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Repeated administration of mazindol reduces spontaneous pain-related behaviors without modifying bone density and microarchitecture in a mouse model of complete Freund's adjuvant-induced knee arthritis.

ABSTRACT: The role of dopaminergic system in the development of rheumatoid arthritis-related pain, a major symptom in this disease, has not been explored. Therefore, the anti-nociceptive effect of mazindol, a dopamine uptake inhibitor, was evaluated in a model of complete Freund's adjuvant (CFA)-induced arthritis. Furthermore, as studies have shown that the dopaminergic system regulates bone metabolism, the effect of mazindol on bone mass and microarchitecture was determined.Adult ICR male mice received intra-articular injections of either CFA or saline into the right knee joint every week. Spontaneous pain-like behaviors (flinching and guarding) and locomotor activity were assessed at day 26 post-first CFA, following which, a single intraperitoneally (i.p.) administered dose of mazindol was given (1, 3 and 10 mg/kg). Then, the antinociceptive effect of a repeated administration of 3 mg/kg mazindol (daily, i.p.; day 15-day 26) was evaluated. Additionally, at day 26, the participation of D1-like, D2-like or opioid receptors in the antinociceptive effect of mazindol was evaluated. The effect of mazindol on bone density and microarchitecture was evaluated by micro-computed tomography.Acute administration of mazindol decreased the spontaneous pain-like behaviors in a dose-dependent manner without reducing the knee edema. However, mazindol at 10 mg/kg significantly increased the locomotor activity; therefore, 3 mg/kg mazindol was used for further studies. Repeated administration of 3 mg/kg mazindol significantly decreased the pain-like behaviors without modifying locomotor activity. The antinociceptive effect of mazindol was blocked by administration of a D2-like receptor antagonist (haloperidol), but not by administration of D1-like receptor antagonist (SCH 23390) or an opioid receptor antagonist (naloxone). Repeated administration of mazindol did not significantly modify the density and microarchitecture of periarticular bone of the arthritic and nonarthritic knee joints.Results suggest that mazindol via D2-like receptors has an antinociceptive role in mice with CFA-induced knee arthritis without modifying the bone health negatively.

SUBMITTER: Robledo-Gonzalez LE

PROVIDER: S-EPMC5538698 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Project description:ObjectiveTo explore the outcome and surgical technique of minimally invasive unicompartmental knee arthroplasty (UKA) for spontaneous osteonecrosis of the knee.MethodsTwenty-seven patients with medial compartmental spontaneous osteonecrosis treated by minimally invasive Oxford phase 3 UKA from January 2009 to June 2013 were reviewed retrospectively. Twelve subjects were men and 15 women, with an average age of 64.6 ± 8.6 years (52-82 years). At the time of diagnosis, 11 patients had with grade III necrosis and 16 grade IV according to Mont's classification. Pain, range of motion (ROM) and Hospital for Special Surgery (HSS) knee scores were evaluated before and after UKA. Pre-and postoperative alignment of the lower limbs was measured and compared. Postoperative radiographic assessments were made according to the guidelines proposed by the Oxford group at the final follow-up.ResultsAll patients were followed for a mean time of 27.8 ± 15.9 months (6-59 months). There were no serious adverse events, such as infection, bearing dislocation, aseptic loosening, pulmonary embolism, deep venous thrombosis, cardio-cerebral vascular incident or psychological problems. One revision was required for unrelated causes (fracture of tibia plateau) 3 years after arthroplasty. One femoral component was tilted with a postoperative radiographic angle >10°. One radiolucent line was observed in a patient with spontaneous osteonecrosis of the knee. The two patients with implant failure had no symptoms at last follow-up. Visual analogue scale scores decreased from 6.9 ± 0.9 to 2.0 ± 1.1 (t = 19.27, P = 0.00). Pain was relieved in 96.3% of subjects (26/27). The mean post-operative ROM and femorotibial angle were 125.7° ± 9.6° and 177.7° ± 3.1°, respectively. HSS scores increased from 61.3 ± 9.7 to 93.0 ± 4.8 (t = 14.46, P = 0.00). Of the 27 patients, 26 (96.3%) were satisfied with the outcome of this surgical procedure.ConclusionMinimally invasive UKA is an effective means of managing spontaneous osteonecrosis of the knee. The short-term outcome of UKA is encouraging.

