Synthesis of Gemini-type imidazoline quaternary ammonium salt using by-product fatty acid as corrosion inhibitor for Q235 steel.

Gemini-type imidazoline quaternary ammonium salt is a new type of environmentally friendly corrosion inhibitor has been widely used in engineering materials. However, most of them are hazardous/toxic compounds derived from petroleum-based products, which did harm to environment. In this work, an environmentally friendly Gemini-shaped imidazoline quaternary ammonium salt corrosion inhibitor (G211) was synthesized using cheap fatty acid recycled from dimer acid industry as feedstock. The corrosion inhibition effects of G211 on Q235 steel in 1 M HCl solution were investigated through weight loss experiments, potential polarization curves, and alternating current impedance spectroscopy experiments. The results show that the inhibition rate of G211 as a mixed-type inhibitor is up to 94.4% and the concentration drop as low as 500 ppm at 25 â„ƒ. The adsorption of G211 on Q235 surface follows Langmuir adsorption isothermal curve. The chemical composition of the Q235 steel surface was analyzed through scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). Furthermore, the possible corrosion inhibition mechanism of G211 on the surface of Q235 steel is proposed. This article not only presents an outstanding solution for safeguarding Q235 steel against corrosion but also introduces a feasible method for high-value utilization of monomer acid (MA).

Not first-line antihypertensive agents, but still effective-The efficacy and safety of imidazoline receptor agonists: A network meta-analysis.

Cardiovascular disorders are the leading cause of death in the world. Many organ diseases (kidney, heart, and brain) are substantially more prone to develop in people with hypertension. In the treatment of hypertension, first-line medications are recommended, while imidazoline receptor agonists are not first-line antihypertensives. Our goal was to conduct a network meta-analysis to assess the efficacy and safety of imidazoline receptor agonists. The meta-analysis was performed following the PRISMA guidelines using the PICOS format, considering the CONSORT recommendations. Studies were collected from four databases: PubMed, Cochrane Library, Web of Science, and Embase. A total of 5960 articles were found. After filtering, 27 studies remained eligible for network meta-analysis. Moxonidine reduced blood pressure in sitting position statistically significantly after 8 weeks of treatment (SBP MD: 23.80; 95% CI: 17.45-30.15; DBP MD: 10.90; 95% CI: 8.45-13.35) compared to placebo. Moreover, moxonidine reduced blood pressure more effectively than enalapril; however, this difference was not significant (SBP MD: 3.10; 95% CI: -2.60-8.80; DBP MD: 1.30; 95% CI: -1.25-3.85). Dry mouth was experienced as a side effect in the case of all imidazoline receptor agonists. After 8 weeks of treatment, the appearance of dry mouth was highest with clonidine (OR: 9.27 95% CI: 4.70-18.29) and lowest with rilmenidine (OR: 6.46 95% CI: 0.85-49.13) compared to placebo. Somnolence was less frequent with moxonidine compared to rilmenidine (OR: 0.63 95% CI: 0.17-2.31). Imidazoline receptor agonists were nearly as effective as the first-line drugs in the examined studies. However, their utility as antihypertensives is limited due to their side effects. As a result, they are not first-line antihypertensives and should not be used in monotherapy. However, in the case of resistant hypertension, they are a viable option. According to our findings, from the point of view of safety and efficacy, moxonidine appears to be the best choice among imidazoline receptor agonists.

The Effect of Basic Ligands and Alkenes on the Regioselectivity of C-H Additions of Tertiary Amines to Alkenes.

Highly regioselective C-H alkylation reactions of tertiary anilines and tertiary alkyl amines with simple alkenes have been achieved by the use of imidazolin-2-iminato scandium alkyl complexes. This protocol provided an efficient and atom-economical route to structurally diverse tertiary amine derivatives. The basic ligand, a coordinating THF in the catalyst and the substitution of alkene substrates were found to switch the regioselectivity of the C-H alkylation reactions of tertiary anilines presumably due to the generation of different types of catalytically active species or the formation of relatively stable intermediates. On the basis of the deuterium labeling experiments and KIE experiments, possible catalytical cycles were provided to understand the reaction mechanism as well as the regioselectivity.

Molecular Modeling, Synthesis, and Antihyperglycemic Activity of the New Benzimidazole Derivatives - Imidazoline Receptor Agonists.

