Ultramicronized N-palmitoylethanolamine associated with analgesics: Effects against persistent pain.

Current epidemiological data estimate that one in five people suffers from chronic pain with considerable impairment of health-related quality of life. The pharmacological treatment is based on first- and second-line analgesic drugs, including COX-2 selective and nonselective nonsteroidal anti-inflammatory drugs, paracetamol, antidepressants, anti-seizure drugs and opioids, that are characterized by important side effects. N-palmitoylethanolamine (PEA) is a body's own fatty-acid ethanolamide belonging to the family of autacoid local injury antagonist amides. The anti-inflammatory and pain-relieving properties of PEA have been recognized for decades and prompted to depict its role in the endogenous mechanisms of pain control. Together with its relative abundance in food sources, this opened the way to the use of PEA as a pain-relieving nutritional intervention. Naïve PEA is a large particle size lipid molecule with low solubility and bioavailability. Reducing particle size is a useful method to increase surface area, thereby improving dissolution rate and bioavailability accordingly. Micron-size formulations of PEA (e.g., ultramicronized and co-(ultra)micronized) have shown higher oral efficacy compared to naïve PEA. In particular, ultramicronized PEA has been shown to efficiently cross the intestinal wall and, more importantly, the blood-brain and blood-spinal cord barrier. Several preclinical and clinical studies have shown the efficacy, safety and tolerability of ultramicronized PEA. This narrative review summarizes the available pharmacokinetic/pharmacodynamic data on ultramicronized PEA and focuses to its contribution to pain control, in particular as 'add-on' nutritional intervention. Data showing the ability of ultramicronized PEA to limit opioid side effects, including the development of tolerance, have also been reviewed.

Ultramicronized N-palmitoylethanolamine Contributes to Morphine Efficacy Against Neuropathic Pain: Implication of Mast Cells and Glia.

BACKGROUND: In the current management of neuropathic pain, in addition to antidepressants and anticonvulsants, the use of opioids is wide, despite their related and well-known issues. OBJECTIVE: N-palmitoylethanolamine (PEA), a natural fatty-acid ethanolamide whose anti-inflammatory, neuroprotective, immune-modulating and anti-hyperalgesic activities are known, represents a promising candidate to modulate and/or potentiate the action of opioids. METHODS: This study was designed to evaluate if the preemptive and morphine concomitant administration of ultramicronized PEA, according to fixed or increasing doses of both compounds, delays the onset of morphine tolerance and improves its analgesic efficacy in the chronic constriction injury (CCI) model of neuropathic pain in rats. RESULTS: Behavioral experiments showed that the preemptive and co-administration of ultramicronized PEA significantly decreased the effective dose of morphine and delayed the onset of morphine tolerance. The activation of spinal microglia and astrocytes, commonly occurring both on opioid treatment and neuropathic pain, was investigated through GFAP and Iba-1 immunofluorescence. Both biomarkers were found to be increased in CCI untreated or morphine treated animals in a PEA-sensitive manner. The increased density of endoneural mast cells within the sciatic nerve of morphine-treated and untreated CCI rats was significantly reduced by ultramicronized PEA. The decrease of mast cell degranulation, evaluated in terms of reduced plasma levels of histamine and N-methyl-histamine metabolite, was mainly observed at intermediate-high doses of ultramicronized PEA, with or without morphine. CONCLUSION: Overall, these results show that the administration of ultramicronized PEA in CCI rats according to the study design fully fulfilled the hypotheses of this study.

Transcriptome analysis reveals genes associated with stem cell activation by physical exercise in the dentate gyrus of aged p16Ink4a knockout mice.

