such as germacrone, which can be used as a natural and sustainable therapeutic agent with industrial applications.
Subject(s)
Fabaceae , Oils, Volatile , Peritonitis , Mice , Animals , Oils, Volatile/therapeutic use , Oils, Volatile/toxicity , Carrageenan , Brazil , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/toxicity , Analgesics/therapeutic use , Analgesics/toxicity , Pain/drug therapy , Pain/chemically induced , Plant Extracts/therapeutic use , Plant Extracts/toxicity , Inflammation/drug therapy , Peritonitis/drug therapy , Plant Leaves/chemistry , Edema/chemically induced , Edema/drug therapyABSTRACT
The ostrich oil (OO) has been topically used for decades to treat skin diseases. Its oral use has been encouraged through e-commerce advertising several health benefits to OO without scientific evidence on its safety or effectiveness. This study presents the chromatographic profile of a commercially available OO and its acute and 28-day repeated dose in vivo toxicological profiles. OO anti-inflammatory and antinociceptive effects were also investigated. Omega-9 (ω-9; oleic acid; 34.6%) and -6 (linoleic acid; 14.9%) were detected as OO main constituents. A high single dose of the OO (2 g/kg of ω-9) demonstrated no or low acute toxicity. However, when orally treated with OO (30-300 mg/kg of ω-9) for 28 consecutive days, mice exhibited altered locomotor and exploratory activities, hepatic damage, and increased hindpaw sensitivity accompanied by increased levels of cytokine and brain-derived neurotrophic factor in their spinal cords and brains. Lack of anti-inflammatory or antinociceptive activities was also evidenced in 15-day-OO treated mice. These results indicate that chronic consumption of OO induces hepatic injury, in addition to neuroinflammation and subsequent hypersensitivity and behavioural changes. Thus, there is no evidence to support OO use to treating illness in humans.
Subject(s)
Struthioniformes , Humans , Animals , Mice , Olive Oil/chemistry , Neuroinflammatory Diseases , Toxicity Tests , Analgesics/toxicityABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Newbouldia laevis is a popular medicinal plant whose leaves and roots are used in Nigeria as ethnomedicinal prescriptions for pain, inflammation, convulsion, and epilepsy. These claims have not been scientifically verified prior to this study. AIM OF THE STUDY: To determine pharmacognostic profiles of the leaves and roots and evaluate the analgesic, anti-inflammatory, and anticonvulsant activities of methanol leaf and root extracts in Wistar rats. MATERIAL AND METHODS: The pharmacognostic profiles of the leaves and roots were determined using standard procedures to serve as fingerprints for the plant. The methanol leaf and root extracts of Newbouldia laevis were tested for acute toxicity using the OECD's up and down method at the maximum dose of 2000 mg/kg (orally) in Wistar rats. Analgesic studies were carried out in acetic acid-induced writhing in rats and tail immersion. The anti-inflammatory activity of the extracts was evaluated using carrageenan-induced rat paw-oedema and formalin-induced inflammation in rats' mode. The anticonvulsant activity was determined using strychnine-induced, pentylenetetrazol-induced, and maximal electroshock-induced rat convulsion models. For each of these studies, the extracts doses of 100, 200 and 400 mg/kg were administered to the rats following the oral route. RESULTS: The pharmacognostic profiles showed that the leaves possessed deep-sunken paracytic stomata (5-8-16 mm2; adaxial, 8-11-24 mm2; abaxial epidermis), vein islets (2-4-10 mm2; adaxial), vein terminations (10-14-18 mm2; adaxial), palisade ratio (8.3-12.5-16.4 mm2; adaxial, 2.5-6.8-12.2 mm2; adaxial), covering unicellular trichome (8-14; adaxial), spheroidal calcium oxalate crystals (3-5 µm), and oval-shaped striated starch grain with no hilum (0.5-4.3 µm). The transverse section of the leaf showed the presence of spongy and palisade parenchyma as well as a closed vascular bundle. The root powder showed the presence of brachy sclereid, fibers without lumen, and lignin. All physicochemical parameters fall within the acceptable limits, phytochemical contents showed mainly glycosides, alkaloids, and steroids while acute oral toxicity (LD50) of the parts for 14 days did not produce any toxicity signs or mortality in the rats. The extracts produced dose-dependent (100-400 mg/kg) analgesic involving opioid receptors, anti-inflammatory, and anticonvulsant activities in the rats which were significant (p ≤ 0.05) when compared to the standard drugs. The leaf extract possessed the most potent analgesic and anti-inflammatory effects in the rats, while the most anticonvulsant effects were observed in rats treated with the leaf extract. Both extracts showed elevated levels of protection against strychnine-induced, pentylenetetrazol-induced, and maximal electroshock-induced seizure in rats. CONCLUSION: Our study revealed some pharmacognostic profiles of Newbouldia laevis leaves and roots that are vital for its identification from closely related species often used for adulteration in traditional medicine. The study further showed that the leaf and root extracts of the plant possessed dose-dependent analgesics, anti-inflammatory and anti-convulsant activities in rats, thus, justifying its use for the treatment of these diseases in Nigerian traditional medicine. There is a need to further study its mechanisms of action towards drug discovery.
