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      Dietary Supplementation with Palmitoyl-Glucosamine Co-Micronized with Curcumin Relieves Osteoarthritis Pain and Benefits Joint Mobility

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          Abstract

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          Canine osteoarthritis is a chronic degenerative joint disease and a major cause of elective euthanasia. The disorder increasingly limits joint motion, might cause lameness as well as pain, and impacts quality of life. An unmet need remains for safe and effective therapies for osteoarthritis. Palmitoyl-glucosamine and curcumin are used in animal nutrition. A co-micronized formulation, with the two substances being jointly processed to reduce their particle size and increase the extent to which they can be absorbed, is currently available on the European market. The present study investigated if this formulation could relieve joint pain and benefit mobility. Two well-established rat models of inflammation and osteoarthritis pain were used. Results from the first set of experiments showed that the dietary supplement relieved experimentally induced paw edema, infiltration of inflammatory cells, and decreased sensitivity to painful stimuli (thermal hyperalgesia). In the osteoarthritis model, the supplement proved to protect joint cartilage against degradation and successfully address neuropathic pain (i.e., pain from normally non-painful stimuli). Locomotor function recovered by 45% under supplement administration. The present findings suggest that the dietary supplement with palmitoyl-glucosamine co-micronized with curcumin might help manage osteoarthritis.

          Abstract

          Chronic mixed pain and orthopedic dysfunction are the most frequently associated consequences of canine osteoarthritis (OA). An unmet need remains for safe and effective therapies for OA. Palmitoyl-glucosamine (PGA) and curcumin are safe and naturally occurring compounds whose use is limited by poor bioavailability. Micronization is an established technique to increase bioavailability. The aim of this study was to investigate if the dietary supplementation with PGA co-micronized with curcumin (PGA-Cur, 2:1 ratio by mass) could limit pathologic process in two well-established rat models of inflammation and OA pain, i.e., subplantar carrageenan (CAR) and knee injection of sodium monoiodoacetate (MIA), respectively. In CAR-injected animals, a single dose of PGA-cur significantly reduced paw edema and hyperalgesia, as well as tissue damage and neutrophil infiltration. The repeated administration of PGA-Cur three times per week for 21 days, starting the third day after MIA injection resulted in a significant anti-allodynic effect. Protection against cartilage damage and recovery of locomotor function by 45% were also recorded. Finally, PGA-cur significantly counteracted MIA-induced increase in serum levels of TNF-α, IL-1β, NGF, as well as metalloproteases 1, 3, and 9. All the effects of PGA-Cur were superior compared to the compounds used singly. PGA-Cur emerged as a useful dietary intervention for OA.

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          Most cited references72

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          Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis.

          Osteoarthritis (OA) has long been viewed as a degenerative disease of cartilage, but accumulating evidence indicates that inflammation has a critical role in its pathogenesis. Furthermore, we now appreciate that OA pathogenesis involves not only breakdown of cartilage, but also remodelling of the underlying bone, formation of ectopic bone, hypertrophy of the joint capsule, and inflammation of the synovial lining. That is, OA is a disorder of the joint as a whole, with inflammation driving many pathologic changes. The inflammation in OA is distinct from that in rheumatoid arthritis and other autoimmune diseases: it is chronic, comparatively low-grade, and mediated primarily by the innate immune system. Current treatments for OA only control the symptoms, and none has been FDA-approved for the prevention or slowing of disease progression. However, increasing insight into the inflammatory underpinnings of OA holds promise for the development of new, disease-modifying therapies. Indeed, several anti-inflammatory therapies have shown promise in animal models of OA. Further work is needed to identify effective inhibitors of the low-grade inflammation in OA, and to determine whether therapies that target this inflammation can prevent or slow the development and progression of the disease.
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            A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia

            A method to measure cutaneous hyperalgesia to thermal stimulation in unrestrained animals is described. The testing paradigm uses an automated detection of the behavioral end-point; repeated testing does not contribute to the development of the observed hyperalgesia. Carrageenan-induced inflammation resulted in significantly shorter paw withdrawal latencies as compared to saline-treated paws and these latency changes corresponded to a decreased thermal nociceptive threshold. Both the thermal method and the Randall-Selitto mechanical method detected dose-related hyperalgesia and its blockade by either morphine or indomethacin. However, the thermal method showed greater bioassay sensitivity and allowed for the measurement of other behavioral parameters in addition to the nociceptive threshold.
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              Neuropathic pain: a maladaptive response of the nervous system to damage.

              Neuropathic pain is triggered by lesions to the somatosensory nervous system that alter its structure and function so that pain occurs spontaneously and responses to noxious and innocuous stimuli are pathologically amplified. The pain is an expression of maladaptive plasticity within the nociceptive system, a series of changes that constitute a neural disease state. Multiple alterations distributed widely across the nervous system contribute to complex pain phenotypes. These alterations include ectopic generation of action potentials, facilitation and disinhibition of synaptic transmission, loss of synaptic connectivity and formation of new synaptic circuits, and neuroimmune interactions. Although neural lesions are necessary, they are not sufficient to generate neuropathic pain; genetic polymorphisms, gender, and age all influence the risk of developing persistent pain. Treatment needs to move from merely suppressing symptoms to a disease-modifying strategy aimed at both preventing maladaptive plasticity and reducing intrinsic risk.
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                Author and article information

                Journal
                Animals (Basel)
                Animals (Basel)
                animals
                Animals : an Open Access Journal from MDPI
                MDPI
                2076-2615
                08 October 2020
                October 2020
                : 10
                : 10
                : 1827
                Affiliations
                [1 ]Department of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, 98168 Messina, Italy; egugliandolo@ 123456unime.it (E.G.); aperitore@ 123456unime.it (A.F.P.); dimpellizzeri@ 123456unime.it (D.I.); cordarom@ 123456unime.it (M.C.); rsiracusa@ 123456unime.it (R.S.); rfusco@ 123456unime.it (R.F.); rdamico@ 123456unime.it (R.D.); dipaolar@ 123456unime.it (R.D.P.)
                [2 ]Innovative Statistical Research srl, Prato Della Valle 24, I-35123 Padova, Italy; cs@ 123456i-stat.it
                [3 ]Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA
                [4 ]Department of Veterinary Science, University of Messina, 98168 Messina, Italy; rcrupi@ 123456unime.it
                Author notes
                [* ]Correspondence: salvator@ 123456unime.it
                [†]

                Equal contribution.

                Author information
                https://orcid.org/0000-0001-6840-3154
                https://orcid.org/0000-0001-8545-990X
                https://orcid.org/0000-0001-9492-3161
                https://orcid.org/0000-0002-3980-0043
                https://orcid.org/0000-0001-7868-2505
                https://orcid.org/0000-0003-0223-1403
                https://orcid.org/0000-0003-0389-3871
                https://orcid.org/0000-0001-6725-8581
                https://orcid.org/0000-0001-6131-3690
                https://orcid.org/0000-0002-7629-3132
                Article
                animals-10-01827
                10.3390/ani10101827
                7601140
                33049960
                b4b60892-b871-4c68-8f4f-5e632d6f797d
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 03 September 2020
                : 06 October 2020
                Categories
                Article

                osteoarthritis,mobility,pain,allodynia,hyperalgesia,inflammation,palmitoyl-glucosamine,curcumin,endocannabinoid system,aliamides

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