Throughout adulthood neural stem cells divide in neurogenic niches-the dentate gyrus of the hippocampus and the subventricular zone-producing progenitor cells and new neurons. Stem cells self-renew, thus preserving their pool. Furthermore, the number of stem/progenitor cells in the neurogenic niches decreases with age. We have previously demonstrated that the cyclin-dependent kinase inhibitor p16Ink4a maintains, in aged mice, the pool of dentate gyrus stem cells by preventing their activation after a neurogenic stimulus such as exercise (running). We showed that, although p16Ink4a ablation by itself does not activate stem/progenitor cells, exercise strongly induced stem cell proliferation in p16Ink4a knockout dentate gyrus, but not in wild-type. As p16Ink4a regulates stem cell self-renewal during aging, we sought to profile the dentate gyrus transcriptome from p16Ink4a wild-type and knockout aged mice, either sedentary or running for 12 days. By pairwise comparisons of differentially expressed genes and by correlative analyses through the DESeq2 software, we identified genes regulated by p16Ink4a deletion, either without stimulus (running) added, or following running. The p16Ink4a knockout basic gene signature, i.e., in sedentary mice, involves upregulation of apoptotic, neuroinflammation- and synaptic activity-associated genes, suggesting a reactive cellular state. Conversely, another set of 106 genes we identified, whose differential expression specifically reflects the pattern of proliferative response of p16 knockout stem cells to running, are involved in processes that regulate stem cell activation, such as synaptic function, neurotransmitter metabolism, stem cell proliferation control, and reactive oxygen species level regulation. Moreover, we analyzed the regulation of these stem cell-specific genes after a second running stimulus. Surprisingly, the second running neither activated stem cell proliferation in the p16Ink4a knockout dentate gyrus nor changed the expression of these genes, confirming that they are correlated to the stem cell reactivity to stimulus, a process where they may play a role regulating stem cell activation.

Label-free electrochemical immunosensor as a reliable point-of-care device for the detection of Interleukin-6 in serum samples from patients with psoriasis.

Interleukin-6 (IL-6) plays a crucial role in autoimmunity and chronic inflammation. This study aims to develop a low-cost, simple-to-manufacture, and user-friendly label-free electrochemical point-of-care device for the rapid detection of IL-6 in patients with psoriasis. Precisely, a sandwich-based format immunosensor was developed using two primary antibodies (mAb-IL6 clone-5 and clone-7) and screen-printed electrodes modified with an inexpensive recycling electrochemical enhancing material, called biochar. mAb-IL6 clone-5 was used as a covalently immobilized capture bioreceptor on modified electrodes, and mAb-IL6 clone-7 was used to recognize the immunocomplex (Anti-IL6 clone-5 and IL-6) and form the sandwich. Cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) were used to conduct electrochemical characterization of the layer-by-layer assembly of the immunosensor, while square wave voltammetry (SWV) was used to perform the sensing. The developed immunosensor demonstrated robust analytical performance in buffer solution, with a wide linear range (LR) by varying from 2 to 250 pg/mL, a good limit of detection (LOD) of 0.78 pg/mL and reproducibility (RSD<7%). In addition, a spectrophotometric ELISA kit was employed to validate the results obtained with the label-free device by analyzing twenty-five serum samples from control and patients affected by psoriasis. A strong correlation in terms of pg/mL concentration of IL-6 was found comparing the two methods, with the advantage for our label-free biosensor of an ease use and a quicker detection time. Based on IL-6 levels, the proposed immunosensor is a dependable, non-invasive screening device capable of predicting disease onset, progression, and treatment efficacy.

Anti-Hyperalgesic Efficacy of Acetyl L-Carnitine (ALCAR) Against Visceral Pain Induced by Colitis: Involvement of Glia in the Enteric and Central Nervous System.