Subject(s)
Anticonvulsants , Plant Extracts , Rats , Animals , Rats, Wistar , Anticonvulsants/therapeutic use , Anticonvulsants/toxicity , Plant Extracts/therapeutic use , Plant Extracts/toxicity , Methanol/chemistry , Strychnine/therapeutic use , Pentylenetetrazole , Analgesics/therapeutic use , Analgesics/toxicity , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/toxicity , Inflammation/drug therapy , Seizures/chemically induced , Seizures/drug therapy , Edema/chemically induced , Edema/drug therapy , Plant LeavesABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: One of the native species of the genus most often mentioned by traditional people is Psidium cattleyanum Sabine, which is used mostly to treat disorders of the respiratory, genitourinary, and digestive systems. These symptoms are mainly treated by the decoction of the leaves. Additionally, there are gaps in the in vivo and toxicity investigations of this species. AIM OF THE STUDY: The aim of this study was evaluate antinociceptive and anti-inflammatory potential of essential oil from P. cattleyanum leaves in vivo. MATERIALS AND METHODS: Gas chromatography-mass spectrometry (GC/MS) was used to examine the essential oil of P. cattleyanum. The acute toxicity test was then done with a 2000 mg/kg dosage. The oil at 50, 100, and 200 mg/kg orally, as well as the reference medications Morphine 10.0 mg/kg IP and/or Indomethacin 20.0 mg/kg IP, were tested using nociception (abdominal writhing, formalin, and tail immersion) and inflammatory models (paw edema and peritonitis). RESULTS: The phytochemical assay showed a high concentration of ß-caryophyllene (46.68%) and α-caryophyllene (10.81%). In the in vivo assays, P. cattleyanum essential oil proved to be an important antinociceptive agent, reaching 76.96% inhibition of abdominal writhing with acetic acid and 67.12% in the formalin assay. An increase in latency time in the tail test was also reported. In the test with carrageenan, the oil showed significant inhibition compared to the control. A decrease in the migration of leukocytes was also reported in the group treated with P. cattleyanum, reaching 60.49% at the dose of 200 mg/kg. CONCLUSIONS: The essential oil from the leaves of P. cattleyanum has anti-inflammatory and antinociceptive action and has potential for application in the pharmaceutical and food industry.