Introduction: The paper presents the results of a study on the first synthesized benzimidazole derivatives obtained from labile nature carboxylic acids. The synthesis conditions of these substances were studied, their structure was proved, and some components were found to have sugar-reducing activity on the model of alloxan diabetes in rats. Methods: The study used molecular modeling methods such as docking based on the evolutionary model (igemdock), RP_HPLC method to monitor the synthesis reaction, and 1H NMR and 13C NMR, and other methods of organic chemistry to confirm the structures of synthesized substances. Results & Discussion: The docking showed that the ursodeoxycholic acid benzimidazole derivatives have high tropics to all imidazoline receptor carriers (PDB ID: 2XCG, 2bk3, 3p0c, 1QH4). The ursodeoxycholic acid benzimidazole derivative and arginine and histidine benzimidazole derivatives showed the highest sugar-lowering activity in the experiment on alloxan-diabetic rats. For these derivatives, the difference in glucose levels of treated rats was significant against untreated control. Therefore, the new derivatives of benzimidazole and labile natural organic acids can be used to create new classes of imidazoline receptor inhibitors for the treatment of diabetes mellitus and hypertension.

Synthesis of Antiprotozoal 2-(4-Alkyloxyphenyl)-Imidazolines and Imidazoles and Their Evaluation on Leishmania mexicana and Trypanosoma cruzi.

Twenty 2-(4-alkyloxyphenyl)-imidazolines and 2-(4-alkyloxyphenyl)-imidazoles were synthesized, with the former being synthesized in two steps by using MW and ultrasonication energy, resulting in good to excellent yields. Imidazoles were obtained in moderate yields by oxidizing imidazolines with MnO2 and MW energy. In response to the urgent need to treat neglected tropical diseases, a set of 2-(4-alkyloxyphenyl)- imidazolines and imidazoles was tested in vitro on Leishmania mexicana and Trypanosoma cruzi. The leishmanicidal activity of ten compounds was evaluated, showing an IC50 < 10 µg/mL. Among these compounds, 27-31 were the most active, with IC50 values < 1 µg/mL (similar to the reference drugs). In the evaluation on epimastigotes of T. cruzi, only 30 and 36 reached an IC50 < 1 µg/mL, showing better inhibition than both reference drugs. However, compounds 29, 33, and 35 also demonstrated attractive trypanocidal activities, with IC50 values < 10 µg/mL, similar to the values for benznidazole and nifurtimox.

Regulation of I1-imidazoline receptors on the sedation effect of dexmedetomidine in mice.

Dexmedetomidine has been used as a sedative drug in the clinic for a long time. Many studies demonstrated that the sedative mechanism of dexmedetomidine might be related to the activation of α2-adrenoceptor (α2AR). In addition, it was reported that dexmedetomidine had some affinity for the I1-imidazoline receptor (I1R); however, the role of I1R in dexmedetomidine-induced sedative effects and its possible mechanism are poorly studied. In the present study, we found that agmatine, an I1R agonist, was able to enhance the sedative effect of dexmedetomidine in mice. Efaroxan, an α2AR and I1R antagonist, could prevent and rescue the sedative action of dexmedetomidine in mice, and its preventive effect was better than atipamezole, the specific α2AR antagonist. Knockout of imidazoline receptor antisera-selected (IRAS), the functional I1R candidate protein, suppressed the dexmedetomidine-induced sedation. Moreover, IRAS knockout led to the inhibition of agmatine and efaroxan in regulating dexmedetomidine-induced sedative effects in mice, but not of atipamezole. We then used CHO cell lines that stably expressed α2AR and IRAS to investigate the possible molecular mechanism of IRAS in regulating the dexmedetomidine-induced sedative effect. The results showed that IRAS expression significantly up-regulated dexmedetomidine-induced ERK phosphorylation, which was enhanced by agmatine and inhibited by efaroxan at low concentrations. Therefore, by taking advantage of pharmacological and genetic approaches, our finding revealed the evidence that IRAS plays an important role in the sedative effects of dexmedetomidine, and the ERK signal pathway may be involved in the mechanism of IRAS in regulating dexmedetomidine-induced sedation. This study may offer valuable insights for the advancement of novel anesthetic adjuvants.

Fabrication of imidazoline-linked cationic covalent triazine framework for enrichment of environmental estrogens.