The management of abdominal pain in patients affected by inflammatory bowel diseases (IBDs) still represents a problem because of the lack of effective treatments. Acetyl L-carnitine (ALCAR) has proved useful in the treatment of different types of chronic pain with excellent tolerability. The present work aimed at evaluating the anti-hyperalgesic efficacy of ALCAR in a model of persistent visceral pain associated with colitis induced by 2,4-dinitrobenzene sulfonic acid (DNBS) injection. Two different protocols were applied. In the preventive protocol, ALCAR was administered daily starting 14 days to 24 h before the delivery of DNBS. In the interventive protocol, ALCAR was daily administered starting the same day of DNBS injection, and the treatment was continued for 14 days. In both cases, ALCAR significantly reduced the establishment of visceral hyperalgesia in DNBS-treated animals, though the interventive protocol showed a greater efficacy than the preventive one. The interventive protocol partially reduced colon damage in rats, counteracting enteric glia and spinal astrocyte activation resulting from colitis, as analyzed by immunofluorescence. On the other hand, the preventive protocol effectively protected enteric neurons from the inflammatory insult. These findings suggest the putative usefulness of ALCAR as a food supplement for patients suffering from IBDs.

DDD-028: A potent, neuroprotective, non-opioid compound for the treatment of diabetic neuropathy.

Diabetic neuropathy (DN) is a painful, chronic ailment that affects a large segment of diabetic population worldwide. Current medications such as pregabalin or duloxetine treat only the pain symptom associated with DN, but not the underlying nerve damage. DDD-028 (1) is a small molecule that displays potent pain-relieving activity in streptozotocin (STZ)-induced rodent model of DN. Combined with other studies indicating that DDD-028 suppresses astrogliosis and nerve damage induced by the anti-cancer drug, paclitaxel, the present study suggests that DDD-028 would be useful as a disease modifying therapeutic in the treatment of DN. The 3-dimensional structure of DDD-028 was confirmed by single crystal X-ray crystallography.

Discovery of a novel series of potent carbonic anhydrase inhibitors with selective affinity for µ Opioid receptor for Safer and long-lasting analgesia.

In this study, we investigated the development of dual-targeted ligands that bind to both µ-opioid receptor (MOR) and carbonic anhydrase (CA) enzymes, using fentanyl structure as a template. We synthesized and evaluated 21 novel compounds with dual-targeted affinity identifying the lead candidate compound 8, showing selective affinity for MOR and potent inhibition of several cytosolic CA isoforms. By means of repeated treatment of 3 daily administrations for 17 days, fentanyl (0.1 mg/kg, subcutaneously) led to tolerance development, pain threshold alterations and withdrawal symptoms in CD-1 mice, as well as astrocyte and microglia activation in the dorsal horn of the lumbar spinal cord. In contrast, compound 8 (0.32 mg/kg s.c.) maintained stable during days its analgesic effect at the higher dose tested with fewer withdrawal symptoms, allodynia development and glial cells activation. Our results suggest that targeting both MOR and CA enzymes can lead to the development of new class of potent analgesic agents with fewer side effects and reduced tolerance development. Further studies are needed to explore the potential mechanisms underlying these effects and to further optimize the therapeutic potential of these compounds.

Neurofilament light chain in plasma as a sensitive diagnostic biomarker of peripheral neurotoxicity: In Vivo mouse studies with oxaliplatin and paclitaxel - NeuroDeRisk project.

Identifying compounds that are neurotoxic either toward the central or the peripheral nervous systems (CNS or PNS) would greatly benefit early stages of drug development by derisking liabilities and selecting safe compounds. Unfortunately, so far assays mostly rely on histopathology findings often identified after repeated-dose toxicity studies in animals. The European NeuroDeRisk project aimed to provide comprehensive tools to identify compounds likely inducing neurotoxicity. As part of this project, the present work aimed to identify diagnostic non-invasive biomarkers of PNS toxicity in mice. We used two neurotoxic drugs in vivo to correlate functional, histopathological and biological findings. CD1 male mice received repeated injections of oxaliplatin or paclitaxel followed by an assessment of drug exposure in CNS/PNS tissues. Functional signs of PNS toxicity were assessed using electronic von Frey and cold paw immersion tests (oxaliplatin), and functional observational battery, rotarod and cold plate tests (paclitaxel). Plasma concentrations of neurofilament light chain (NF-L) and vascular endothelial growth factor A (VEGF-A) were measured, and histopathological evaluations were performed on a comprehensive list of CNS and PNS tissues. Functional PNS toxicity was observed only in oxaliplatin-treated mice. Histopathological findings were observed dose-dependently only in paclitaxel groups. While no changes of VEGF-A concentrations was recorded, NF-L concentrations were increased only in paclitaxel-treated animals as early as 7 days after the onset of drug administration. These results show that plasma NF-L changes correlated with microscopic changes in the PNS, thus strongly suggesting that NF-L could be a sensitive and specific biomarker of PNS toxicity in mice.