Subject(s)
Oils, Volatile , Psidium , Mice , Animals , Oils, Volatile/therapeutic use , Oils, Volatile/toxicity , Psidium/chemistry , Plant Extracts/therapeutic use , Plant Extracts/toxicity , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/toxicity , Analgesics/therapeutic use , Analgesics/toxicity , Formaldehyde , Plant Leaves/chemistry , Edema/chemically induced , Edema/drug therapyABSTRACT
BACKGROUND: An array of commercially viable intermediate molecules necessary for the synthesis of a variety of bioactive molecules are chemically synthesized by pyrrolidine and its derivatives, which play a significant role in drug design and development process. AIM: The aim of the present research work was to explore the synthesis of some new pyrrolidine derivatives and to perform their in silico studies and finally evaluation of analgesic and anti-inflammatory activity. OBJECTIVE: The purpose of this study was to synthesis new pyrrolidine derivatives, examine how they affected the COX-1 and COX-2 enzymes computationally, and to screen their in vivo analgesic and anti-inflammatory activity on laboratory animals. METHOD: The new pyrrolidine derivatives were synthesized by condensing N-(3-acetylphenyl)-2-(pyrrolidin-1-yl)acetamide with substituted aniline in ethanol in the presence of catalytic amounts of glacial acetic acid. The structures of novel pyrrolidine derivatives were characterised using IR, NMR, and mass spectroscopy. Several molecular properties of the newly synthesized derivatives were calculated in order to evaluate the nature of the drug-like candidate. A specific reference cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzyme was used to dock the newly synthesized pyrrolidine derivatives. RESULTS: From the observed data, it was noted that amongst all newly synthesized compounds, A-1 and A-4 exhibited the highest anti-inflammatory and analgesic effects, respectively. CONCLUSION: On the basis of findings of present research, it was concluded that A-1 and A-4 might be utilized as a promising new lead compound for Non-Steroidal Anti-Inflammatory Drug (NSAIDs) development.
Subject(s)
Analgesics , Anti-Inflammatory Agents, Non-Steroidal , Pyrrolidines , Computer Simulation , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Pyrrolidines/toxicity , Analgesics/chemical synthesis , Analgesics/pharmacology , Analgesics/toxicity , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/toxicity , Male , Female , Animals , Rats , Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/pharmacology , Cyclooxygenase Inhibitors/toxicityABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Daniellia oliveri (Rolfe) Hutch. & Dalziel (Fabaceae) is used for the treatment of inflammatory diseases and pains (chest pain, toothache and lumbago) and rheumatism. AIM OF THE STUDY: The study investigates the anti-inflammatory and antinociceptive properties of D. oliveri and possible mechanism of antiinflammatory action. MATERIALS AND METHODS: Acute toxicity of the extract was evaluated in mice using the limit test. The anti-inflammatory activity was assessed in xylene-induced paw oedema and carrageenan-induced air-pouch models at doses of 50, 100 and 200 mg/kg, p.o. Volume of exudate, total protein, leukocyte counts, myeloperoxidase (MPO) and concentration of cytokines (TNF-α and IL-6) were measured in the exudate of rats in the carrageenan-induced air-pouch model. Other parameters include lipid peroxidation (LPO), nitric oxide (NO) and antioxidant indices (SOD, CAT and GSH). Histopathology of the air pouch tissue was also carried out. The antinociceptive effect was assessed using acetic acid-induced writhing, tail flick and formalin tests. Locomotor activity was done in the open field test. The extract was analysed with HPLC-DAD-UV technique. RESULTS: The extract showed significant anti-inflammatory effect (73.68 and 75.79%, inhibition) in xylene-induced ear oedema test at the dose of 100 and 200 mg/kg, respectively. In carrageenan air pouch model, the extract significantly reduced exudate volume, protein concentration, the migration of leukocytes and MPO production in the exudate. The concentrations of cytokines TNF-α (12.25 ± 1.80 pg/mL) and IL-6 (21.12 pg/mL) in the exudate at the dose of 200 mg/kg were reduced compared to carrageenan alone group (48.15 ± 4.50 pg/mL; 82.62 pg/mL) respectively. The extract showed significant increase in the activities of CAT and SOD and GSH concentration. The histopathological assessment of the pouch lining revealed reduction of immuno-inflammatory cell influx. Nociception was significantly inhibited by the extract in acetic acid-induced writhing model and the second phase of formalin test indicating a peripheral mechanism of action. The open field test showed that D. oliveri did not alter locomotor activity. The acute toxicity study did not cause mortality or signs of toxicity at 2000 mg/kg, p.o. We identified and quantified caffeic acid, p-coumaric acid, ferulic acid, rutin, apigenin-7-glucoside, quercetin and kaempferol in the extract. CONCLUSION: The results of our study showed that the stem bark extract of D. oliveri possesses anti-inï¬ammatory and antinociceptive activities thereby supporting its traditional use in the treatment of some inflammatory and painful disorders.