Imidazoline-linked cationic covalent triazine framework (IM-iCTF) was facilely prepared through the Debus-Radziszewski reaction, involving 4,4',4''-(1,3,5-triazine-2,4,6-triyl)trianiline, formaldehyde and methylglyoxal. The IM-iCTF was applied as a sorbent for cartridge solid-phase extraction (SPE). It provided good adsorption performance for estrogen and estrogen mimics including bisphenol F, bisphenol A, 7ß-estradiol, bisphenol B and estrone. The adsorption isotherm, adsorption kinetic model, thermodynamic calculations and adsorption mechanism were investigated to reveal the adsorption behavior. The IM-iCTF was employed for the extraction of the estrogens and estrogen mimics from water, fish and shrimp (fish and shrimp samples were extracted with acetonitrile before the SPE). The analytes were then determined by high-performance liquid chromatography with diode array detection. The limits of detection were 0.008-0.05 ng mL-1 for water, 0.015-0.11 µg g-1 for fish, and 0.012-0.10 µg g-1 for shrimp samples. This research not only offers a new approach to construct cationic covalent triazine framework, but also provides a reliable strategy for the adsorption/enrichment trace level of organic pollutants.

The imidazoline I2 receptor agonist 2-BFI reduces abuse-related effects of morphine: self-administration and drug discrimination.

RATIONALE: Increasing evidence shows that imidazoline I2 receptor agonists enhance opioid-induced analgesia, suggesting that the combination of I2 receptor agonists with opioids could be a favorable strategy for pain control. However, the effect of I2 receptor agonists on the abuse liability of opioids is unknown. This study examined the impact of the I2 receptor agonist 2-BFI on some abuse-related behavioral effects of the opioid morphine in rats. OBJECTIVES: The von Frey filament test was used to determine the antinociceptive effects of 2-BFI (intravenous, i.v.) in a rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain. IV self-administration was used to assess the reinforcing effects of 2-BFI alone and to assess the effects of non-contingent injections of 2-BFI (i.p.) on morphine self-administration. A two-lever drug discrimination paradigm in which rats were trained to discriminate 3.2 mg/kg morphine (i.p.) from saline was used to examine whether 2-BFI or another I2 receptor agonist 2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride (BU224) affected the discriminative stimulus effects of morphine. RESULTS: 2-BFI could not maintain reliable self-administration behavior in rats with no pain or CFA-treated inflammatory pain. However, pretreatment with 2-BFI (i.p.) produced dose-dependent decreases in the dose-effect curve of morphine self-administration. Both 2-BFI and BU224 did not substitute for morphine but significantly attenuated the discriminative stimulus effects of morphine. CONCLUSIONS: These results suggest that I2 receptor agonists do not enhance, but in fact appear to decrease, the abuse liability of opioids, further supporting the potential utility of I2 receptor agonist-opioid combination therapy for pain control.

Novel synthesis of 11 C-labeled imidazolines via Pd(0)-mediated 11 C-carbomethoxylation using [11 C]CO and arylborons.

A labeling technique was developed for the imidazoline I2 receptor ligand 2-(3-fluoro-tolyl)-4, 5-dihydro-1H-imidazole (FTIMD) using Pd(0)-mediated 11 C-carbomethoxylation with [11 C]CO, followed by imidazoline ring formation with ethylenediamine-trimethylaluminium (EDA-AlMe3 ). To achieve this, [11 C]CO was passed through a methanol (MeOH) solution containing 3-fluoro-4-methylphenylboronic acid (1), palladium (II) acetate (Pd [OAc]2 ), triphenylphosphine (PPh3 ), and p-benzoquinone (PBQ). The mixture was then heated at 65°C for 5 min. EDA was introduced into the reaction mixture, and MeOH was completely evaporated at temperatures exceeding 100°C. The dried reaction mixture was combined with an EDA-AlMe (1:1) toluene solution and heated at 145°C for 10 min. Portions of the reaction mixture were analyzed through high-performance liquid chromatography, resulting in [11 C]FTIMD with 26% (n = 2) decay-corrected radiochemical yield (RCY). This method could be utilized for various arylborons to produce [2-11 C]imidazolines 4a-h with RCYs ranging from low to moderate. Notably, [2-11 C]benazoline was obtained with a moderate RCY of 65%. The proposed technique serves as an alternative to the Grignard method, which uses [11 C]CO to generate a [2-11 C]-labeled imidazoline ring.

Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer's Disease.