Broad-spectrum neuroprotection exerted by DDD-028 in a mouse model of chemotherapy-induced neuropathy.

ABSTRACT: Neurotoxicity of chemotherapeutics involves peculiar alterations in the structure and function, including abnormal nerve signal transmission, of both the peripheral and central nervous system. The lack of effective pharmacological approaches to prevent chemotherapy-induced neurotoxicity necessitates the identification of innovative therapies. Recent evidence suggests that repeated treatment with the pentacyclic pyridoindole derivative DDD-028 can exert both pain-relieving and glial modulatory effects in mice with paclitaxel-induced neuropathy. This work is aimed at assessing whether DDD-028 is a disease-modifying agent by protecting the peripheral nervous tissues from chemotherapy-induced damage. Neuropathy was induced in animals by paclitaxel injection (2.0 mg kg -1 i.p). DDD-028 (10 mg kg -1 ) and the reference drug, pregabalin (30 mg kg -1 ), were administered per os daily starting concomitantly with the first injection of paclitaxel and continuing 10 days after the end of paclitaxel treatment. The behavioural tests confirmed the antihyperalgesic efficacy of DDD-028 on paclitaxel-induced neuropathic pain. Furthermore, the electrophysiological analysis revealed the capacity of DDD-028 to restore near-normal sensory nerve conduction in paclitaxel-treated animals. Histopathology evidence indicated that DDD-028 was able to counteract effectively paclitaxel-induced peripheral neurotoxicity by protecting against the loss of intraepidermal nerve fibers, restoring physiological levels of neurofilament in nerve tissue and plasma, and preventing morphological alterations occurring in the sciatic nerves and dorsal root ganglia. Overall, DDD-028 is more effective than pregabalin in preventing chemotherapy-induced neurotoxicity. Thus, based on its potent antihyperalgesic and neuroprotective efficacy, DDD-028 seems to be a viable prophylactic medication to limit the development of neuropathies consequent to chemotherapy.

Electrochemical and Structural Characterization of Lanthanum-Doped Hydroxyapatite: A Promising Material for Sensing Applications.

In the quest to find powerful modifiers of screen-printed electrodes for sensing applications, a set of rare earth-doped Ca10-xREx(PO4)6(OH)2 (RE = La, Nd, Sm, Eu, Dy, and Tm and x = 0.01, 0.02, 0.10, and 0.20) hydroxyapatite (HAp) samples were subjected to an in-depth electrochemical characterization using electrochemical impedance spectroscopy and cyclic and square wave voltammetry. Among all of these, the inorganic phosphates doped with lanthanum proved to be the most reliable, revealing robust analytical performances in terms of sensitivity, repeatability, reproducibility, and reusability, hence paving the way for their exploitation in sensing applications. Structural data on La-doped HAp samples were also provided by using different techniques, including optical microscopy, X-ray diffraction, Rietveld refinement from X-ray data, Fourier transform infrared, and Raman vibrational spectroscopies, to complement the electrochemical characterization.

Ultrasound-Stimulated PVA Microbubbles as a Green and Handy Tool for the Cleaning of Cellulose-Based Materials.

