[Effects of tetramethylpyrazine on pharmacokinetics in plasma and brain dialysate and neuropathic pain in rat model of spared sciatic nerve injury].

This study aims to explore the effects of tetramethylpyrazine(TMP) on pharmacokinetics in plasma and brain dialysate and neuropathic pain in the rat model of partial sciatic nerve injury(SNI), and to investigate the correlation between the analgesic effect of TMP and its concentrations in the plasma and brain dialysate. Male SD rats were randomized into Sham, SNI, and SNI+TMP groups. Mechanical stimulation with von frey filaments and cold spray method were employed to evaluate the mechanical sensitivity and cold sensitivity of rats. Another two groups, Sham+TMP and SNI+TMP, were used to intubate the common jugular vein and implant microdialysis probes into the anterior cingulate gyrus(ACC), respectively.After intraperitoneal injection of TMP at a dose of 80 mg·kg~(-1), automatic blood collection and intracerebral microdialysis(perfusion rate of 1 µL·min~(-1)) systems were used to collect the blood and brain dialysate for 24 h. HSS T3 C_(18) reversed-phase chromatographic column(2.1 mm×50 mm, 2.5 µm) was used for liquid chromatographic separation. Gradient elution was carried out with the mobile phase of methanol-water(containing 0.005% formic acid) at a flow rate of 0.25 mL·min~(-1). Electrospray ion source was used for mass spectrometry, and the scanning mode was multi-reaction monitoring under the positive ion mode. The ion pairs for quantitative analysis were TMP m/z 137/122 and aspirin m/z 179/137, respectively. DAS 2.11 was used to calculate the pharmacokinetic parameters. The optimal time of TMP to exert the analgesia effect and inhibit cold pain sensitivity was 60 min after treatment. The TMP in the plasma and brain dialysate of SNI rats showed the T_(max) of 15 min and 30 min, the C_(max) of(2 866.43±135.39) and(1 462.14±197.38) µg·L~(-1), the AUC_(0-t) of(241 463.30±28 070.31) and(213 115.62±32 570.07) µg·min·L~(-1), the MRT_(0-t) of(353.13±47.73) and(172.16±12.72) min, and the CL_Z of 0.73 and 0.36 L·min·kg~(-1), respectively. The analgesic effect of TMP had a significant correlation with the blood drug concentration in the ACC, which indicated that this method was suitable for the detection of TMP in rat plasma and brain dialysate. The method is accurate, reliable, and sensitive and can realize the important value of the application of correlation analysis theory of "automatic blood collection-microdialysis/PK-PD" in the research on neuropathic pain.

Phytochemical, Pharmacological, and Molecular Docking Study of Dry Extracts of Matricaria discoidea DC. with Analgesic and Soporific Activities.

Pineapple weed (Matricaria discoidea DC.) is a widespread plant in Europe and North America. In ethnomedicine, it is well-known for its anti-inflammatory and spasmolytic activities. The aim of this research was to develop novel methods of M. discoidea processing to obtain essential oil and dry extracts and to investigate their phytochemical compositions. Moreover, the molecular docking of the main substances and the in vivo studies on their soporific and analgesic activities were conducted. The essential oil and two dry extracts from M. discoidea were prepared. A total of 16 phenolic compounds (seven flavonoids, seven hydroxycinnamic acids, and two phenolic acids) in the dry extracts were identified by means of UPLC-MS/MS. In the essential oil, nine main terpenoids were identified by gas chromatography (GC). It was shown that phenolic extraction from the herb was successful when using 70% ethanol in a triple extraction method and at a ratio of 1:14-1:16. The in vivo studies with rodents demonstrated the analgesic activity of the M. discoidea extracts and improvements in the sleep of animals. The dry extracts of M. discoidea did not show any toxicity. The molecular docking analysis showed a high probability of COX-1,2 inhibition and NMDA receptor antagonism by the extracts.

Chemical composition and potential antioxidant, anti-inflammatory, and analgesic efficacy of Cistus albidus L.