Subject(s)
Fabaceae , Plant Extracts , Rats , Mice , Animals , Carrageenan/toxicity , Plant Extracts/therapeutic use , Plant Extracts/toxicity , Analgesics/therapeutic use , Analgesics/toxicity , Tumor Necrosis Factor-alpha , Xylenes/toxicity , Plant Bark/metabolism , Interleukin-6 , Anti-Inflammatory Agents/adverse effects , Cytokines/therapeutic use , Edema/chemically induced , Edema/drug therapy , Edema/metabolism , Superoxide DismutaseABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Eugenia brasiliensis Lam., popularly known as "grumixama" or "Brazilian cherry", is widely used in folk medicine with astringent, diuretic, energizing, anti-rheumatic, and anti-inflammatory properties. AIM OF THE STUDY: Despite its traditional use, detailed toxicological studies of Eugenia brasiliensis are few. Thus, in the current study, we evaluate the toxicological effects of hydroalcoholic extract of Eugenia brasiliensis (HEEb) and its antinociceptive and anti-inflammatory activity. MATERIALS AND METHODS: We used male, and female Swiss mice. Acute toxicity study was performed following the Organization for Economic Cooperation and Development (OECD) guideline 425, and subacute toxicity was assessed following OECD guideline 407. We observed behavioral responses, in addition to hematological, biochemical, and histological evaluations. The antinociceptive and anti-inflammatory activity of HEEb were assessed using the Carrageenan-induced mechanical allodynia and paw edema model. Mechanical allodynia, levels of inflammatory cytokines, and oxidative damage were evaluated. RESULTS: The treatment with HEEb was not able to generate important toxicological alterations. Moreover, doses of 100 and 300 mg/kg of HEEb were able to reduce mechanical allodynia, paw edema, and inflammatory cytokines (TNF-α, IL-1ß, and IL-6), decrease malondialdehyde and increase superoxide dismutase enzyme activity in the paw. CONCLUSIONS: This study demonstrated that HEEb does not present important toxic effects. Additionally, an important antinociceptive, anti-inflammatory, and antioxidant potential were observed.
Subject(s)
Eugenia , Myrtaceae , Mice , Male , Female , Animals , Eugenia/chemistry , Plant Extracts/toxicity , Plant Extracts/chemistry , Hyperalgesia/drug therapy , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/toxicity , Carrageenan , Cytokines/therapeutic use , Analgesics/therapeutic use , Analgesics/toxicity , Edema/chemically induced , Edema/drug therapyABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Eugenia gracillima is widely used by the population in the manufacture of pulps and jellies, with popular reports of its use in the treatment of infections in the urinary system, respiratory and dermatological problems. A previous study reports that EO from E. gracillima leaves proved to be a promising antioxidant agent in combating the promastigote forms of protozoa. Despite this, this species has been little studied due to its pharmacological properties. STUDY OBJECTIVE: In this study, an essential oil extracted (EO) from Eugenia gracillima leaves was evaluated for its acute toxicity and anti-inflammatory, antinociceptive and behavioral effects in mice. METHODS: The EO was obtained by hydrodistillation, and the composition analysis was performed by gas chromatography coupled to mass spectrometry. Acute toxicity assessment was performed with observation of hematological parameters and histopathological evaluation, as well as tests to investigate antinociceptive, anti-inflammatory activities and behavioral effects. RESULTS: Chromatographic analysis showed D-germacrene (16.10%), γ-muurolene-g (15.60%) and bicyclogermacrene (8.53%) as the majority of compounds. In the toxicity evaluation, no death or physiological changes were observed in mice treated with a single oral dose of up to 5000 mg/kg, and it did not lyse erythrocytes in vitro. The hematological parameters evaluated were not changed after treatment; however, 5,000 mg/kg promoted an increase in transaminase levels. In the histopathological evaluation, only the animals that received the dose of 5000 mg/kg showed discrete leukocyte infiltration around the centrilobular vein in the liver. Antinociceptive activity was detected through tests of acetic acid-induced writhing, formalin, and tail flick, promoted in part by the opioid receptor pathway. In the evaluation of anti-inflammatory activity, a reduction in inflammation was observed in the paw edema test and a decrease in the migration of leukocytes and neutrophils in the peritonitis test. The open field and elevated plus maze tests showed that EO did not affect the animals' motor functions or exploratory activity. CONCLUSION: It was concluded that the essential oil of E. gracillima has potential for the development of pharmaceutical formulations with analgesic and anti-inflammatory actions in non-toxic concentrations.