Project description:Rheumatoid arthritis is an autoimmune and inflammatory disease that affects synovial joint tissues and skeletal muscle. Clinical-like cryotherapy benefits signs of joint inflammation in knee osteoarthritis after 60 days of anterior cruciate ligament transection surgery. However, it is unknown whether it also benefits acute knee arthritis (e.g., reduces inflammatory process and protects neuromuscular junction [NMJ] and muscle fibers). We aimed to analyze the effects of clinical-like cryotherapy on NMJ and quadriceps muscle fibers in a model of acute knee arthritis. Twenty-four male C57BL/6 mice (20 to 25 g) were randomly allocated into three groups: control (mice with no intervention), antigen-induced arthritis (AIA; mice sensitized and immunized with intra-articular [i.a.] injection of methylated bovine serum albumin [mBSA]), and AIA+cryotherapy (mice sensitized, immunized with i.a. injection of mBSA, and submitted to a clinical-like cryotherapy protocol). Twenty-one days after sensitization, arthritis was induced in immunized mice via i.a. injection of mBSA (100 μg/joint). Two clinical-like cryotherapy sessions (crushed ice pack for 20 min) were applied two hours apart. The first session was applied immediately after i.a. injection of mBSA. The quadriceps was removed two hours after the second clinical-like cryotherapy session for morphological analysis of muscle fibers (cross-sectional area), frequency distribution of muscle fiber area (%), and NMJ (area, perimeter, and maximum diameter). Gene expressions of mRNA involved in NMJ signaling (γ-nAChR, α1-nAChR, ε-nAChR, Agrin-MusK-Rapsyn, α-dystrobrevin, and utrophin) and atrophy (muscle RING-finger protein-1 and Atrogin-1) pathways were analyzed. Inflammatory signs were assessed in knee joint (swelling, articular surface temperature, and neutrophil migration in synovial fluid). Regarding morphological analysis of muscle fibers, 180 to 270 and >270 μm2 classes were higher in the AIA+cryotherapy than the AIA group. Area, perimeter, and maximum diameter of NMJ also increased in the AIA+cryotherapy compared with the control group. Agrin mRNA expression increased in the AIA+cryotherapy compared with the control and AIA groups. In the atrophy pathway, Atrogin-1 increased compared with the control and AIA groups. The AIA+cryotherapy group reduced knee swelling and neutrophil migration compared with the AIA group. In conclusion, clinical-like cryotherapy increased Agrin expression, contributing to NMJ maintenance and increased Atrogin-1 expression, thus protecting NMJ and muscle fiber. Furthermore, clinical-like cryotherapy reduced inflammatory signs (swelling and neutrophil migration) of acute knee arthritis.

Project description:Naringin (NAR), a naturally occurring essential flavonoid, present in grapefruit and Chinese herbal medicines, creates great interest in researchers due to its diverse biological and pharmacological activities. However, further development of NAR is hindered due to its poor water solubility and dissolution rates in GIT. To address these limitations, in this study, we report polymeric nanoparticles (NPs) of NAR (NAR-PLGA-NPs) for enhancing the oral NAR efficiency, with a biodegradable polymer (PLGA) to improve its absorption and bioavailability. NAR-PLGA-NPs were fabricated by a modified solvent emulsification-evaporation technique. Physicochemical properties were evaluated by SEM, particle size distribution, entrapment efficiency, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and differential scanning calorimetry (DSC). In vitro drug release and ex vivo permeation studies were carried out in phosphate buffer (pH 6.8) for 24 h. Furthermore, in vivo anti-arthritic studies were performed on a mouse model, and the results were compared with free NAR. The modulation of inflammatory mediators was also evidently supported by docking studies. Optimized nanoformulation FN4 (NAR-PLGA-NPs) prepared with acetone-ethanol (2:1) as a solvent system in a combination of stabilizers, i.e., poloxamer-188 and sodium deoxylate (1:1), along with 2% PVA solution, was prepared. From size characterization studies, it was observed that nanoformulations possessed a low particle size (179.7 ± 2.05 nm), a low polydispersity index (0.206 ± 0.001), and a negative zeta potential (-9.18 ± 0.78 mV) with a maximum entrapment efficiency (74 ± 3.61%). The drug release followed a Korsmeyer-Peppas release kinetic model (anomalous non-Fickian diffusion), providing greater NAR release after lyophilization (82.11 ± 3.65%) drug release in pH 6.8 phosphate buffer for 24 h. Ex vivo permeation analysis through an isolated goat intestinal membrane revealed 80.02 ± 3.69% drug release in 24 h. Encapsulation of a drug into PLGA is well described by the results of FTIR, DSC, and XRD. Finally, the therapeutic efficacy of optimized FN4 (NAR-PLGA-NPs) and its possible application on RA were further confirmed in a Freund's complete adjuvant-induced rat arthritic model as against free NAR at a dose of 20 mg/kg body wt. Our findings demonstrate that sustained action of NAR from optimized FN4 NPs with a rate-controlling polymeric carrier system exhibited prolonged circulation time and reduced arthritic inflammation, hence indicating the possibility as a novel strategy to secure the unpropitious biological interactions of hydrophobic NAR in a gastric environment.

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Repeated administration of mazindol reduces spontaneous pain-related behaviors without modifying bone density and microarchitecture in a mouse model of complete Freund's adjuvant-induced knee arthritis.

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