This study aims to assess the chemical composition of the aqueous extract of Cistus albidus L. leaves, as well as the potential of aqueous and hydroethanol extracts of the leaves and seeds as analgesic, anti--inflammatory, and antioxidant agents. The contents of phenolics and inorganic constituents were determined in C. albidus seeds and leaves; antioxidant capacity was assessed by 3 complementary and diverse tests. The carrageenan-induced paw edema technique was used to investigate the anti-inflammatory effect in vivo, and albumin denaturation to evaluate the anti-inflammatory effect in vitro. The acetic acid-induced contortion test, the tail-flick test, and the plantar test were used to assess the analgesic effi cacy in vivo. Chemical analysis was performed by UPLC-MS/MS to quantify several phenolic compounds including catechin (1,627.6 mg kg-1), quercitrin (1,235.8 mg kg-1) and gallic acid (628. 2 mg kg-1). The ICP analysis revealed that potassium and calcium were the main inorganic components in the seeds and leaves of C. albidus. The hydroethanolic extract of the leaves showed the highest content of polyphenols/flavonoids, whereas the highest value of proantho cyanidins was detected in the aqueous extract of the seeds. All extracts showed potent antioxidant activity related to different phenolic compounds (quercetin, gallic acid, astragalin, catechin, and rutin). The aqueous extract of the leaves strongly inhibited paw edema (76.1 %) after 6 h of treatment and showed maximal inhibition of protein denaturation (191.0 µg mL-1 for 50 % inhibition) and analgesic activity in different nociceptive models. The presented data reveal that C. albidus extracts potentially show antioxidant, anti-inflammatory, and analgesic activities that could confirm the traditional use of this plant.

Exploring the impact of seasonal variations on the chemical composition, antinociceptive, and anti-inflammatory properties of Pogostemon heyneanus Benth. essential oil.

Background: Pogostemon heyneanus leaves infusions are relevant in ethnopharmacology for treating colds, coughs, headaches, and asthma. Purpose: The essential oil chemical composition of a Pogostemon heyneanus specimen was monthly monitored from October 2021 to July 2022 to evaluate the climatic influences on its yield and chemical composition and antinociceptive, andanti-inflammatory properties. Methods: The leaves, collected monthly over a 10-month period, were submitted to hydrodistillation. The oils obtained were analyzed by gas chromatography coupled to a mass spectrometer and gas chromatography coupled to flame ionization detector. The P. heyneanus essential oil (PhEO) was tested in vivo to evaluate its peripheral analgesic actions through the abdominal writhing test induced by acetic acid, and peripheral analgesia by tail immersion. Neurogenic and inflammatory pain were evaluated by formalin test, and acute oral toxicity of the oil was also verified. Results: PhEO presented 27 chemical constituents with the highest predominance of patchoulol (43.6%-76.9%), α-bulnesene (0.2%-12.7%), α-guaiene (0.4%-8.9%), seychellene (3.8%-5.1%) and pogostol (0.0%-8.2%). The climatic parameters insolation, humidity, rainfall, and temperature did not influence the essential oil yield or the main chemical constituents, except for pogostol, which presented a strong (r = 0.73) and statistically significant (p < 0.05) correlation with temperature. PhEO did not display toxicity at the maximum 300 mg/kg dosage. The oil showed low peripheral and central analgesic action at 100 mg/kg, while in the neurogenic and inflammatory pain inhibition tests, no actions related to PhEO were observed. In the carrageenan-induced peritonitis test, PhEO did not reduce the migration of leukocytes to the peritoneal cavity compared to the control group. Conclusion: Pogostemon heyneanus is a resistant plant to seasonal influences and a source of patchoulol. Despite ethnopharmacological indications, no in-vivo biological activities such as neurogenic or inflammatory pain were identified in the present work. So, the low influence of the climatic parameters on chemical composition can infer that the low pharmacological activity is also not subject to climatic variations, that is, it does not change due to the climate.

Phytochemical, Technological, and Pharmacological Study on the Galenic Dry Extracts Prepared from German Chamomile (Matricaria chamomilla L.) Flowers.

