Metabotropic glutamate receptor (mGluR) subtypes (mGluR1 to mGluR8) act as important pre-and postsynaptic regulators of neurotransmission in the CNS. These receptors consist of two domains, an extracellular region containing the orthosteric agonist site and a transmembrane heptahelical domain involved in G protein activation and recognition of several recently synthesized pharmacological modulators. The presynaptic receptor mGluR7 shows the highest evolutionary conservation within the family, but no selective pharmacological tool was known. Here we characterize an mGluR7-selective agonist, N,N-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), which directly activates receptor signaling via an allosteric site in the transmembrane domain. At transfected mammalian cells expressing mGluR7, AMN082 potently inhibits cAMP accumulation and stimulates GTP␥S binding (EC50-values, 64 -290 nM) with agonist efficacies comparable with those of L-2-amino-4-phosphonobutyrate (L-AP4) and superior to those of L-glutamate. AMN082 (<10 M) failed to show appreciable activating or inhibitory effects at other mGluR subtypes and selected ionotropic GluRs. Chimeric receptor studies position the binding site of AMN082 in the transmembrane region of mGluR7, and we demonstrate that this allosteric agonist has little, if any, effect on the potency of orthosteric ligands. Here we provide evidence for full agonist activity mediated by the heptahelical domain of family 3 G protein-coupled receptors (which have mGluR-like structure) that may lead to drug development opportunities. Further, AMN082 is orally active, penetrates the bloodbrain barrier, and elevates the plasma stress hormones corticosterone and corticotropin in an mGluR7-dependent fashion. Therefore, AMN082 is a valuable tool for unraveling the role of mGluR7 in stress-related CNS disorders.G protein ͉ mGluR G protein-coupled receptors in vertebrates constitute a superfamily of 1,000-2,000 transmembrane heptahelical proteins that can be activated by a large number of extracellular signals such as photons, hormones, neurotransmitters, and growth and development factors. These receptors transduce and amplify cellular signals by the activation of G proteins, which in turn modulates cytoplasmic second-messenger and ion levels (1). Sequence comparison among the different G protein-coupled receptors revealed the existence of at least six receptor families (2). One of them, family 3, comprises receptors for extracellular calcium, pheromones, GABA, and L-glutamate. This receptor family is characterized by a large N-terminal extracellular domain that has been demonstrated by site-directed mutagenesis and x-ray crystallography to contain the binding site for orthosteric agonists (3-5). Metabotropic glutamate receptors (mGluRs) are members of family 3 and are activated by the major excitatory neurotransmitter of the mammalian brain, L-glutamate. The mGluRs act as important pre-and postsynaptic regulators of neurotransmission in the CNS, and there are at least eight subtypes (mGluR1 to m...
Activation of group III metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7, and mGluR8) has been established to be neuroprotective in vitro and in vivo. To disclose the identity of the receptor subtype(s) that exert(s) the protective effect, we have used group III agonists in combination with mGluR4 subtype-deficient mice (Ϫ/Ϫ). In cortical cultures prepared from wild-type (ϩ/ϩ) mice and exposed to a toxic pulse of NMDA, the selective group III agonist (ϩ)-4-phosphonophenylglycine [(ϩ)-PPG] reversed excitotoxicity with an EC 50 value of 4.9 M, whereas its enantiomer (Ϫ)-PPG was inactive. This correlated closely with the potency of (ϩ)-PPG in activating recombinant mGluR4a. In cortical neurons from Ϫ/Ϫ mice, (ϩ)-PPG showed no protection against the NMDA insult up to 300 M, whereas group I/II mGluR ligands still retained their protective activity. Classical group III agonists (L-2-amino-4-phosphonobutyrate and L-serine-O-phosphate) were also substantially neuroprotective against NMDA toxicity in ϩ/ϩ and heterozygous (ϩ/Ϫ) cultures but were inactive in Ϫ/Ϫ cultures. Interestingly, Ϫ/Ϫ cultures were more vulnerable to low concentrations of NMDA and showed higher extracellular glutamate levels compared with ϩ/ϩ cultures.We have also examined neurodegeneration induced by intrastriatal infusion of NMDA in wild-type or mGluR4-deficient mice. Low doses of ( R, S)-PPG (10 nmol/0.5 l) substantially reduced NMDA toxicity in ϩ/ϩ mice but were ineffective in Ϫ/Ϫ mice. Higher doses of ( R, S)-PPG were neuroprotective in both strains of animals. Finally, microdialysis studies showed that intrastriatal infusion of NMDA increased extracellular glutamate levels to a greater extent in Ϫ/Ϫ than in ϩ/ϩ mice, supporting the hypothesis that the mGluR4 subtype is necessary for the maintenance of the homeostasis of extracellular glutamate levels.