Subject(s)
Eugenia , Oils, Volatile , Mice , Animals , Oils, Volatile/therapeutic use , Oils, Volatile/toxicity , Eugenia/chemistry , Gas Chromatography-Mass Spectrometry , Pain/chemically induced , Pain/drug therapy , Analgesics/therapeutic use , Analgesics/toxicity , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/toxicity , Inflammation/chemically induced , Inflammation/drug therapy , Plant Extracts/pharmacology , Plant Leaves , Edema/chemically induced , Edema/drug therapyABSTRACT
The C18-diterpenoid alkaloid lappaconitine (LA) is a non-addictive analgesic used in China. The toxicity (LD50 = 11.7 mg/kg) limits its application. Two series of LA derivatives, including amides and sulfonamides (1-93), were designed and synthesized by modification on their C4 acetamidobenzoate side chains in this work. In vivo analgesic activity and toxicity of all derivatives were evaluated, and the structure-activity relationship was summarized. Six lead compounds (35, 36, 39, 49, 70, and 89) exhibited approximate analgesic activity to LA but with significantly reduced toxicity. The therapeutic index of these compounds is 14-30 times that of LA. In vivo metabolism study of the lead compounds 39, 49, 70, and 89 were conducted by UPLC-MSE, indicating the reason for the low toxicity of the potential derivatives might be they are difficult to metabolize to toxic metabolite N-deacetyllappaconitine compared to LA. The effects of lead compounds on sodium channels and hERG channels were also studied by ion channel reader (ICR) which further revealed their analgesic and toxicity-attenuating mechanisms. Sodium channel assay revealed that the analgesic mechanism of these lead compounds was inhibiting the Nav 1.7 channels. Taken together, compound 39 was provided as a new analgesic lead compound with significantly low toxicity and comparable activity to LA.
Subject(s)
Aconitine , Tandem Mass Spectrometry , Chromatography, Liquid , Aconitine/toxicity , Analgesics/toxicity , Analgesics/chemistry , Sodium ChannelsABSTRACT
Bufotenines, a natural component from toad venom, showed great potential for development as a novel anti-inflammation and analgesia agent, but the potential toxicity limited its clinic use. In this paper, bufotenines-loaded liposome was prepared and optimized. Then, the therapeutic effects and drug safety of bufotenines-liposome were investigated against inflammation and pain on animal models, with a focus on gastrointestinal toxicity. Bufotenines and its liposome significantly increased paw withdrawal mechanical threshold (PWMT) in Von Frey test and hot paw withdrawal latency (HPWL) in hot-plate test. Moreover, intestinal absorption in vitro and pathological analysis in vivo showed that total bufotenines-loaded liposome significantly reduced the gastrointestinal irritation through reducing exposure of total bufotenines on intestinal tissue. High-sensitivity lipidomics analysis revealed the effect of total bufotenines-loaded liposome were be related to the down-regulation of inflammatory mediators from cyclooxygenase (COX) and lipoxygenase (LOX), the up-regulation of cytochrome P450 (CYP450), and other pathways, thus regulating lipid metabolism pathway and ultimately reducing gastrointestinal irritation. This study shows that liposome-loaded bufotenines has anti-inflammatory, analgesic effects and achieves toxicity reduction. These results provide systematic evidences for efficacy and safety of toad venom active ingredients.