Galenic preparations of German chamomile are used to treat mild skin diseases, inflammation, and spasms, and they have also been reported to have anxiolytic and sedative effects. The medicinal use of chamomile is well known in ethnomedicine. After obtaining its galenic preparations, there is lots of waste left, so it is expedient to develop waste-free technologies. The aims of this study were to gain knowledge of the ethnomedical status of chamomile in the past and present, develop methods for preparing essential oils and dry extracts from German chamomile flowers using complex processing, reveal the phytochemical composition of such extracts, and verify the analgesic and soporific activity of the extracts. Two methods for the complex processing of German chamomile flowers were developed, which allowed us to obtain the essential oil and dry extracts of the tincture and aqueous extracts as byproducts. A total of 22 phenolic compounds (7 hydroxycinnamic acids, 13 flavonoids, and 2 phenolic acids) were found in the dry extracts by using UPLC-MS/MS. In total, nine main terpenoids were identified in the chamomile oil, which is of the bisabolol chemotype. During the production of chamomile tincture, a raw material-extractant ratio of 1:14-1:16 and triple extraction are recommended for its highest yield. In in vivo studies with mice and rats, the extracts showed analgesic activity and improvements in sleep. The highest sedative and analgesic effects in rodents were found with the dry extract prepared by using a 70% aqueous ethanol solution for extraction at a dose of 50 mg/kg. The developed methods for the complex processing of German chamomile flowers are advisable for implementation into the pharmaceutical industry to reduce the volume of waste during the production of its essential oil and tincture, and to obtain new products.

Structurally diverse analgesic diterpenoids from the flowers of Rhododendron molle.

Thirteen diterpenoids (1-13), classified into four structurally diverse carbon skeletons, including 1,5-seco-kalmane (1 and 6), grayanane (2-11), kalmane (12), and rhodomollane (13), were isolated from the flowers extract of Rhododendron molle. Among them, rhodomollinols A - E (1-5) were five new diterpenoids and their structures were elucidated by extensive spectroscopic methods including HRESIMS, UV, IR, 1D and 2D NMR, as well as quantum ECD calculations. Rhodomollinol A (1) is the first representative of a 6-deoxy-1,5-seco-kalmane diterpenoid. The abnormal NMR phenomenon of the presence of only 9 carbon resonances instead of 20 carbons in the 13C NMR spectrum of 1 was observed and elucidated by the quantum NMR calculations. All diterpenoids 1-13 showed significant analgesic activities in an acetic acid-induced writhing model. It's the first time to report the analgesic activity of a rhodomollane-type diterpenoid. At a dose of 1.0 mg/kg, diterpenoids 1-3, 6, 8, 9, and 12 reduced the writhe numbers with inhibition rates over 50%, and 9 exhibited stronger analgesic activity with a writhe inhibition rate of 89.7% than that of the positive control morphine. Importantly, even at the lowest dose of 0.04 mg/kg, rhodomollinols A (1) and B (2), rhodomollein X (7), and 2-O-methylrhodojaponin VI (9) still showed more potent analgesic effects than morphine with the writhe inhibition rates of 51.8%, 48.0%, 61.7%, and 60.0%, respectively. A preliminary structure-activity relationship might provide some clues to design potential analgesics on the basis of structurally diverse Ericaceae diterpenoids.

Discovery of highly functionalized grayanane diterpenoids from the flowers of Rhododendron molle as potent analgesics.

A systematical investigation on the chemical constituents of the flowers of Rhododendron molle (Ericaceae) led to the isolation and characterization of thirty-eight highly functionalized grayanane diterpenoids (1-38), including twelve novel analogues molleblossomins A-L (1-12). Their structures were elucidated by comprehensive methods, including 1D and 2D NMR analysis, calculated ECD, 13C NMR calculations with DP4+ probability analysis, and single crystal X-ray diffraction. Molleblossomins A (1), B (2), and E (5) are the first representatives of 2ß,3ß:9ß,10ß-diepoxygrayanane, 2,3-epoxygrayan-9(11)-ene, and 5,9-epoxygrayan-1(10),2(3)-diene diterpenoids, respectively. Molleblossomins G (7) and H (8) represent the first examples of 1,3-dioxolane-grayanane conjugates furnished with the acetaldehyde and 4-hydroxylbenzylidene acetal moieties, respectively. All grayanane diterpenoids 1-38 were screened for their analgesic activities in the acetic acid-induced writhing model, and all of them exhibited significant analgesic activities. Diterpenoids 6, 13, 14, 17, 20, and 25 showed more potent analgesic effects than morphine at a lower dose of 0.2 mg/kg, with the inhibition rates of 51.4%, 68.2%, 94.1%, 66.9%, 97.7%, and 60.0%, respectively. More importantly, even at the lowest dose of 0.04 mg/kg, rhodomollein X (14), rhodojaponin VI (20), and rhodojaponin VII (22) still significantly reduced the number of writhes in the acetic acid-induced pain model with the percentages of 61.7%, 85.8%, and 64.6%, respectively. The structure-activity relationship was summarized and might provide some hints to design novel analgesics based on the functionalized grayanane diterpenoids.