One of the main issues in the cultural heritage field of restoration chemistry is the identification of greener and more effective methods for the wet cleaning of paper artefacts, which serve as witnesses to human history and custodians of cultural values. In this context, we propose a biocompatible method to perform wet cleaning on paper based on the use of 1 MHz ultrasound in combination with water-dispersed polyvinyl alcohol microbubbles (PVAMBs), followed by dabbing with PVA-based hydrogel. This method can be applied to both old and new papers. FTIR spectroscopy, X-ray diffraction, HPLC analysis, pH measurements and tensile tests were performed on paper samples, to assess the efficacy of the cleaning system. According to the results, ultrasound-activated PVAMB application allows for an efficient interaction with rough and porous cellulose paper profiles, promoting the removal of cellulose degradation byproducts, while the following hydrogel dabbing treatment guarantees the removal of cleaning materials residues. Moreover, the results also pointed out that after the treatment no thermal or mechanical damages had affected the paper. In conclusion, the readability of these kinds of artifacts can be improved without causing an alteration of their structural properties, while mitigating the risk of ink diffusion.

Protective and Pain-Killer Effects of AMC3, a Novel N-Formyl Peptide Receptors (FPRs) Modulator, in Experimental Models of Rheumatoid Arthritis.

Rheumatoid arthritis is an autoimmune disorder that causes chronic joint pain, swelling, and movement impairment, resulting from prolonged inflammation-induced cartilage and bone degradation. The pathogenesis of RA, which is still unclear, makes diagnosis and treatment difficult and calls for new therapeutic strategies to cure the disease. Recent research has identified FPRs as a promising druggable target, with AMC3, a novel agonist, showing preclinical efficacy in vitro and in vivo. In vitro, AMC3 (1-30 µM) exhibited significant antioxidant effects in IL-1ß (10 ng/mL)-treated chondrocytes for 24 h. AMC3 displayed a protective effect by downregulating the mRNA expression of several pro-inflammatory and pro-algic genes (iNOS, COX-2, and VEGF-A), while upregulating genes essential for structural integrity (MMP-13, ADAMTS-4, and COLIAI). In vivo, AMC3 (10 mg kg-1) prevented hypersensitivity and restored postural balance in CFA-injected rats after 14 days. AMC3 attenuated joint alterations, reduced joint inflammatory infiltrate, pannus formation, and cartilage erosion. Chronic AMC3 administration reduced transcriptional changes of genes causing excitotoxicity and pain (EAATs and CCL2) and prevented morphological changes in astrocytes, including cell body hypertrophy, processes length, and thickness, caused by CFA in the spinal cord. This study demonstrates the usefulness of AMC3 and establishes the groundwork for further research.

Antinociceptive Action of Thymoquinone-Loaded Liposomes in an In Vivo Model of Tendinopathy.

Tendinopathies represent about 45% of musculoskeletal lesions and they are a big burden in clinics characterized by activity-related pain, focal tendon tenderness and intra-tendinous imaging changes. Many approaches have been proposed for tendinopathies' management (e.g., nonsteroidal anti-inflammatory drugs, corticosteroids, eccentric exercises, laser therapy), unfortunately with very little support of efficacy or serious side effects, thus making the identification of new treatments fundamental. The aim of the study was to test the protective and pain reliever effect of thymoquinone (TQ)-loaded formulations in a rat model of tendinopathy induced by carrageenan intra-tendon injection (20 µL of carrageenan 0.8% on day 1). Conventional (LP-TQ) and hyaluronic acid (HA)-coated TQ liposomes (HA-LP-TQ) were characterized and subjected to in vitro release and stability studies at 4 °C. Then, TQ and liposomes were peri-tendon injected (20 µL) on days 1, 3, 5, 7 and 10 to evaluate their antinociceptive profile using mechanical noxious and non-noxious stimuli (paw pressure and von Frey tests), spontaneous pain (incapacitance test) and motor alterations (Rota rod test). Liposomes containing 2 mg/mL of TQ and covered with HA (HA-LP-TQ2) reduced the development of spontaneous nociception and hypersensitivity for a long-lasting effect more than the other formulations. The anti-hypersensitivity effect matched with the histopathological evaluation. In conclusion, the use of TQ encapsulated in HA-LP liposomes is suggested as a new treatment for tendinopathies.

