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Paclitaxel induces microglial activation and production of proinflammatory mediators in the dorsal horn, which contribute to the development and maintenance of central sensitization and pain behavior. MDA7, 1-([3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl]carbonyl) piperidine, is a novel highly selective cannabinoid type 2 (CB2) agonist. We tested the hypothesis that activation of CB2 receptor by MDA7 modulates microglial dysregulation, suppresses the overexpression of brain-derived neurotrophic factor (BDNF) in microglia in the dorsal horn, and attenuates the central sensitization and pain behavior induced by paclitaxel. For 4 consecutice days, groups of rats randomly received saline or 1.0 mg/kg of paclitaxel daily intraperitoneally for a total cumulative dose of 4 mg/kg. MDA7 15 mg/kg intraperitoneally or vehicle were administered 15 min before administering paclitaxel for 4 days and then continued for another 10 days. Behavioral and molecular studies were performed. Paclitaxel induced the expression of CB2 receptors and production of interleukin (IL)-6 in microglia in the dorsal horn. MDA7 attenuated the expression of IL-6 and promoted the expression of IL-10. Paclitaxel induced epigenetic upregulation of IRF8 and P2X purinoceptor 4 (P2X4) in microglia and subsequently increased the expression of alpha isoform of calcium/calmodulin-dependent protein kinase II (CaMKIIα), transcriptional factors p-CREB and ΔFosB, leading to the overproduction of BDNF in microglia. Paclitaxel also upregulated the expression of glutamate receptor subunits GluR1 and NR2B, decreased the expression of K+-Cl- cotransporter, and induced mechanical allodynia in rats. All of the aforementioned molecular changes were attenuated by MDA7. Our data show that MDA7 attenuated paclitaxel-induced molecular and behavioral changes in rats. Perspective: This study provides evidence that paclitaxel induced microglia dysregulation and epigenetically upregulated the microglial expression of BDNF, which led to sensitization of dorsal horn neurons and mechanical allodynia in rats. The CB2 agonist MDA7 alleviated these pathological processes. MDA7 represents an innovative therapeutic approach for treatment of chemotherapy-induced neuropathy. [ABSTRACT FROM AUTHOR]

Abstract: Background and study aims: Gastric antral vascular ectasia (GAVE) is a distinct vascular abnormality, mainly involving the gastric antrum. It is a rare but well-known cause of occult gastrointestinal bleeding. Various endoscopic treatment modalities have been tried in this condition. The aim of the study is to show the long-term effect of argon plasma coagulation (APC) on GAVE. Patients and methods: Twenty-nine patients with endoscopically proved GAVE were enrolled in the study. Clinical assessment of GAVE patients, haemoglobin (Hb) level and transfused blood units were recorded after APC using 60–80-W power setting. A second session was done 1month after the therapeutic procedure to ensure complete ablation of all lesions. Results: The documented Hb levels and number of blood units transfused 3months after APC were recorded. At endoscopy, all patients had the classic type of GAVE. The mean Hb level increased from 7.5±1.7gdl−1 before APC to 10.2±0.8gdl−1 after APC (p value <0.001). The transfusion requirements significantly decreased to 0.2±0.5units/patient (p value <0.001). Conclusion: Endoscopic APC is a safe, effective and inexpensive modality in treating GAVE and could be an alternative to the currently available endoscopic methods. [Copyright &y& Elsevier]

Abstract: (S)-(3-Benzyl-3-methyl-2,3-dihydro-benzofuran-6-yl)-piperidin-1-yl-methanone, a selective CB2 receptor agonist, was obtained from 3-hydroxy-4-iodo benzoic acid in nine steps with 97.4% ee and 3.4% total yield, which involved palladium catalyzed tandem intramolecular Heck/Suzuki cross coupling reaction, chemical resolution with (+)-norephedrine and Wolf–Kishner reaction as the key steps. (S)-(3-Benzyl-3-methyl-2,3-dihydro-benzofuran-6-yl)-piperidin-1-yl-methanone will be evaluated in vivo studies and this approach will be applied in the optimization process of CB2 receptor agonist. [Copyright &y& Elsevier]

Abstract: New hyperstar polymers (HSP) based on a hyperbranched polyester core (HBP-OH) and PMMA or P(MMA-b-HEMA) block copolymer arms have been prepared for use as nanoscale soft particle-like additives in an epoxy matrix cured cationically either by UV light or thermally. The effects of the additive as well as the curing process on the epoxy group conversion, gel content, morphology and the thermal and viscoelastic properties of the cured materials were evaluated. It was found that in both curing processes the non-reactive hyperstar HBP-PMMA resulted in phase-separated materials with low effect on flexibilization whereas by use of HBP-P(MMA-b-HEMA) the OH groups in the HEMA units allowed chemical bonding of the HSP to the epoxy network and hindered phase separation. The epoxy group conversion was enhanced in thermally cured samples but significantly decreased in photocured ones showing the most effective flexibilization demonstrated as reduction in Tg, whereas in both cases, high gel contents have been achieved using the reactive HSPs. Thus, the increased temperature in the thermal curing process enhances the effectiveness of the HSPs as multifunctional crosslinkers leading to higher curing rates and crosslinking density, whereas in photocuring the flexibilization effect can be enhanced by having high gel content at lower epoxy group conversion. [Copyright &y& Elsevier]