Exploring the therapeutic potential of Prinsepia utilis Royle seed oil: A comprehensive study on chemical composition, physicochemical properties, anti-inflammatory, and analgesic activities.

ETHNOPHARMACOLOGICAL RELEVANCE: Prinsepiautilis (PU) Royle, native to the Himalayan region, is a deciduous thorny shrub with numerous traditional uses of its roots, leaves and seeds for treatment of conditions such as rheumatic pain, joint pain, arthritis, and inflammation. AIM OF THE STUDY: Keeping in mind the growing demand of products of natural origin as alternate medicine, the present study was undertaken to scientifically validate for the first time the traditional claims of healing pain and inflammation by evaluating the fatty oil isolated from the seeds using established in vitro and in vivo models. MATERIALS AND METHODS: PU Seeds were Soxhlet extracted using n-hexane and fatty oil was isolated. Chemical composition of the oil was established with the aid of Gas Chromatography-Flame Ionization Detection (GC-FID) and Gas Chromatography-Mass Spectrometry (GC-MS). The oil was then subjected to in vitro anti-inflammatory activity by following the established protocols of trypsin inhibitory and bovine serum albumin denaturation assays. The acute toxicity of the oil was also studied using OECD guidelines 423. The anti-inflammatory property of the oil was further evaluated using carrageenan-induced and formalin-induced edema in the rat paw. Moreover, hot plate latency and tail immersion assay were employed to evaluate analgesic activity of the oil. To establish the quality of the oil, various physicochemical properties were also studied. RESULTS: GC-FID and GC-MS analysis of the oil revealed the presence of linoleic acid (59.06 ± 0.00%), oleic acid (28.11 ± 0.01%), palmitic acid (9.51 ± 0.01%) and stearic acid (3.32 ± 0.01%). In vitro trypsin inhibitory and bovine serum albumin denaturation assay revealed dose-dependent notable activity of the oil with IC50 value of 63.57 µg/mL and 518.14 µg/mL, respectively. The physico-chemical characterization demonstrated that the oil possesses a low acidity and a high oxidative stability index. The oil was found to be non-toxic and displayed effective anti-inflammatory activities with significant inhibition till 4 h in carrageenan-induced and formalin-induced rat paw edema at maximum tested dose of 200 mg/kg b.w. The oil also exhibited significant results in hot plate latency and tail immersion assay with positive effects showing up to 4 h after dose administration. CONCLUSION: These findings, besides supporting the traditional claims, suggest that P. utilis seed oil has potential therapeutic applications as a natural anti-inflammatory and analgesic agent. Further studies are warranted to explore its mechanisms of action and potential use in pharmaceutical and nutraceutical industries.

Analgesic effect of Centaurium erythraea and molecular docking investigation of the major component swertiamarin.

Centaurium erythraea Rafn is employed in Algerian traditional medicine for treating pain. The analgesic activity of the ethanolic extract (EE) from the flowering aerial parts of this plant was examined, and molecular docking of the main bioactive compound was performed. The EE, characterised by the iridoid swertiamarin, was administered to Wistar albino rats in pain models. Peripheral analgesic activity was evaluated using the acetic acid-induced writhing test, and a hot plate test was performed for central antinociceptive activity evaluation. Treatment with EE significantly decreased rats' writhing induced by acetic acid suggesting peripheral analgesic activity. Furthermore, the elevation of mean basal reaction time in the hot plate method indicated central analgesic activity. Molecular docking studies showed good docking energy with acceptable binding interactions of swertiamarin with cyclooxygenase-2 protein. This supports the analgesic activity of C. erythraea EE, justifying the traditional use of the plant as an analgesic herbal remedy.

Comprehensive Analysis of the Chemical and Bioactivity Profiles of Endemic Crataegus turcicus Dönmez in Comparison with Other Crataegus Species.