Escinosome thermosensitive gel optimizes efficacy of CAI-CORM in a rat model of rheumatoid arthritis.

Rheumatoid arthritis is among the most common disabling diseases associated with chronic inflammation. The efficacy of the current therapeutic strategies is limited; therefore, new pharmacological agents and formulation approaches are urgently needed. In this work, we developed a thermosensitive gel incorporating escinosomes, innovative nanovesicles made of escin, stabilized with 10% of tween 20 and loaded with a Carbonic Anhydrase Inhibitor (CAI) bearing a Carbon Monoxide Releasing Moiety (CORM) (i.e., CAI-CORM 1), previously synthesized by some of the authors as a new potent pain-relieving agent. The light scattering analysis of the developed formulation showed optimal physical parameters, while the chromatographic analysis allowed the quantification of the encapsulation efficiency (90.1 ± 5.91 and 91.6 ± 8.46 for CAI-CORM 1 and escin, respectively). The thermosensitive gel, formulated using 23% w/v of poloxamer 407, had a sol-gel transition time of 40 s and good syringeability. Its stability in simulated synovial fluid (SSF) was morphologically evaluated by electron microscopy. Nanovesicles were physically stable in contact with the medium for two weeks, maintaining their original dimensions and spherical shape. The viscosity increased by about 30- to 100-fold with the temperature change from 25 °C to 37 °C. The gel erosion in SSF occurred within 9 h (88.2 ± 0.743%), and the drug's passive diffusion from escinosomes lasted 72 h, allowing a potential sustained therapeutic effect. The efficacy of a single intra-articular injection of the gel containing escinosomes loaded with CAI-CORM 1 (3 mg/mL; 30 µL, CAI-CORM 1 formulation) and the gel containing unloaded escinosomes (30 µL, blank formulation) was evaluated in a rat model of Complete Freund's Adjuvant (CFA)-induced rheumatoid arthritis. CAI-CORM 1 formulation was assessed to counteract mechanical hyperalgesia, spontaneous pain, and motor impairments on days 7 and 14 after treatment. The histological evaluation of the joints stressed the improvement of several morphological parameters in CFA + CAI-CORM 1 formulation-treated rats. In conclusion, the hybrid molecule CAI-CORM 1 formulated in escinosome-based thermosensitive gel could represent a new valid approach for managing rheumatoid arthritis.

The Antinociceptive Activity of (E)-3-(thiophen-2-yl)- N -(p-tolyl)acrylamide in Mice Is Reduced by (E)-3-(furan-2-yl)- N -methyl- N -(p-tolyl)acrylamide Through Opposing Modulatory Mechanisms at the α7 Nicotinic Acetylcholine Receptor.

BACKGROUND: The primary objective of this study was to characterize the pharmacological and behavioral activity of 2 novel compounds, DM497 [(E)-3-(thiophen-2-yl)- N -(p-tolyl)acrylamide] and DM490 [(E)-3-(furan-2-yl)- N -methyl- N -(p-tolyl)acrylamide], structural derivatives of PAM-2, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor (nAChR). METHODS: A mouse model of oxaliplatin-induced neuropathic pain (2.4 mg/kg, 10 injections) was used to test the pain-relieving properties of DM497 and DM490. To assess possible mechanisms of action, the activity of these compounds was determined at heterologously expressed α7 and α9α10 nAChRs, and voltage-gated N-type calcium channel (Ca V 2.2) using electrophysiological techniques. RESULTS: Cold plate tests indicated that 10 mg/kg DM497 was able to decrease neuropathic pain in mice induced by the chemotherapeutic agent oxaliplatin. In contrast, DM490 induced neither pro- nor antinociceptive activity but inhibited DM497's effect at equivalent dose (30 mg/kg). These effects are not a product of changes in motor coordination or locomotor activity. At α7 nAChRs, DM497 potentiated whereas DM490 inhibited its activity. In addition, DM490 antagonized the α9α10 nAChR with >8-fold higher potency than that for DM497. In contrast, DM497 and DM490 had minimal inhibitory activity at the Ca V 2.2 channel. Considering that DM497 did not increase the mouse exploratory activity, an indirect anxiolytic mechanism was not responsible for the observed antineuropathic effect. CONCLUSIONS: The antinociceptive activity of DM497 and the concomitant inhibitory effect of DM490 are mediated by opposing modulatory mechanisms on the α7 nAChR, whereas the involvement of other possible nociception targets such as the α9α10 nAChR and Ca V 2.2 channel can be ruled out.