Subject(s)
Amphibian Venoms , Liposomes , Analgesics/toxicity , Animals , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal , Bufotenin , Cyclooxygenase 2/metabolism , LipidsABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Grayanoids are natural diterpenoids that are mostly found in the Ericaceae family, such as Rhododendron molle (Blume) G. Don (Relevant herb: nao yang hua), Rhododendron micranthum Turcz (also known as: zhao shan bai), which have traditionally been used to treat abdominal pain, cephalgia, and rheumatoid arthritis. AIMS OF THE REVIEW: The review investigated advancements in notable anti-nociception, toxicity, and probable mechanisms of grayanoids. Meanwhile some binding sites of these compounds on voltage-gated sodium channels (VSGCs) were also analyzed and evaluated. MATERIALS AND METHODS: The substantial grayanoids literature published before 2022, in SCI Finder, PubMed, Science Direct, Springer, Scopus, Wiley Online Library, J-Stage, and other literature databases had been exhaustively consulted and thoroughly screened. RESULTS: More than 50 compounds in grayanoids exhibited exceptionally significant anti-nociception (intraperitoneal injection, less than 1 mg/kg), and the alteration of several substituents that were closely associated to the change in activity were investigated. Multiple possible mechanisms of analgesic action and toxicity had been proposed, with VSGCs playing a key part in both. As a result, the binding locations of these compounds on VGSCs (mostly grayanotoxin I and III) had been summarized. CONCLUSIONS: The considerable anti-nociception, toxicity, and probable mechanisms of grayanoids, as well as the investigation of the binding sites on VSGCs, were discussed in this review. Furthermore, the homology of toxicity and anti-nociception of these substances was considered, as well as the possibility of grayanoids being developed as analgesics.
Subject(s)
Ericaceae , Rhododendron , Analgesics/therapeutic use , Analgesics/toxicity , Ericaceae/chemistry , Plant Extracts/pharmacology , Rhododendron/chemistryABSTRACT
Alzheimer's disease (AD) is a neurodegenerative disease (ND) that represents the principal cause of dementia. Effective treatment is still lacking. Without prevention, Alzheimer's disease (AD) incidence is expected to triple within 30 years. The risk increases in highly polluted areas and is positively linked to chronic aluminum (Al) exposure. Canonical Wingless-Int (Wnt)/ß-catenin pathway has been found to play a considerable role in ND pathogenesis. Resins of Boswellia serrata (frankincense) have been used traditionally for their psychoactive activity, in addition to their memory-boosting effects. Boswellic acids (BA) are pentacyclic triterpenes. They have antioxidant, anti-inflammatory, antinociceptive, and immunomodulatory activities. This study aimed to elucidate the role of the Wnt/ß-catenin pathway in BA protective activity against aluminum-induced Alzheimer's disease. For 6 weeks, rats were treated daily with AlCl3 (100 mg/kg/i.p.) either alone or with BA (125 or 250 mg/kg PO). Results indicated that BA significantly improved learning and memory impairments induced by AlCl3 treatment. Moreover, BA treatment significantly decreased acetylcholinesterase levels and reduced amyloid-beta (Aß) expression. In addition, BA ameliorated the increased expression of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß), inhibited lipid peroxidation, and increased total antioxidants in the brain. Indeed, BA significantly suppressed AlCl3-induced decrease of brain-derived neurotrophic factor, pGSK-3ß (Ser 9), and ß-catenin. BA (250 mg/kg) showed a significant protective effect compared to a lower dose. The results conclude that BA administration modulated the expression of Wnt/ß-catenin pathway-related parameters, contributing to BA's role against Al-induced Alzheimer's disease. Effect of Boswellic acids on AlCl3-induced neurodegenerative changes. ChE cholinesterase, Ach acetylcholine, BDNF brain-derived neurotrophic factor, IL-1ß interleukin-1ß, TNF-α tumor necrosis factor-α.