Crataegus turcicus is a plant endemic to Türkiye. For the first time, this study aimed to comparatively assess its flower-bearing branches, leaves, and fruits with other well-known Crataegus species (C. monogyna, C. pentagyna, and C. orientalis) in terms of chemical composition and bioactivity studies to evaluate its potential use as a food supplement. Firstly, the contents of total phenolics (TPC), flavonoids (TFC), proanthocyanidin (TPAC), and anthocyanin (TAC) in different plant parts of Crataegus species were evaluated. The highest TPAC was found in the hydroalcoholic extract of C. turcicus flower-bearing branches. Moreover, all plant parts had comparatively higher amounts of TPC, TFC, and TAC compared to other Crataegus species. The chemical screening by high-performance thin-layer chromatography (HPTLC) resulted that C. turcicus parts were rich with chlorogenic acid, neochlorogenic acid, quercetin and vitexin derivatives, epicatechin, procyanidin, etc., and their quantities were evaluated by high-performance liquid chromatography (HPLC). In terms of several in vitro antioxidant activity outcomes, the flower-bearing branches of C. turcicus showed the highest antioxidant activity by a 2,2-diphenyl-1-picrylhydrazyl (DPPH) test among the assessed antioxidant assays. Additionally, hydroalcoholic extracts of C. turcicus significantly decreased LPS-induced nitric oxide, tumor necrosis factor-alpha, and interleukin-6 production more potently than indomethacin (positive control). In addition to its remarkable anti-inflammatory activity, C. turcicus showed analgesic activity by reducing prostaglandin E2 levels.

Identification of Protein Quality Markers in Toad Venom from Bufo gargarizans.

Toad venom is a traditional Chinese medicine with high medicinal value. The existing quality evaluation standards of toad venom have obvious limitations because of the lack of research on proteins. Thus, it is necessary to screen suitable quality markers and establish appropriate quality evaluation methods for toad venom proteins to guarantee their safety and efficacy in clinical applications. SDS-PAGE, HPLC, and cytotoxicity assays were used to analyze differences in protein components of toad venom from different areas. Functional proteins were screened as potential quality markers by proteomic and bioinformatic analyses. The protein components and small molecular components of toad venom were not correlated in content. Additionally, the protein component had strong cytotoxicity. Proteomics analysis showed that 13 antimicrobial proteins, four anti-inflammatory and analgesic proteins, and 20 antitumor proteins were differentially expressed extracellular proteins. A candidate list of functional proteins was coded as potential quality markers. Moreover, Lysozyme C-1, which has antimicrobial activity, and Neuropeptide B (NPB), which has anti-inflammatory and analgesic activity, were identified as potential quality markers for toad venom proteins. Quality markers can be used as the basis of quality studies of toad venom proteins and help to construct and improve safe, scientific, and comprehensive quality evaluation methods.

Voltage-gated sodium channels, potential targets of Tripterygium wilfordii Hook. f. to exert activity and produce toxicity.

ETHNOPHARMACOLOGY RELEVANCE: Tripterygium wilfordii Hook. f. has been widely used in clinical practice due to its good anti-inflammatory and analgesic activities. However, its application is limited by potential toxicity and side effects. AIM OF THE STUDY: The study aimed to identify the mechanisms responsible for the pharmacological activity and cardiotoxicity of the main monomers of Tripterygium wilfordii. MATERIALS AND METHODS: Database analysis predicted that ion channels may be potential targets of Tripterygium wilfordii. The regulatory effects of monomers (triptolide, celastrol, demethylzeylasteral, and wilforgine) on protein Nav1.5 and Nav1.7 were predicted and detected by Autodock and patch clamping. Then, we used the formalin-induced pain model and evaluated heart rate and myocardial zymograms to investigate the analgesic activity and cardiotoxicity of each monomer in vivo. RESULTS: All four monomers were able to bind to Nav1.7 and Nav1.5 with different binding energies and subsequently inhibited the peak currents of both Nav1.7 and Nav1.5. The monomers all exhibited analgesic effects on formalin-induced pain; therefore, we hypothesized that Nav1.7 is one of the key analgesic targets. Demethylzeylasteral reduced heart rate and increased the level of creatine kinase-MB, thus suggesting a potential cardiac risk; data suggested that the inhibitory effect on Nav1.5 might be an important factor underlying its cardiotoxicity. CONCLUSION: Our findings provide an important theoretical basis for the further screening of active monomers with higher levels of activity and lower levels of toxicity.

Integrating in vivo and in silico approaches to investigate the potential of Zingiber roseum rhizome extract against pyrexia, inflammation and pain.