Objective: To evaluate the role of preoperative testicular shear wave elastography (SWE) in the prediction of improvement of semen analysis parameters after subinguinal microsurgical varicocele ligation in patients with primary infertility and clinically detectable varicocele.Patients and Methods: Testicular SWE before the surgical intervention was done. Forty-eight patients were scheduled for subinguinal microsurgical varicocele ligation as a treatment option. Computer-assisted semen analysis was repeated 6 months after the intervention.Results: At a cutoff value of 4.5 kPa, the stiffness index had a sensitivity of 86.4% and a specificity of 84.2% for semen parameter improvement after varicocelectomy. Correlation between different parameters of semen analysis and SWE showed a statistically significant negative correlation between SWE stiffness index and both sperm count (million/mL) and total motility. On the other hand, a nonsignificant negative correlation was found between SWE stiffness index and percentage of normal form.Conclusion: Testicular SWE is a good test that can be used in the assessment of male infertility with clinically detectable varicocele, and its results may predict semen parameter improvement after varicocelectomy. Further studies on a larger number of patients are needed to verify our results. [ABSTRACT FROM AUTHOR]

Abstract: The abnormal accumulation of amyloid fibrils in the brain is pathognomonic of Alzheimer's disease. Amyloid fibrils induce significant neuroinflammation characterized by the activation of microglia and impairment of synaptic plasticity in the brain that eventually leads to cognitive decline. Chemokine fractalkine receptor (CX3CR1) is primarily located in the microglia in the brain and its role in the amyloid fibril-induced neuroinflammation and memory deficiency remains debated. We found that bilateral microinjection of amyloid beta (Aβ)1–40 fibrils into the hippocampal CA1 area of rats resulted in significant upregulation of CX3CR1 messenger RNA (mRNA) and protein expression (via increasing histone H3 acetylation in the Cx3cr1 promoter region), synaptic dysfunction, and cognitive impairment, compared with the control group. Suppressing CX3CR1 signaling with CX3CR1 small interfering RNA in rats injected with Aβ1–40 fibrils blunted Aβ1–40-induced CX3CR1 upregulation, microglial activation, interleukin-1β expression, restored basal glutamatergic strength and electric stimuli-induced long-term potentiation, and cognitive capacities. These findings suggest that activation of CX3CR1 plays an important role in the neuroinflammatory response and Aβ-induced neuroinflammation and neurotoxicity. [Copyright &y& Elsevier]

Abstract: Cannabinoid type 2 (CB2) agonists are neuroprotective and appear to play modulatory roles in neurodegenerative processes in Alzheimer''s disease. We have studied the effect of 1-((3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl) carbonyl) piperidine (MDA7)—a novel selective CB2 agonist that lacks psychoactivity—on ameliorating the neuroinflammatory process, synaptic dysfunction, and cognitive impairment induced by bilateral microinjection of amyloid-β (Aβ)1–40 fibrils into the hippocampal CA1 area of rats. In rats injected with Aβ1–40 fibrils, compared with the administration of intraperitoneal saline for 14 days, treatment with 15 mg/kg of intraperitoneal MDA7 daily for 14 days (1) ameliorated the expression of CD11b (microglia marker) and glial fibrillary acidic protein (astrocyte marker), (2) decreased the secretion of interleukin-1β, (3) decreased the upsurge of CB2 receptors, (4) promoted Aβ clearance, and (5) restored synaptic plasticity, cognition, and memory. Our findings suggest that MDA7 is an innovative therapeutic approach for the treatment of Alzheimer''s disease. [Copyright &y& Elsevier]

Enabling formulations based on hydroxypropyl-β-cyclodextrins (HPβCD), micellar preparation, and liposomes have been designed to deliver the racemic mixture of a lipophilic cannabinoid type 2 agonist, MDA7. The antiallodynic effects of MDA7 formulated in these three different systems were compared after intravenous (i.v.) administration in rats. Stoichiometry of the inclusion complex formed by MDA7 in HPβCD was determined by continuous variation plot, electrospray ionization-mass spectrometry (ESI-MS) analysis, phase solubility, and nuclear magnetic resonance studies and indicate formation of exclusively 1:1 adduct. Morphology and particle sizes determined by dynamic light scattering and transmission electron microscopy show the presence of a homogeneous population of closed round-shaped oligolamellar MDA7 containing liposomes, with an average size of 118 nm [polydispersity index (PDI) 0.03]. Monodisperse micelles exhibited an average size of 14 nm (PDI 0.09). HPβCD-based formulation administrated in vivo was composed of two discrete particles populations with a narrow size distribution of 3 nm (PDI 0.04) and 510 nm (PDI 0.02). HPβCD-based formulation dramatically improved antiallodynic effect of MDA7 in comparison with the liposomes preparation. Through inclusion complexation and possibly formation of aggregates, HPβCD can enhance the aqueous solubility of lipophilic drugs, thereby improving their bioavailability for i.v. administration. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:352-364, 2013 [ABSTRACT FROM AUTHOR]