Subject(s)
Alzheimer Disease , Boswellia , Frankincense , Neurodegenerative Diseases , Acetylcholine/therapeutic use , Acetylcholine/toxicity , Acetylcholinesterase/metabolism , Aluminum/toxicity , Aluminum Chloride/toxicity , Alzheimer Disease/drug therapy , Analgesics/toxicity , Animals , Anti-Inflammatory Agents , Antioxidants/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Frankincense/therapeutic use , Frankincense/toxicity , Interleukin-1beta/metabolism , Neurodegenerative Diseases/chemically induced , Neurodegenerative Diseases/drug therapy , Pentacyclic Triterpenes/therapeutic use , Pentacyclic Triterpenes/toxicity , Rats , Triterpenes , Tumor Necrosis Factor-alpha/metabolism , beta Catenin/metabolismABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Bocconia arborea S. Watson (Papaveraceae) is known as "palo llora sangre" and is used in Mexican traditional medicine for the treatment of infections, it is also used as anxiolytic, analgesic, and antidiabetic, among others. AIM OF THE STUDY: to evaluate the antinociceptive and gastroprotective activities of extracts from B. arborea and dihydrosanguinarine (DHS) in murine models. MATERIALS AND METHODS: Organic extracts [hexane (HEX), dichloromethane (DCM) and methanol (MeOH)] were obtained by maceration. DHS was isolated and purified from HEX and DCM by precipitation and chromatographic column, respectively. Organic extracts and DHS were evaluated to determine their antinociceptive effect using formalin test in murine model. Also, the ambulatory effect of the HEX and DHS was determined in Open field test. The possible mechanism of action of DHS was explored in the presence of naltrexone (NTX, 1 mg/kg, i.p.), and picrotoxin (PTX, 1 mg/kg, i.p.). Gastric damage as possible adverse effect or gastroprotection were also investigated. Whereas DHS acute toxicological study was done, and 100 mg/kg of DHS was examined by electroencephalographic (EEG) analysis to discard neurotoxic effects. RESULTS: The B. arborea extracts significantly showed effects in both neurogenic and inflammatory phases of the formalin test, where the HEX extract reached the major antinociceptive effect. A significant and dose-response (10, 30, and 100 mg/kg) antinociceptive activity was observed with the HEX (ED50 = 69 mg/kg) and DHS (ED50 = 85 mg/kg) resembling the effect of the reference analgesic drug tramadol (30 mg/kg). The significant effect of DHS was inhibited in the presence of NTX and PTX. Neither the extracts or DHS produced sedative effects or gastric damage per se at antinociceptive doses. The EEG analysis demonstrated central depressant activity but not sedative or neurotoxic effects at the highest antinociceptive dosage tested, and LD50 is higher than 2000 mg/kg. CONCLUSIONS: HEX, DCM, and MeOH extracts showed significant antinociceptive activity, and DHS was identified as one of bioactive compounds without producing sedative, neurotoxic or gastric damage effects, as possible adverse effects reported for analgesic drugs. A role of opioid and GABAA neurotransmission appears to be involved as mechanisms of action of DHS, suggesting its potential for pain therapy and reinforcing the traditional use of B. arborea.
Subject(s)
Pain , Papaveraceae , Analgesics/therapeutic use , Analgesics/toxicity , Animals , Benzophenanthridines , Disease Models, Animal , Isoquinolines , Methanol/therapeutic use , Mice , Pain/drug therapy , Plant Extracts/chemistry , Plant Extracts/pharmacology , Plant Extracts/therapeutic useABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: In Chinese traditional medicine, Rhododendron molle G. Don is a recognized herb to ease pain. Rhodojaponin III (RJ-III) has been identified as the main pharmacological activity and toxic component of the herb; however, oral antinociception and mechanism of RJ-III have not yet been investigated. AIM OF THE STUDY: The significance of this study is to evaluate the effects of RJ-III on nociceptive and neuropathic pain, and to preliminarily explore the underlying mechanisms and subacute toxicity. MATERIALS AND METHODS: The antinociception of RJ-III was evaluated by hot plate, tail-immersion, acetic acid writhing, formalin test and chronic constriction injury (CCI) model in rodents. An experimental validation was conducted using whole-cell patch clamp technique based on the most likely mechanisms of action after screening and prediction by molecular docking study. In addition, the oral subacute toxicity of RJ-III was assessed. RESULTS: Behavioral experiments showed that RJ-III (0.20 mg/kg) reduced the latency of the nociceptive response in the hot plate and tail-immersion tests. Acetic acid and formalin-induced pain were significantly inhibited by RJ-III (0.10 and 0.05 mg/kg, respectively). Furthermore, 0.30 mg/kg of RJ-III improved hyperalgesia in the CCI-induced rats. Based on molecular docking results, electrophysiological experiments were used to demonstrate mild inhibition of voltage-gated sodium channel-related subtypes. Additionally, oral subacute toxicity that may cause leukopenia and abnormal liver function requires further attention in subsequent studies. CONCLUSION: RJ-III mildly blocks voltage-gated sodium channel to inhibit nociceptive pain and peripheral neuralgia, but 0.375 mg/kg and above may cause side effect after long-term oral administration.