Zingiber roseum is a perennial herb in the Zingiberaceae family. The plant is native to Bangladesh, and rhizomes are frequently used in traditional medicine to cure gastric ulcers, asthma, wounds, and rheumatic disorders. Therefore, the present study aimed to analyse the antipyretic, anti-inflammatory, and analgesic properties of Z. roseum rhizome to confirm its efficacy in traditional applications. After 24 h of treatment, ZrrME (400 mg/kg) showed a considerable drop in rectal temperature (3.42°F) compared to standard paracetamol (5.26°F). At both doses (200 and 400 mg/kg), ZrrME showed a substantial dose-dependent decrease in paw oedema. However, after 2, 3 and 4 h of testing, the extract (200 mg/kg) had a lower anti-inflammatory response than standard indomethacin, whereas the higher dose (400 mg/kg) of rhizome extract had a more robust response compared to standard. ZrrME also showed substantial analgesic activity against all in vivo analgesic test models. The in vivo findings were further evaluated by in silico study of our previously identified compounds of ZrrME with the cyclooxygenase-2 enzyme (3LN1). The substantial binding energy (ranges from-6.2 to-7.7 Kcal/mol) of the polyphenols (excluding catechin hydrate) to the COX-2 enzyme affirm the in vivo test results of the present studies. In addition, the compounds were found effective as antipyretic, anti-inflammatory, and analgesic agents, according to the biological activity prediction software. Both in vivo and in silico results demonstrated promising antipyretic, anti-inflammatory, and pain-relieving effects of Z. roseum rhizome extract, which corroborate the claim of its traditional uses.

Structurally modified Cyclovirobuxine-D Buxus alkaloids as effective analgesic agents through Cav3.2 T-Type calcium channel inhibition.

Cyclovirobuxine-D (CVB-D) is a Buxus alkaloid and a major active constituent in the Chinese medicinal herb Buxus microphylls. Traditionally, the natural alkaloid cyclovirobuxine-D has a long history of use as a traditional Chinese medicine for cardiovascular diseases as well as to treat a wide variety of medical conditions. As we found that CVB-D inhibited T-type calcium channels, we designed and synthesized a variety of fragments and analogues and evaluated them for the first time as new Cav3.2 inhibitors. Compounds 2-7 exhibited potency against Cav 3.2 channels, and two of them were more active than their parent molecules. As a result of the in vivo experiments, both compounds 3 and 4 showed significantly reduced writhes in the acetic acid-induced writhing test. Studies of molecular modeling have identified possible mechanism(s) of Cav3.2 binding. Moreover, the relationship between structure and activity was studied in a preliminary manner. Our results indicated that compounds 3 and 4 could play an important role in the discovery and development of novel analgesics.

Extracts of Brocchia cinerea (Delile) Vis Exhibit In Vivo Wound Healing, Anti-Inflammatory and Analgesic Activities, and Other In Vitro Therapeutic Effects.

The plant Brocchia cinerea (Delile) (B. cinerea) has many uses in traditional pharmacology. Aqueous (BCAE) and ethanolic extracts (BCEE) obtained from the aerial parts can be used as an alternative to some synthetic drugs. In vitro, DPPH, FRAP and TAC are three tests used to measure antioxidant efficacy. Antibacterial activities were determined against one Gram positive and two Gram negative strains of bacteria. The analgesic power was evaluated in vivo using the abdominal contortion model in mice, while carrageenan-induced edema in rats was the model chosen for the anti-inflammatory test; wound healing was evaluated in an experimental second degree burn model. The results of the phytochemical analysis showed that BCEE had the greatest content of polyphenols (21.06 mg AGE/g extract), flavonoids (10.43 mg QE/g extract) and tannins (24.05 mg TAE/g extract). HPLC-DAD reveals the high content of gallic acid, quercetin and caffeic acid in extracts. BCEE has a strong antiradical potency against DPPH (IC50 = 0.14 mg/mL) and a medium iron reducing activity (EC50 = 0.24 mg/mL), while BCAE inhibited the growth of the antibiotic resistant bacterium, P. aeruginosa (MIC = 10 mg/mL). BCAE also exhibited significant pharmacological effects and analgesic efficacy (55.81% inhibition 55.64% for the standard used) and the re-epithelialization of wounds, with 96.91% against 98.60% for the standard. These results confirm the validity of the traditional applications of this plant and its potential as a model to develop analogous drugs.

In Vivo and In Silico Analgesic Activity of Ficus populifolia Extract Containing 2-O-ß-D-(3',4',6'-Tri-acetyl)-glucopyranosyl-3-methyl Pentanoic Acid.