Humanity is facing a vast prevalence of neurodegenerative diseases, with Alzheimer's disease (AD) being the most dominant, without efficacious drugs, and with only a few therapeutic targets identified. In this scenario, we aim to find molecular entities that modulate imidazoline I2 receptors (I2-IRs) that have been pointed out as relevant targets in AD. In this work, we explored structural modifications of well-established I2-IR ligands, giving access to derivatives with an imidazole-linked heterocycle as a common key feature. We report the synthesis, the affinity in human I2-IRs, the brain penetration capabilities, the in silico ADMET studies, and the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of this new bunch of I2-IR ligands. Selected compounds showed neuroprotective properties and beneficial effects in an in vitro model of Parkinson's disease, rescued the human dopaminergic cell line SH-SY5Y from death after treatment with 6-hydroxydopamine, and showed crucial anti-inflammatory effects in a cellular model of neuroinflammation. After a preliminary pharmacokinetic study, we explored the action of our representative 2-(benzo[b]thiophen-2-yl)-1H-imidazole LSL33 in a mouse model of AD (5xFAD). Oral administration of LSL33 at 2 mg/Kg for 4 weeks ameliorated 5XFAD cognitive impairment and synaptic plasticity, as well as reduced neuroinflammation markers. In summary, this new I2-IR ligand that promoted beneficial effects in a well-established AD mouse model should be considered a promising therapeutic strategy for neurodegeneration.

Thermal Decomposition Path-Studied by the Simultaneous Thermogravimetry Coupled with Fourier Transform Infrared Spectroscopy and Quadrupole Mass Spectrometry-Of Imidazoline/Dimethyl Succinate Hybrids and Their Biological Characterization.

The thermal decomposition path of synthetically and pharmacologically useful hybrid materials was analyzed in inert and oxidizing conditions for the first time and presented in this article. All the imidazoline/dimethyl succinate hybrids (1-5) were studied using the simultaneous thermogravimetry (TG) coupled with Fourier transform infrared spectroscopy (FTIR) and quadrupole mass spectrometry (QMS). It was found that the tested compounds were thermally stable up to 200-208 °C (inert conditions) and up to 191-197 °C (oxidizing conditions). In both furnace atmospheres, their decomposition paths were multi-step processes. At least two major stages (inert conditions) and three major stages (oxidizing conditions) of their decomposition were observed. The first decomposition stage occurred between T5% and 230-237 °C. It was connected with the breaking of one ester bond. This led to the emission of one methanol molecule and the formation of radicals capable of further radical reactions in both used atmospheres. At the second decomposition stage (Tmax2) between 230-237 °C and 370 °C (inert conditions), or at about 360 °C (oxidizing conditions), the cleavage of the second ester bond and N-N and C-C bonds led to the emission of CH3OH, HCN, N2, and CO2 and other radical fragments that reacted with each other to form clusters and large clusters. Heating the tested compounds to a temperature of about 490 °C resulted in the emission of NH3, HCN, HNCO, aromatic amines, carbonyl fragments, and the residue (Tmax2a) in both atmospheres. In oxidizing conditions, the oxidation of the formed residues (Tmax3) was related to the production of CO2, CO, and H2O. These studies confirmed the same radical decomposition mechanism of the tested compounds both in inert and oxidizing conditions. The antitumor activities and toxicities to normal cells of the imidazoline/dimethyl succinate hybrids were also evaluated. As a result, the two hybrid materials (3 and 5) proved to be the most selective in biological studies, and therefore, they should be utilized in further, more extended in vivo investigations.

Imidazoline-I2 PET Tracers in Neuroimaging.

Targeting neuroinflammation, and in particular, microglial activation and astrocytosis, is a current area of the focus of new treatment interventions for a number of neurodegenerative disorders. Probing the roles of microglia and astrocytes in human disease requires the development of useful tools, such as PET imaging tools that are specific for the cell type(s) of interest. This review concentrates on the recent advances in the development of Imidazoline2 binding site (I2BS) PET tracers, which are purported to target astrocytes, and hence could represent key clinical imaging tools for targeting astrocytes in neurodegenerative disease. Five PET tracers for the I2BS are described in this review, with only one (11C-BU99008) being currently validated to GMP for clinical use, and data reported from healthy volunteers, Alzheimer's disease patients, and Parkinson's disease patients. The clinical data utilising 11C-BU99008 have revealed the potential early involvement of astrogliosis in neurodegeneration that might precede the activation of microglia, which, if confirmed, could provide a vital new means for potentially targeting neurodegeneration earlier in the disease course.