Role of Hydroxytyrosol and Oleuropein in the Prevention of Aging and Related Disorders: Focus on Neurodegeneration, Skeletal Muscle Dysfunction and Gut Microbiota.

Aging is a multi-faceted process caused by the accumulation of cellular damage over time, associated with a gradual reduction of physiological activities in cells and organs. This degeneration results in a reduced ability to adapt to homeostasis perturbations and an increased incidence of illnesses such as cognitive decline, neurodegenerative and cardiovascular diseases, cancer, diabetes, and skeletal muscle pathologies. Key features of aging include a chronic low-grade inflammation state and a decrease of the autophagic process. The Mediterranean diet has been associated with longevity and ability to counteract the onset of age-related disorders. Extra virgin olive oil, a fundamental component of this diet, contains bioactive polyphenolic compounds as hydroxytyrosol (HTyr) and oleuropein (OLE), known for their antioxidant, anti-inflammatory, and neuroprotective properties. This review is focused on brain, skeletal muscle, and gut microbiota, as these systems are known to interact at several levels. After the description of the chemistry and pharmacokinetics of HTyr and OLE, we summarize studies reporting their effects in in vivo and in vitro models of neurodegenerative diseases of the central/peripheral nervous system, adult neurogenesis and depression, senescence and lifespan, and age-related skeletal muscle disorders, as well as their impact on the composition of the gut microbiota.

Ellagitannins and triterpenoids extracts of Anogeissus leiocarpus stem bark extracts: Protective effects against osteoarthritis.

Osteoarthritis (OA) is a complex joint disease characterized by persistent pain. Unfortunately, current pharmacological therapies are unsatisfactory and characterized by side effects, reason why new strategies are needed. We tested the efficacy of different classes of compounds, ellagitannins and olean-type triterpenoids, contained in Anogeissus leiocarpus extract (Combretaceae family) in comparison to ellagitannins of Castanea sativa extract in a rat model of osteoarthritis induced by the intra-articular injection of sodium monoiodoacetate (MIA). The decoction of stem bark of A. leiocarpus AL-DEC-TOT (300 mg/kg; 4.8% triterpenoids; 11.0% tannins), the butanol extract AL-BuOH-EXT (120 mg/kg; triterpenoids 20.9%; tannins 6.4%) and its correlated aqueous residue AL-Res-H2 O (300 mg/kg; triterpenoids 0.7%; tannins 8.7%) and the decoction of C. sativa, CS-DEC-TOT, (240 mg/kg; triterpenoids 0.65%; tannins 10.8%) were orally administered for two weeks starting from the day of the damage. Behavioural tests highlighted that all stem bark extracts of A. leiocarpus counteracted hypersensitivity development, reduced spontaneous pain, and improved motor skills. Histologically, AL-DEC-TOT, AL-BuOH-EXT and AL-Res-H2 O were effective in preventing joint alterations. In conclusion, all the extracts were effective demonstrating that both olean-type triterpenoid and ellagitannin fractions have anti-hypersensitivity and restorative properties running the stem bark extracts of A. leiocarpus as a candidate in the treatment of OA.