Natural product-based structural templates have immensely shaped small molecule drug discovery, and new biogenic natural products have randomly provided the leads and molecular targets in anti-analgesic activity spheres. Pain relief achieved through opiates and non-steroidal anti-inflammatory drugs (NSAIDs) has been under constant scrutiny owing to their tolerance, dependency, and other organs toxicities and tissue damage, including harm to the gastrointestinal tract (GIT) and renal tissues. A new, 3',4',6'-triacetylated-glucoside, 2-O-ß-D-(3',4',6'-tri-acetyl)-glucopyranosyl-3-methyl pentanoic acid was obtained from Ficus populifolia, and characterized through a detailed NMR spectroscopic analysis, i.e., 1H-NMR, 13C-DEPT-135, and the 2D nuclear magnetic resonance (NMR) correlations. The product was in silico investigated for its analgesic prowess, COX-2 binding feasibility and scores, drug likeliness, ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, possible biosystem's toxicity using the Discovery Studio®, and other molecular studies computational software programs. The glycosidic product showed strong potential as an analgesic agent. However, an in vivo evaluation, though at strong levels of pain-relieving action, was estimated on the compound's extract owing to the quantity and yield issues of the glycosidic product. Nonetheless, the F. populifolia extract showed the analgesic potency in eight-week-old male mice on day seven of the administration of the extract's dose in acetic acid-induced writhing and hot-plate methods. Acetic acid-induced abdominal writhing for all the treated groups decreased significantly (p < 0.0001), as compared to the control group (n = 6) by 62.9%, 67.9%, and 70.9% of a dose of 100 mg/kg (n = 6), 200 mg/kg (n = 6), and 400 mg/kg (n = 6), respectively. Similarly, using the analgesia meter, the reaction time to pain sensation increased significantly (p < 0.0001), as compared to the control (n = 6). The findings indicated peripheral and central-nervous-system-mediated analgesic action of the product obtained from the corresponding extract.

Neuropharmacological Effects in Animal Models and HPLC-Phytochemical Profiling of Byrsonima crassifolia (L.) Kunth Bark Extracts.

B. crassifolia is a species that grows in various areas of Latin America. It was known to be useful for the treatment of different human ailments. The present work evaluated the neuropharmacological and analgesic effects of hydroalcoholic and dichloromethane extracts of B. crassifolia. The effect on the central nervous system (CNS) of both extracts obtained from bark, administered by the intraperitoneal route in mice, was evaluated by different tests: spontaneous motor activity, hole-board, motor coordination, pentobarbital induced hypnosis, and rectal temperature. Analgesic activity was evaluated using a hot plate test. Phytochemical analysis was performed by high-performance liquid chromatography (HPLC) using reversed-phase and gradient of elution. The hydroalcoholic extract (dose 0.5 g dry plant/kg weigh) administration caused an important reduction of the head-dipping response in the hole board test. A decrease in spontaneous motor activity test and a disturbance of motor coordination in the rotarod test was observed. The hydroalcoholic extract produced a significant prolongation of pentobarbital induced sleeping time. This extract prevented hot plate test induced nociception. The phytochemical analysis revealed the presence of catechin, epicatechin, and procyanidin B12. Therefore, this study revealed that the hydroalcoholic extract of B. crassifolia possesses analgesic and sedative CNS activity.

Design, Synthesis and Biological Evaluation of Novel N-Alkyl-4-Methyl-2,2- Dioxo-1H-2λ6,1-Benzothiazine-3-Carboxamides as Promising Analgesics.