Investigation on the Anticancer and Antibacterial Mechanism of Thiazoline/Imidazoline Derived Palladium(II) Complexes.

Biological activities of a series of palladium(II) complexes (M1-M9) bearing N∩ N, N∩ S, and N∩ O chelating ligands are reported. The palladium complexes were tested for their cytotoxic properties against human cervical cancer (HeLa) cells and antibacterial activity against Gm+ve and Gm-ve bacteria. Among the palladium complexes studied (M1-M9), the complex M5, M8, and M9 were found to be more effective in inhibiting the proliferation of HeLa cells. Hence, these complexes were further investigated for their potential role in cellular damage and apoptosis. DCFDA staining, Rhodamine 123 staining and DNA cleavage assay revealed that complex M5, M8 and M9 induced apoptotic cell death in HeLa cells through ROS generation, DNA damage and mitochondrial depolarization. Computational and titration studies also indicated strong electrostatic interaction with DNA groove. Most of the complexes exhibited good antibacterial activity against both Gm+ve and Gm-ve bacteria. The antibacterial activity of the compounds could not be correlated with their anticancer activity indicating a differential mechanism at their effective concentrations. The detailed study on the antibacterial mechanism of the most potent complex M7 revealed that it exerted its antibacterial activity by inhibiting the function of FtsZ and perturbing the localization of the Z-ring at the mid cell.

Discovery of Bis-Imidazoline Derivatives as New CXCR4 Ligands.

The chemokine receptor CXCR4 and its ligand CXCL12 regulate leukocyte trafficking, homeostasis and functions and are potential therapeutic targets in many diseases such as HIV-1 infection and cancers. Here, we identified new CXCR4 ligands in the CERMN chemical library using a FRET-based high-throughput screening assay. These are bis-imidazoline compounds comprising two imidazole rings linked by an alkyl chain. The molecules displace CXCL12 binding with submicromolar potencies, similarly to AMD3100, the only marketed CXCR4 ligand. They also inhibit anti-CXCR4 mAb 12G5 binding, CXCL12-mediated chemotaxis and HIV-1 infection. Further studies with newly synthesized derivatives pointed out to a role of alkyl chain length on the bis-imidazoline properties, with molecules with an even number of carbons equal to 8, 10 or 12 being the most potent. Interestingly, these differ in the functions of CXCR4 that they influence. Site-directed mutagenesis and molecular docking predict that the alkyl chain folds in such a way that the two imidazole groups become lodged in the transmembrane binding cavity of CXCR4. Results also suggest that the alkyl chain length influences how the imidazole rings positions in the cavity. These results may provide a basis for the design of new CXCR4 antagonists targeting specific functions of the receptor.

A pH-Controlled Solid Inhibitor Based on PAM Hydrogel for Steel Corrosion Protection in Wide Range pH NaCl Medium.

To provide carbon steel a long-term corrosion protection effect in NaCl solutions with different pH values, based on poly-acrylamide (PAM) and oleate imidazoline (OIM), a solid corrosion inhibitor with the properties of pH-controlled release was synthesized. SEM, FTIR and TGA results indicated that the OIM inhibitors were successfully loaded into PAM hydrogel with a high OIM encapsulation content (39.64 wt.%). The OIM release behavior from the hydrogel structure has two stages, quick release and sustained release. The pH of solutions could affect the initial release kinetics of OIM inhibitors and the diffusion path in the hydrogel structure. Weight loss measurement of L80 steel in different pH solutions with OIM@PAM proved the inhibitor responsive release mechanism and anticorrosion performance. The inhibition efficiency of OIM@PAM can maintain over 80% after long-term immersion in a harsh corrosive environment (pH 3), which is much higher than the inhibition efficiency of OIM@PAM in a moderate corrosive solution.

Synthesis and structures of dinuclear palladium complexes with 1,3-benzimidazolidine-2-thione and 1,3-imidazoline-2-thione.