INTRODUCTION: Gastrointestinal (GI) symptoms in coronavirus-19 disease (COVID-19) have been reported with great variability and without standardization. In hospitalized patients, we aimed to evaluate the prevalence of GI symptoms, factors associated with their occurrence, and variation at 1 month. METHODS: The GI-COVID-19 is a prospective, multicenter, controlled study. Patients with and without COVID-19 diagnosis were recruited at hospital admission and asked for GI symptoms at admission and after 1 month, using the validated Gastrointestinal Symptom Rating Scale questionnaire. RESULTS: The study included 2036 hospitalized patients. A total of 871 patients (575 COVID+ and 296 COVID−) were included for the primary analysis. GI symptoms occurred more frequently in patients with COVID-19 (59.7%; 343/575 patients) than in the control group (43.2%; 128/296 patients) (P < 0.001). Patients with COVID-19 complained of higher presence or intensity of nausea, diarrhea, loose stools, and urgency as compared with controls. At a 1-month follow-up, a reduction in the presence or intensity of GI symptoms was found in COVID-19 patients with GI symptoms at hospital admission. Nausea remained increased over controls. Factors significantly associated with nausea persistence in COVID-19 were female sex, high body mass index, the presence of dyspnea, and increased C-reactive protein levels. DISCUSSION: The prevalence of GI symptoms in hospitalized patients with COVID-19 is higher than previously reported. Systemic and respiratory symptoms are often associated with GI complaints. Nausea may persist after the resolution of COVID-19 infection.
Objective Keeping in mind the rising prevalence of nonalcoholic fatty liver disease (NAFLD) and the need to establish noninvasive tests for its detection, the aim of our study was to investigate whether platelet count (PC), mean platelet volume (MPV), and platelet distribution width (PDW) can predict the presence of liver fibrosis in this group of patients. Methods In 98 patients with NAFLD and 60 healthy volunteers, complete blood counts with automated differential counts were performed and values of PC, PDW, MPV, and PCT were analyzed. Results Patients with NAFLD had lower PC and higher MPV, PCT, and PDW compared to the controls (P < 0.05). When NAFLD group was stratified according to severity of liver fibrosis, there was a statistically significant difference in the average values of PDW and PC between the groups (P < 0.05). Conclusion Patients with NAFLD have significantly higher values of PCT, PDW, and MPV when compared to the healthy controls. Further studies are needed to establish their potential use for prediction of the degree of liver steatosis and fibrosis in NAFLD patients.
ObjectivesThe long-term consequences of COVID-19 infection on the gastrointestinal tract remain unclear. Here, we aimed to evaluate the prevalence of gastrointestinal symptoms and post-COVID-19 disorders of gut–brain interaction after hospitalisation for SARS-CoV-2 infection.DesignGI-COVID-19 is a prospective, multicentre, controlled study. Patients with and without COVID-19 diagnosis were evaluated on hospital admission and after 1, 6 and 12 months post hospitalisation. Gastrointestinal symptoms, anxiety and depression were assessed using validated questionnaires.ResultsThe study included 2183 hospitalised patients. The primary analysis included a total of 883 patients (614 patients with COVID-19 and 269 controls) due to the exclusion of patients with pre-existing gastrointestinal symptoms and/or surgery. At enrolment, gastrointestinal symptoms were more frequent among patients with COVID-19 than in the control group (59.3% vs 39.7%, p<0.001). At the 12-month follow-up, constipation and hard stools were significantly more prevalent in controls than in patients with COVID-19 (16% vs 9.6%, p=0.019 and 17.7% vs 10.9%, p=0.011, respectively). Compared with controls, patients with COVID-19 reported higher rates of irritable bowel syndrome (IBS) according to Rome IV criteria: 0.5% versus 3.2%, p=0.045. Factors significantly associated with IBS diagnosis included history of allergies, chronic intake of proton pump inhibitors and presence of dyspnoea. At the 6-month follow-up, the rate of patients with COVID-19 fulfilling the criteria for depression was higher than among controls.ConclusionCompared with controls, hospitalised patients with COVID-19 had fewer problems of constipation and hard stools at 12 months after acute infection. Patients with COVID-19 had significantly higher rates of IBS than controls.Trial registration numberNCT04691895.
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