INTRODUCTION: An analysis of the literature on the painkillers long used in traditional medicine, which are isolated from plant materials, has shown that many of them are alkylamides of various carboxylic acids. This fact served as the basis for the study of a large group of N-alkyl-4- methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides as potential new analgesics. The objects of the study were synthesized in the traditional way involving the initial conversion of 4-methyl- 2,2-dioxo-1H-2λ6,1- benzothiazine-3-carboxylic acid to imidazolide, in which imidazolide was used as an acylating agent. The method is simple to implement and, as a rule, gives high yields of final alkylamides. However, in reaction with sterically hindered tert-butylamine, along with the "normal" product, an unexpected formation of N-tert-butyl-4-methyl-1-(4-methyl-2,2-dioxo-1H-2λ6,1- benzothiazine-3-carbonyl)-2,2-dioxo-2λ6,1-benzothiazine-3-carboxamide was observed, which was characterized by X-ray diffraction analysis as a monosolvate with N,N-dimethylformamide. These synthetic problems can be avoided using a more powerful acylating agent, 4-methyl-2,2-dioxo-1H- 2λ6,1- benzothiazine-3-carbonyl chloride. BACKGROUND: A large group of new N-alkyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3- carboxamides was synthesized. OBJECTIVE: On the basis of molecular docking, some derivatives of N-alkyl-4-methyl-2,2-dioxo-1H- 2λ6,1-benzothiazine-3-carboxamides have been designed. Their preliminary structure-activity relationships (SAR) have been studied. The most rational approaches to the synthesis of lead compounds have been developed. The most active compounds have shown high anti-inflammatory and analgesic activities. METHODS: The structure of all compounds prepared has been confirmed by the data of elemental analysis, 1H- and 13C NMR spectroscopy, and electrospray ionization liquid chromato-mass spectrometry. For rational drug design, optimization of further pharmacological screening and prediction of a possible mechanism of pharmacological action, molecular docking has been performed. For the determination of activity, pharmacological studies have been carried out. RESULTS: Pharmacological tests have determined that the transition from N-aryl(heteroaryl) alkylamides to "pure" N-alkylamides we carried out is accompanied by a significant reduction and even complete loss of anti-inflammatory effect with remaining analgesic activity. CONCLUSION: According to the studies, compounds from N-alkyl-4-methyl-2,2-dioxo-1H-2λ6,1- benzothiazine-3-carboxamides are potential anti-inflammatory and analgesic agents.

Fimbristylis aestivalis Vahl: a potential source of cyclooxygenase-2 (COX-2) inhibitors.

Cyclooxygenase-2 (COX-2) is an inducible enzyme that accelerates the biosynthesis of PGs during inflammation and has emerged as an important therapeutic target for anti-inflammatory drugs. Natural compounds may serve as a source of inspiration for pharmaceutical chemists and a foundation for developing innovative COX-2 inhibitors with fewer side effects. Therefore, the objective of this study was to identify the potent COX-2 inhibitor and anti-inflammatory activity of the Fimbristylis aestivalis whole plant extract (FAWE). The plant extract was found dominant with rosmarinic acid followed by catechin hydrate, syringic acid, rutin hydrate, (-) epicatechin, quercetin, myricetin, and catechol. FAWE exhibited considerable dose-dependent analgesic efficacy in all analgesic test models. FAWE also showed promising anti-inflammatory potential in carrageenan-induced inflammations in mice. This result was corroborated by molecular docking, revealing that the aforesaid natural polyphenols adopt the same orientation as celecoxib in the COX-2 active site. On the other hand, molecular dynamics (MD) simulations were performed between the most abundant components (rosmarinic acid, catechin hydrate, and syringic acid) and COX-2. Based on hydrogen bonding, RMSD, RMSF, radius of gyration, PCA, and Gibbs free energy landscape analysis, the results demonstrated that these compounds are very stable in the active site of COX-2, indicating substantial COX-2 inhibitory activity.

Synthesis and Investigation of the Analgesic Potential of Enantiomerically Pure Schiff Bases: A Mechanistic Approach.

Schiff bases are a class of organic compounds with azomethine moiety, exhibiting a wide range of biological potentials. In this research, six chiral Schiff bases, three 'S' series (H1−H3) and three 'R' series (H4−H6), were synthesized. The reaction was neat, which means without a solvent, and occurred at room temperature with a high product yield. The synthesized compounds were evaluated for analgesic potential in vivo at doses of 12.5 and 25 mg/kg using acetic-acid-induced writhing assay, formalin test, tail immersion and hot plate models, followed by investigating the possible involvement of opioid receptors. The compounds H2 and H3 significantly (*** p < 0.001) reduced the writhing frequency, and H3 and H5 significantly (*** p < 0.001) reduced pain in both phases of the formalin test. The compounds H2 and H5 significantly (*** p < 0.001) increased latency at 90 min in tail immersion, while H2 significantly (*** p < 0.001) increased latency at 90 min in the hot plate test. The 'S' series Schiff bases, H1−H3, were found more potent than the 'R' series compounds, H4−H6. The possible involvement of opioid receptors was also surveyed utilizing naloxone in tail immersion and hot plate models, investigating the involvement of opioid receptors. The synthesized compounds could be used as alternative analgesic agents subjected to further evaluation in other animal models to confirm the observed biological potential.