The synthesis and structures of dinuclear palladium complexes with 1,3-benz-imidazolidine-2-thione (bzimtH) and 1,3-imidazoline-2-thione (imtH) are reported, namely, bis-(µ-1H-benzimidazole-2-thiol-ato)-κ2 N 3:S;κ2 S:N 3-bis-[cyanido(tri-phenyl-phosphine-κP)palladium(II)], [Pd2(C7H5N2S)2(CN)2(C18H15P)2] or [Pd2(µ-N,S-bzimtH)2(CN)2(PPh3)2] (1), and bis-(µ-1H-imidazole-2-thiol-ato)-κ2 N 3:S;κ2 S:N 3-bis-[cyanido(tri-phenyl-phosphine-κP)palladium(II)] aceto-nitrile 0.58-solvate, [Pd2(C3H3N2S)2(CN)2(C18H15P)2]·0.58C2H3N or [Pd2(µ-N,S-imtH)2(CN)2(PPh3)2]·0.58C2H3N (2). The compound [Pd2(µ-N,S-bzimtH)2(CN)2(PPh3)2] is located on a crystallographic twofold axis while [Pd2(µ-N,S-imtH)2(CN)2(PPh3)2]. 0.58(C2H3N) contains two partially occupied aceto-nitrile solvent mol-ecules with occupancies of 0.25 and 0.33. In both of these compounds, the anionic bzimtH- and imtH- ligands coordinate through N,S-donor atoms in a bridging mode, covering four coordination sites of two metal centers and other two sites are occupied by two PPh3 ligand mol-ecules. Finally, the remaining two sites of two metal centers are occupied by cyano groups, abstracted by the metals from the solvent during reaction. In the packing of the 1,3-benzimidazolidine- 2-thione and 1,3-imidazoline-2-thione complexes, there are intra-molecular π-π inter-actions involving the thione moiety as well as an N-H⋯N hydrogen bond linking the thione and cyano ligands. In addition, in 2, as well as the π-π inter-action involving the thione moieties, there is an additional π-π inter-action involving one of the thione moieties and an adjacent phenyl ring from the tri-phenyl-phosphine ligand. There are also C-H⋯N inter-actions between the imidazoline rings and the aceto-nitrile N atoms.

Thymoquinone activates imidazoline receptor to enhance glucagon-like peptide-1 secretion in diabetic rats.

Introduction: Thymoquinone (TQ) is one of the principal bioactive ingredients proven to exhibit anti-diabetic effects. Recently, glucagon-like peptide-1 (GLP-1) has been found to be involved in antidiabetic effects in rats. The aim of this study was to evaluate the mediation of GLP-1 in the antidiabetic effect of TQ and to understand the possible mechanisms. Material and methods: NCI-H716 cells and CHO-K1 cells were used to investigate the effects of TQ on GLP-1 secretion in vitro. In type 1 diabetic rats, the changes in plasma glucose and GLP-1 levels were evaluated with TQ treatment. Results: The direct effect of TQ on imidazoline receptors (I-Rs) was identified in CHO-K1 cells overexpressing I-Rs. Additionally, in the intestinal NCI-H716 cells that may secrete GLP-1, TQ treatment enhanced GLP-1 secretion in a dose-dependent manner. However, these effects of TQ were reduced by ablation of I-Rs with siRNA in NCI-H716 cells. Moreover, these effects were inhibited by BU224, the imidazoline I2 receptor (I-2R) antagonist. In diabetic rats, TQ increased plasma GLP-1 levels, which were inhibited by BU-224 treatment. Functionally, TQ-attenuated hyperglycemia is also evidenced through GLP-1 using pharmacological manipulations. Conclusions: This report demonstrates that TQ may promote GLP-1 secretion through I-R activation to reduce hyperglycemia in type-1 diabetic rats.

Reactive astrogliosis: A friend or foe in the pathogenesis of Alzheimer's disease.

Astrocytes are highly efficient homeostatic glial cells playing a crucial role in optimal brain functioning and homeostasis. Astrocytes respond to changes in brain homoeostasis following central nervous system (CNS) injury/diseased state by a specific defence mechanism called reactive astrogliosis. Recent studies have implicated and placed reactive astrogliosis in the centre of pathophysiology of Alzheimer's disease (AD) and other neurodegenerative disorders. The AD biomarker field is evolving rapidly with new findings providing strong evidence which supports the notion that a reactive astrogliosis is an early event in the time course of AD progression which may precede other pathological hallmarks of AD. Clinical/translational in vivo PET and in vitro postmortem brain imaging studies demonstrated 'a first and second wave' of reactive astrogliosis in AD with distinct close-loop relationships with other pathological biomarkers at different stages of the disease. At the end stages, reactive astrocytes are found to be associated, or in proximity, with amyloid plaque and tau pathological deposits in postmortem AD brains. Several new PET-tracers, which are being in pipeline and validated at a very fast pace for mapping and visualising reactive astrogliosis in the brain, will provide further invaluable mechanistic insights into AD and other non-AD dementia pathologies. The complementary roles of microglia and astrocyte activation in AD progression, along with the clinical value of new fluid astrocytes biomarkers in the context of existing biomarkers, are the latest avenue that needs further exploration.

Moxonidine ameliorates cardiac injury in rats with metabolic syndrome by regulating autophagy.

AIMS: Reduced cardiac autophagy, ischemic injury, sympathetic overactivity, and apoptosis all contribute to metabolic syndrome (MetS)-associated cardiovascular risks. NR4A2, an orphan nuclear receptor NR4A family member, induces autophagy while suppressing apoptosis in myocardial infarction. Moxonidine, a sympathoinhibitor imidazoline1 receptor (I1R) agonist, has beneficial metabolic and hemodynamic effects; however, whether autophagy and/or NR4A2 signaling are involved in moxonidine's cardiovascular effects via I1R activation, is unknown, and is the aim of this study. MATERIALS AND METHODS: To induce MetS, rats were fed 3 % salt in their diet and 10 % fructose in their drinking water for 12 weeks. MetS-rats were given either moxonidine (6 mg/kg/day, gavage), efaroxan (I1R antagonist, 0.6 mg/kg/day, i.p), both treatments, or vehicles for the last two weeks. Blood pressure, lipid profile, and glycemic control were evaluated. Histopathological examination, circulating cardiac troponin I (c-TnI), proinflammatory interleukin-6 (IL-6), apoptosis (active caspase-3 and Fas-immunostaining), interstitial fibrosis [transforming growth factor-ß1 (TGF-ß1), Mallory's trichrome staining], and extracellular matrix remodeling [matrix metalloproteinase-9 (MMP-9)], were used to assess cardiac pathology. Cardiac NR4A2 and its downstream factor, p53, as well as autophagic flux markers, SQSTM1/p62, LC3, and Beclin-1 were also determined. KEY FINDINGS: Moxonidine significantly ameliorated MetS-induced metabolic and hemodynamic derangements and the associated cardiac pathology. Moxonidine restored NR4A2 and p53 myocardial levels and enhanced autophagic flux via modulating SQSTM1/p62, LC3, and Beclin-1. Efaroxan reversed the majority of the moxonidine-induced improvements. SIGNIFICANCE: The current study suggests that autophagy modulation via I1R activation is involved in moxonidine-mediated cardiac beneficial effects in MetS.

Modulation of NMDA receptor activity by CR4056, an imidazoline-2 receptor ligand with analgesic properties.

CR4056 is an imidazoline-2 receptor ligand having potent analgesic activity and synergistic effect with opioids. Very recently it has been found that CR4056 can revert the cognitive impairment in animal models of Alzheimer's disease (AD). Since several lines of evidence highlight the importance of NMDAR modulators in nociceptive signaling and in AD progression, we considered as important to investigate the effects of CR4056 on NMDAR activity. In primary culture of cortical neurons, application of NMDA and glycine elicits a current that is decreased in a dose-dependent fashion by CR4056 (IC50 5.3 ± 0.1 µM). CR4056 antagonism is reversible, not competitive and voltage-independent and it is not blocked by pertussis toxin. CR4056 interacts with the co-agonist glycine site in a competitive way, indeed high glycine concentrations diminish its effect. Fibroblasts expressing different recombinant NMDA receptors are differently modulated by CR4056: the potency and the efficacy of the compound are higher in GluN1- GluN2B than in GluN1-GluN2A containing receptors. In lamina II neurons of spinal cord slices, single stimulation of afferent fibers evokes an NMDA-mediated current that is inhibited by 10 µM CR4056. Repetitive stimulation of the dorsal root at high frequency and high intensity produces a firing activity that is significatively depressed by CR4056. Taken together, our results broad the understanding of the molecular mechanisms of CR4056 analgesic activity, involving the modulation of NMDAR activity. Therefore, we propose that the analgesic action of CR4056 and the neuroprotective effects in AD models may be mediated also by NMDAR inhibition.